DISEASES OF THE IMMUNE SYSTEM

Feghiu Iuliana, Tacu Lilia

The normal immune response

The immune system is vital for survival, because our environment is teeming with potentially deadly microbes and
the immune system protects us from infectious pathogens. Predictably, immune deficiencies render individuals easy prey to
infections. But the immune system is similar to the proverbial double-edged sword. Although it normally defends us against
infections, a hyperactive immune system may cause diseases that can sometimes be fatal. Examples of disorders caused by
immune responses include allergic reactions and reactions against an individual's own tissues and cells (autoimmunity).
The classic definition of immunity is protection from infectious pathogens. The mechanisms of defense against
microbes fall into two broad categories. Innate immunity (also called natural, or native, immunity) refers to the mechanisms
that are ready to react to infections even before they occur, and that have evolved to specifically recognize and combat
microbes. Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by
(“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances. Innate immunity is the first
line of defense. It is mediated by cells and molecules that recognize products of microbes and dead cells and induce rapid
protective host reactions. Adaptive immunity develops later, after exposure to microbes and other foreign substances, and is
even more powerful than innate immunity in combating infections. By convention, the term immune response usually refers
to adaptive immunity.

The main mechanisms of innate immunity and adaptive immunity.NK cells, Natural killer cells
(from Robbins and Cotran; Pathologic basis of disease)

Innate immunity is always present, ready to provide defense against microbes and to eliminate damaged cells. The
receptors and components of innate immunity have evolved to serve these purposes. Innate immunity functions in stages:
recognition of microbes and damaged cells, activation of various mechanisms, and elimination of the unwanted
substances.The major components of innate immunity are epithelial barriers that block entry of microbes, phagocytic cells
(mainly neutrophils and macrophages), dendritic cells,natural killer (NK) cells, and several plasma proteins, including the
proteins of the complement system.Epithelia of the skin and gastrointestinal and respiratory tracts provide mechanical
barriers to the entry of microbes from the external environment. Epithelial cells also produce antimicrobial molecules such
as defensins, and lymphocytes located in the epithelia combat microbes at these sites. If microbes do breach epithelial
boundaries, other defense mechanisms are called in. In addition to immune cells, several soluble proteins play important
roles in innate immunity. The proteins of the complement system are plasma proteins that are activated by microbes using
the alternative and lectin pathways in innate immune responses; in adaptive immunity it is activated by antibodies using the
classical pathway. Other circulating proteins of innate immunity are mannose-binding lectin and C-reactive protein, both of
which coat microbes and promote phagocytosis (opsonins). Lung surfactant is also a component of innate immunity,
providing protection against inhaled microbes.
The adaptive immune system consists of lymphocytes and their products, including antibodies. The receptors of
lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for
microbes, and they are capable of recognizing a vast array of foreign substances. In the remainder of this introductory section
we focus on lymphocytes and the reactions of the adaptive immune system.There are two types of adaptive immunity:
humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated (or cellular) immunity,
which is responsible for defense against intracellular microbes. Humoral immunity is mediated by B (bone marrow–derived)
lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig), and cellular immunity is mediated
by T (thymus-derived) lymphocytes. Both classes of lymphocytes express highly specific receptors for a wide variety of
substances, called antigens.
IMMUNE CELLS. The principal cells of the immune system are the lymphocytes, antigen-presenting cells, and
effector cells. Lymphocytes are the cells that specifically recognize and respond to foreign antigens. Accessory cells, such
as macrophages and dendritic cells, function as antigen-presenting cells by the processing of a complex antigen into epitopes
required for the activation of lymphocytes. Functionally, there are two types of immune cells: regulatory cells and effector
cells. The regulatory cells assist in orchestrating and controlling the immune response. For example, helper T lymphocytes
activate other lymphocytes and phagocytes. The final stages of the immune response are accomplished with the elimination
of the antigen by effector cells. Activated T lymphocytes, mononuclear phagocytes, and other leukocytes function as effector
cells in different immune responses.
Lymphocytes represent 25% to 35% of blood leukocytes, and 99% of the lymphocytes reside in the lymph. Like
other blood cells, lymphocytes are generated from stem cells in the bone marrow. Undifferentiated immature lymphocytes
congregate in the central lymphoid tissues, where they develop into distinct types of mature lymphocytes. One class of
lymphocyte, the B lymphocytes (B cells), matures in the bone marrow and is essential for humoral, or antibody-mediated,
immunity. The other class of lymphocyte, the T lymphocytes (T cells), completes its maturation in the thymus and functions
in the peripheral tissues to produce cell-mediated immunity, as well as aiding antibody production. Approximately 60% to
70% of blood lymphocytes are T cells, and 10% to 20% are B cells. The various types of lymphocytes are distinguished by
their function and response to antigen, their cell membrane molecules and receptors, their types of secreted proteins, and
their tissue location. High concentrations of mature T and B lymphocytes are found in the lymph nodes, spleen, skin, and
mucosal tissues, where they can respond to antigen.
The key trigger for the activation of B and T cells is the recognition of the antigen by unique surface receptors.
The B-cell antigen receptor consists of membrane-bound immunoglobulin molecules that can bind a specific epitope.
The T-cell receptor recognizes a processed antigen peptide in association with a self-recognition protein, called a
major histocompatibility complex (MHC) molecule. The appropriate recognition of MHC and self peptides or MHC
associated with for n peptides is essential for lymphocytes to differentiate “self” from “foreign.”
The immune system enlists specialized antigen-presenting cells (APCs), such as macrophages and dendritic cells,
to ensure the appropriate processing and presentation of antigen. On recognition of antigen and after additional stimulation
by various secreted signaling molecules called cytokines, the B and T lymphocytes divide several times to form populations
or clones of cells that continue to differentiate into several types of effector and memory cells. These effector cells and
molecules defend the body in an immune response. In humoral or antibody-mediated immunity, activated B cells produce
effector cells called plasma cells, which secrete protein molecules called antibodies, or immunoglobulins. The binding of
antibodies can neutralize the biologic impact of the microbes and cause subsequent aggregation to ensure their removal.
Phagocytic cells can more efficiently bind, engulf, and digest antigen–antibody aggregates or immune complexes than they
can antigen alone.
T and B cells display additional membrane molecules called clusters of differentiation (CD) molecules. These
molecules aid the function of immune cells and also serve to define functionally distinct subsets of cells, such as CD4+
helper T cells and CD8+ cytotoxic T cells. The many cell surface CD molecules detected on immune cells have allowed
scientists to identify distinct subsets of lymphocytes and study both the normal and abnormal developmental processes
displayed by these cells. In cell-mediated immunity, regulatory CD4+ helper T cells enhance the response of other T cells,
and effector cytotoxic T lymphocytes (CD8+) destroy cellular antigens such as tumor cells and virus-infected cells.
T and B lymphocytes possess all of the key properties associated with the adaptive immune response—specificity,
diversity, memory, and self- and nonself-recognition. These cells can exactly recognize a particular microorganism or foreign
molecule. Each lymphocyte targets a specific antigen and differentiates that invader from other substances that may be
similar. The approximately 1012 lymphocytes in the body have tremendous diversity. They can respond to the millions of
different kinds of antigens encountered daily. This diversity occurs because an enormous variety of lymphocyte populations
have been programmed during development, each to respond to a different antigen.
After lymphocytes have been stimulated by their antigen, they can acquire a memory response. The memory T
and B lymphocytes that are generated remain in the body for a long time and can respond more rapidly on repeat exposure
than naïve cells. Because of this heightened state of immune reactivity, the immune system usually can respond to
commonly encountered microorganisms so efficiently that we are unaware of the response.
Monocytes, Macrophages, and Dendritic Cells. Monocytes, tissue macrophages, and most dendritic cells arise
from a common precursor in the bone marrow. Monocytes and macrophages are key members of the mononuclear phagocytic
system. The monocytes migrate from the blood to various tissues where they mature into the major tissue phagocyte, the
macrophages. Macrophages are characterized as large cells with extensive cytoplasm and numerous vacuoles. As the general
scavenger cells of the body, macrophages can be fixed in a tissue or can be free to migrate from an organ to lymphoid tissues.
The tissue macrophages are scattered in connective tissue or clustered in organs such as the lung (i.e., alveolar macrophages),
liver (i.e., Kupffer’s cells), spleen, lymph nodes, peritoneum, central nervous system (i.e., microglial cells), and other areas.
Macrophages are activated to engulf and digest antigens that associate with their cell membrane. The initial attachment of
the microbe to the phagocyte can be aided by antibody or complement-coated microbes or by pathogen-associated molecular
pattern receptors (i.e., Toll-like receptors) that are integral to innate immune recognition.
On phagocyte membranes, the family of Toll-like receptors (so-called because they correspond in structure to a
Drosophila protein called Toll) recognizes general chemical patterns common to groups of microbes such as the
lipopolysaccharides of gram-negative bacteria or the lipoteichoic acids found in gram-positive bacteria. Once the microbe is
ingested, the cell generates digestive enzymes and toxic oxygen and nitrogen products (i.e., hydrogen peroxide or nitric
oxide) through metabolic pathways. The phagocytic killing of microorganisms helps to contain infectious agents until
adaptive immunity can be marshaled.
In addition to phagocytosis, macrophages function early in the immune response to amplify the inflammatory
response and initiate adaptive immunity. Macrophages direct these processes through the secretion of cytokines (e.g., tumor
necrosis factor [TNF], interleukin-1) that signal inflammation and activation of lymphocytes. Activated macrophages also
influence adaptive immunity as APCs that break down complex antigens into peptide fragments for association with class II
MHC molecules. Macrophages can then present these complexes to the helper T cell so that self- and non-self-recognition
and activation of the immune response can occur. Macrophages also function at the end of an immune response as effector
cells in both humoral and cell-mediated immune responses. Macrophages can remove antigen– antibody aggregates or, under
the influence of T-cell cytokines, can destroy virus-infected cells or tumor cells.
Dendritic cells share with the macrophage the important task of presenting processed antigen to T lymphocytes.
These distinctive, star-shaped cells with long extensions of their cytoplasmic membrane provide an extensive surface rich in
class II MHC molecules and other membrane molecules important for initiation of adaptive immunity. Dendritic cells are
found in most tissues where antigen enters the body and in the peripheral lymphoid tissues where they function as potent
APCs. In these different environments, dendritic cells can acquire specialized functions and appearances, as do macrophages.
Langerhans’ cells are specialized dendritic cells in the skin, whereas follicular dendritic cells are found in the lymph nodes.
Langerhans’ cells are constantly surveying the skin for antigen and can transport foreign material to a nearby lymph node.
Skin dendritic cells and macrophages also are involved in cell-mediated immune reactions of the skin such as delayed allergic
contact hypersensitivity.
B Lymphocytes. The B lymphocytes are responsible for humoral immunity. Humoral immunity provides for
elimination of bacterial invaders, neutralization of bacterial toxins, prevention of viral infection, and immediate allergic
responses.
B lymphocytes can be identified by the presence of membrane immunoglobulin that functions as the antigen
receptor, class II MHC proteins, complement receptors, and specific CD molecules. During the maturation of B cells in the
bone marrow, stem cells change into immature precursor (pre-B) cells. A rearrangement of immunoglobulin genes produces
in each cell a unique membrane receptor and secreted effector antibody (e.g., immunoglobulin M [IgM] or IgD). This stage
of maturation is programmed into the B cells and does not require antigen; it is an antigen-independent process. The various
stages of maturation can be defined by the presence of a partial or complete immunoglobulin receptor and the type of CD
molecules. The mature B cell leaves the bone marrow, enters the circulation, and migrates to the various peripheral lymphoid
tissues, where it is stimulated to respond to a specific antigen.
The commitment of a B-cell line to a specific antigen is evident by the expression of the membrane immunoglobulin
antigen receptor molecule. B cells that encounter antigen complementary to their surface immunoglobulin receptor and
receive T-cell help undergo a series of changes that transform the B cells into antibody-secreting plasma cells or into memory
B cells . B lymphocytes also can function as APCs by ingesting the surface immunoglobulin–antigen complex, processing
the antigen into small peptides, and presenting the peptide, now complexed to the class II MHC molecules, at its cell
membrane. The antigen peptide–class II MHC complex is recognized through cell-to-cell contact and stimulates the helper
T cells to secrete various cytokines. These cytokines trigger the multiplication and maturation of antigen-activated B cells.
The activated B cell divides and undergoes terminal maturation into a plasma cell, which can produce thousands of
antibody molecules per second. The antibodies are released into the blood and lymph, where they bind and remove their
unique antigen with the help of other immune effector cells and molecules. Longer-lived memory B cells are generated and
distributed into the peripheral tissues in preparation for subsequent antigen exposure.
Immunoglobulins. Antibodies comprise a class of proteins called immunoglobulins. The immunoglobulins have
been divided into five classes: IgG, IgA, IgM, IgD, and IgE, each with a different role in the immune defense strategy.
Immunoglobulins have a characteristic four-polypeptide structure consisting of at least two identical antigen-binding sites.
Each immunoglobulin is composed of two identical light (L) chains and two identical heavy (H) chains to form a Y-shaped
molecule.
The two forked ends of the immunoglobulin molecule bind antigen and are called Fab (i.e., antigen-binding)
fragments, and the tail of the molecule, which is called the Fc fragment, determines the biologic properties that are
characteristic of a particular class of immunoglobulins. The amino acid sequence of the heavy and light chains shows constant
(C) regions and variable (V) regions. The constant regions have sequences of amino acids that vary little among the antibodies
of a particular class of immunoglobulin. The constant regions allow separation of immunoglobulins into classes (e.g., IgM,
IgG) and allow each class of antibody to interact with certain effector cells and molecules. For example, IgG can tag an
antigen for recognition and destruction by phagocytes. The variable regions contain the antigen-binding sites of the molecule.
The wide variation in the amino acid sequence of the variable regions seen from antibody to antibody allows this region to
recognize its complementary epitope. A unique amino acid sequence in this region determines a distinctive three-dimensional
pocket that is complementary to the antigen, allowing recognition and binding. Each B-cell clone produces antibody with
one specific antigen-binding variable region or domain. During the course of the immune response, class switching (e.g.,
from IgM to IgG) can occur, causing the B-cell clone to produce one of the following antibody types.
IgG (gamma globulin) is the most abundant of the circulating immunoglobulins. It is present in body fluids and
readily enters the tissues. IgG is the only immunoglobulin that crosses the placenta and can transfer immunity from the
mother to the fetus. This class of immunoglobulin protects against bacteria, toxins, and viruses in body fluids and activates
the complement system. There are four subclasses of IgG (i.e., IgG1, IgG2, IgG3, and IgG4) that have some restrictions in
their response to certain types of antigens. For example, IgG2 appears to be responsive to bacteria that are encapsulated with
a polysaccharide layer, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
IgA, a secretory immunoglobulin, is found in saliva, tears, colostrum (i.e., first milk of a nursing mother), and
bronchial, gastrointestinal, prostatic, and vaginal secretions. This dimeric secretory immunoglobulin is considered a primary
defense against local infections in mucosal tissues. IgA prevents the attachment of viruses and bacteria to epithelial cells.
IgM is a macromolecule that forms a polymer of five basic immunoglobulin units. It cannot cross the placenta and
does not transfer maternal immunity. It is the first circulating immunoglobulin to appear in response to an antigen and is the
first antibody type made by a newborn. This is diagnostically useful because the presence of IgM suggests a current infection
in the infant by a specific pathogen. The identification of newborn IgM rather than maternally transferred IgG to the specific
pathogen is indicative of an in utero or newborn infection.
IgD is found primarily on the cell membranes of B lymphocytes. It serves as an antigen receptor for initiating the
differentiation of B cells.
IgE is involved in inflammation, allergic responses, and combating parasitic infections. It binds to mast cells and
basophils. The binding of antigen to mast cell– or basophil-bound IgE triggers these cells to release histamine and other
mediators important in inflammation and allergies.
T Lymphocyte. T lymphocytes function in the activation of other T cells and B cells, in the control of intracellular
viral infections, in the rejection of foreign tissue grafts, and in delayed hypersensitivity reactions. Collectively, these immune
responses are called cell-mediated, or cellular, immunity.
Besides the ability to respond to cell-associated antigens, the T cell is integral to immunity because it regulates self-
recognition and amplifies the response of B and T lymphocytes.
T lymphocytes arise from bone marrow stem cells, but unlike B cells, pre-T cells migrate to the thymus for their
maturation. There, the immature T lymphocytes undergo rearrangement of the genes needed for expression of a unique T-
cell antigen receptor similar to but distinct from the B-cell receptor. The T-cell receptor (TCR) is composed of two
polypeptides that fold to form a groove that recognizes processed antigen peptide–MHC complexes. The TCR–antigen–
MHC complex is further stabilized by the CD4+ molecule on the helper T cell or by the CD8+ molecules on the cytotoxic T
cells. The TCR is associated with other surface molecules known as the CD3 complex that aid cell signaling. Maturation of
subpopulations of T cells (i.e., CD4+ and CD8+) also occurs in the thymus. Mature T cells migrate to the peripheral lymphoid
tissues and, on encountering antigen, multiply and differentiate into memory T cells and various effector T cells.
Helper T Cells. The CD4+ helper T cell (TH) serves as a master regulator for the immune system. Activation of
helper T cells depends on the recognition of antigen in association with class II MHC molecules. Once activated, the
cytokines they secrete will influence the function of nearly all other cells of the immune system. These cytokines activate
and regulate B cells, cytotoxic T lymphocytes, natural killer (NK) cells, macrophages, and other immune cells. The activated
helper T cell can differentiate into distinct subpopulations of helper T cells (i.e., TH1 or TH2) based on the cytokines secreted
by the APC at the site of activation. The cytokine interleukin-12 (IL-12) produced by macrophages and dendritic cells directs
the maturation of helper T cells toward TH1 cells, whereas IL-4 produced by mast cells and T cells induce differentiation
toward TH2 cells. The distinct pattern of cytokine secreted by mature.
TH1 and TH2 cells determine whether a humoral or cell-mediated response will occur. Activated TH1 cells
characteristically produce the cytokines IL-2 and interferon-γ (IFN-γ), whereas TH2 cells produce IL-4 and IL-5. In most
immune responses, a balanced response of TH 1 and TH2 cells occurs; however, extensive immunization can skew the
response to one or the other subset. For example, the extensive exposure to an allergen in atopic individuals has been shown
to shift the naïve helper T cell toward a TH2 response with the production of the cytokines that influence IgE production and
mast cell priming. An appreciation of these processes has led to clinical research suggesting that redirection of an allergic
TH2 response to a non-allergic TH1 response can occur in atopic individuals through modified immunization protocols.
T Cytotoxic Cells. Activated CD8+ cytotoxic T (Tc) cells become cytotoxic T lymphocytes (CTLs) after recognition
of class I MHC–antigen complexes on target cell surfaces, such as body cells infected by viruses or transformed by cancer.
The recognition of class I MHC–antigen complexes on infected target cells ensures that neighboring uninfected host cells,
which express class I MHC molecules alone or with self-peptide, are not indiscriminately destroyed. The CD8+ cytotoxic T
lymphocytes destroy target cells by releasing cytolytic enzymes, toxic cytokines, and pore-forming molecules (i.e., perforins)
or through programmed cell death of the target cell through triggering membrane molecules and intracellular apoptosis.
Apoptosis is a conserved cell process for the controlled elimination of excessive, dangerous, or damaged cells. In addition,
the perforin proteins can produce pores in the target cell membrane, allowing entry of toxic molecules and loss of cell
constituents. The CD8+ T cells are especially important in controlling replicating viruses and intracellular bacteria because
antibody cannot readily penetrate the membrane of living cells.
Cell-mediated immunity involves both CD4+ and CD8+ T lymphocytes. Activated CD4+ helper T cells release
various cytokines (i.e., IFN-γ) that recruit and activate other lymphocytes, macrophages, and inflammatory cells. Cytokines
(e.g., IL-8) can induce positive migration or chemotaxis of several types of inflammatory cells, including macrophages,
neutrophils, and basophils. Activation of macrophages ensures enhanced phagocytic, metabolic, and enzymatic potential,
resulting in more efficient destruction of infected cells. This type of defense is important against intracellular pathogens such
as Mycobacterium species and Listeria monocytogenes.
A similar sequence of T-cell and macrophage activation, but with sustained inflammation, is elicited in delayed
hypersensitivity reactions. Contact dermatitis due to a poison ivy reaction or dye sensitivity is an example of delayed or cell-
mediated hypersensitivity caused by hapten–carrier complexes.
Natural Killer Cells. Natural killer cells are lymphocytes that are functionally and phenotypically distinct from T
cells, B cells, and monocyte-macrophages. The NK cell is an effector cell important in innate immunity that can kill tumor
cells, virus-infected cells, or intracellular microbes. These cells are called natural killer cells because, unlike cytotoxic T
cells, they do not need to recognize a specific antigen before being activated. Both NK cells and cytotoxic T cells kill after
contact with a target cell. The NK cell is programmed to kill foreign cells automatically, in contrast to the CD8+ T cell,
which needs to be activated to become cytotoxic. However, programmed killing is inhibited in the NK cell if its cell
membrane receptors contact MHC self molecules on normal host cells.
NK cells appear as large, granular lymphocytes with an indented nucleus and abundant, pale cytoplasm containing
red granules. These cells characteristically express CD16 and CD94 cell surface molecules but lack the typical T-cell markers
(i.e., TCR, CD4). The mechanism of NK cytotoxicity is similar to T-cell cytotoxicity in that it depends on production of
pore-forming proteins (i.e., NK perforins), enzymes, and toxic cytokines. NK cell activity can be enhanced in vitro on
exposure to IL-2, a phenomenon called lymphokine-activated killer activity. NK cells also participate in antibody-dependent
cellular cytotoxicity, a mechanism by which a cytotoxic effector cell can kill an antibody-coated target cell. The role of NK
cells is believed to be one of immune surveillance for cancerous or virus-infected cells.
Cellular Receptors for Microbes, Products of Damaged
Cells that participate in innate immunity are capable of recognizing certain microbial components that are shared
among related microbes and are often essential for infectivity (and thus cannot be mutated to allow the microbes to evade
the defense mechanisms). These microbial structures are called pathogen-associated molecular patterns. Leukocytes also
recognize molecules released by injured and necrotic cells, which are called damage-associated molecular patterns.
Collectively, the cellular receptors that recognize these molecules are often called pattern recognition receptors.Pattern
recognition receptors are located in all the cellular compartments where microbes may be present:plasma membrane
receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect
microbes in the cytoplasm. Several classes of these receptors have been identified.
 Cellular receptors for microbes and products of cell injury

(from Robbins and Cotran; Pathologic basis of disease)

Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the
presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other
cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The four major classes of
innate immune receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors (CLRs), and RIG-like
receptors for viral nucleic acids (RLRs).
Complement System. The complement system is a primary effector system forboth innate and adaptive humoral
immune responses. Theactivation of this system results in enhanced inflammatoryresponses, lysis of foreign cells, and
increased phagocytosis.The complement system, like the blood coagulation system,consists of a group of proteins that are
present in the circulationas functionally inactive precursors. Theseproteins, mainly proteolytic enzymes, make up 10% to15%
of the plasma protein fraction. For a complement reactionto occur, the complement components must be activatedin the
proper sequence. Uncontrolled activation ofthe complement system is prevented by inhibitor proteins and the instability of
the activated complement proteins at each step of the process.
There are three parallel but independent mechanismfor recognizing microorganisms that result in the activation of
the complement system: the classic, the alternate, and the lectin-mediated pathways. All three pathways of activation generate
a series of enzymatic reactions that proteolytically cleave successive complement proteins in the pathway. The consequence
is the deposition of some complement protein fragments on the pathogen surface, thereby producing tags for better
recognition by the receptors on phagocytic cells. Other complement fragments are released into the tissue fluids to stimulate
further the inflammatory response.
The classic pathway of complement activation is initiated by antibody bound to epitopes on the surface of microbes
or through soluble immune complexes. The alternate and the lectin pathways do not use antibodies and are part of the innate
immune defenses. The alternate pathway of complement activationis initiated by the interaction of complement proteins (i.e.,
C3b) with certain polysaccharide molecules characteristic of bacterial surfaces. The lectin-mediated pathway is initiated
following the binding of a mannose-binding protein to mannose-containing molecules commonly present on the surface of
bacteria and yeast. The activation of the three pathways produces similar effects on C3 and subsequent complement proteins.
The classic pathway of complement activation was the first discovered and is the best studied. The major proteins
of the classic system are designated by a numbering system from C1 to C9. The classic pathway is triggered when
complement-fixing antibodies, such as IgG or IgM, bind to antigens. The immune complexes with complement trigger a
series of enzyme reactions that act in a cascade fashion to generate modified or split complement proteins (e.g., C3b, C3a,
and C5a). C3 has a central role in the complement pathways because it is integral to all three pathways. The triggering of C3
initiates several mechanisms for microbial destruction. One result of activation of C3 is the formation of the membrane attack
complex formed by C5 to C9. Several structurally modulated complement proteins bind to form pores in the membrane of
foreign cells that lead to eventual cell lysis.
The alternate and lectin pathways are activated by microbial surface molecules and substitute other molecules for
the proteins in the first two steps of the classic complement pathway. The alternate pathway uses proteins B, D, and P for
activation, whereas the lectin pathway uses mannose-binding protein and accessory proteins. Both pathways require the
presence of C3b and subsequent complementproteins to generate biologic effects similar to those of theclassic complement
pathway.
Whatever the mechanism of activation of the complement system, the effects of complement fixation and activation
range from cell lysis to direct mediation of the inflammatory process. First, complement has been shown to mediate the lytic
destruction of many kinds of cells, including red blood cells, platelets, and bacteria. All complement pathways may induce
cytolysis.
Second, a major biologic function of complement activation is opsonization—the coating of antigen–antibody
complexes with complement proteins such that antigens are engulfed and cleared more efficiently by macrophages.
Third, chemotactic complement products (C3a and C5a) can trigger an influx of leukocytes. These white blood cells
remain fixed in the area of complement activation through cell receptor attachment to specific sites on C3b and C4b
molecules. Fourth, production of anaphylatoxin(C3a and C5a) can activate mast cells and basophils to release biologically
active mediators (e.g., histamine) thatproduce contraction of smooth muscle, increased vascular permeability, and edema.
Major Histocompatibility Complex Molecules.An essential feature of adaptive or specific immunity is theability
to discriminate between the body’s own moleculesand foreign antigens. Key recognition molecules essentialfor
distinguishing self from nonself are the cell surface MHCmolecules. These proteins, which in humans are coded byclosely
linked genes on chromosome 6, were first identifiedbecause of their role in organ and tissue transplantation.
When cells are transplanted between individuals who are not identical for their MHC molecules, the immune system
produces a vigorous immune response leading to rejection of the transferred cells or organs. MHC molecules did not evolve
to reject transplanted tissues, a situation not encountered in nature. Rather, these molecules are essential for correct cell-to-
cell interactions among immune and body cells.
The MHC molecules involved in self-recognition and cell-to-cell communication fall into two classes, class I and
class II. Class I MHC (MHC-1) molecules are cell surface glycoproteins that interact with the antigen receptor and the CD8
molecule on cytotoxic T lymphocytes. Class I MHC molecules are found on nearly all nucleated cells in the body and are
capable of alerting the immune system of any cell changes due to viruses, intracellular bacteria, or cancer.The class I MHC
molecule contains a groove that accommodates a peptide fragment of antigen. Cytotoxic T cells can become activated only
when they are presented with the foreign antigen peptide associated with the class I MHC molecule. Antigen peptides
associate with class I molecules in cells that are infected by intracellular pathogens such as a virus. As the virus multiplies,
small peptides from degraded virus proteins associate with class I MHC molecules and are then transported to the infected
cell membrane. This complex communicates to the cytotoxic T cell that the cell must be destroyed for the overall survival
of the host. Class II MHC molecules, which are found primarily on APCs such as macrophages, dendritic cells, and B
lymphocytes, communicate with the antigen receptor and CD4 molecule on helper T lymphocytes.
Class II MHC molecules also have a groove or cleft that binds a fragment of antigen from pathogens that have been
engulfed and digested during the process of phagocytosis. The engulfed pathogen is degraded into peptide in cytoplasmic
vesicles and then complexed with class II MHC molecules. Helper T cells recognize these complexes on the surface of APCs
and then become activated. These triggered helper T cells multiply quickly and direct other immune cells to respond to the
invading pathogen through thesecretion of cytokines. A third group of genes located on the same chromosome near the class
I and class II MHC genes encode other proteins involved in the immune response. Complement and cytokines important for
signaling an immune response are examples of the third class of molecules. These secreted molecules are structurally and
functionally unrelated to the class I and class II MHC molecules.
Each individual has a unique collection of MHC proteins, and a variety of MHC molecules can exist in a population.
Thus, MHC molecules are both polygenic and polymorphic. The MHC genes are the most polymorphic genes known.
Because of the number of MHC genes and the possibility of several alleles for each gene, it is almost impossible for any two
individuals to be identical, exceptif they are identical twins. In contrast to the receptors on T and B lymphocytes that bind a
unique antigen molecule, each MHC protein can bind a broad spectrum of antigen peptides. The antigen fragments bound to
MHC molecules then allow for proper recognition of self and nonself by immune cells, and a subsequent appropriate immune
response results.
Human MHC proteins are called human leukocyte antigens (HLA) because they were first detected on white
bloodcells. Because these molecules play a role in transplantrejection and are detected by immunologic tests, theyare
commonly called antigens. More recently, analysis ofthe genes for the HLA molecules has ensured a morecomplete
identification of the potential antigens presentin an individual. The classic human class I MHC moleculesare divided into
types called HLA-A, HLA-B, and HLA-C,and the class II MHC molecules are identified as HLA-DR,HLA-DP, and HLA-
DQ. The identification or typing of HLA molecules is important in tissue or organ transplantation, forensics, and paternity
evaluations. In organ or tissue transplantation, the closer the matching of HLA types, the greater is the probability of identical
antigens and the lower the chance of rejection.

HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED TISSUE INJURY

 Allergy (hypersensibility) represents exaggerated and qualitatively modified sensibility and
reactivity of the body, in response to antigenic and hapten substances, developing on the basis of
immunological reactions associated with cellular injuries, inflammation and necrosis.
Injurious immune reactions, called hypersensitivity, are the basis of the pathology associated
with immunologic diseases.Therefore, even if allergic reactions have on the basis physiological and
immunological mechanisms, they represent pathologic processes with adverse outcomes and
consequences that are harmful for the organism.
This term arose from the idea that individuals who have been previously exposed to an antigen
manifest detectable reactions to that antigen and are therefore said to be sensitized. Hypersensitivity
implies an excessive or harmful reaction to antigen.
There are several important general features of hypersensitivity disorders:
• Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and
non-microbial) or endogenous self-antigens. Humans live in an environment teeming with substances
capable of eliciting immune responses. Exogenous antigens include those in dust, pollens, foods, drugs,
microbes, and various chemicals. The immune responses against such exogenous antigens may take a
variety of forms, ranging from annoying but trivial discomforts, such as itching of the skin, to potentially
fatal diseases, such as bronchial asthma and anaphylaxis. Some of the most common reactions to
environmental antigens cause the group of diseases known as allergy. Immune responses against self,
or autologous, antigens, result in autoimmune diseases.
• Hypersensitivity usually results from an imbalance between the effector mechanisms of
immune responses and the control mechanisms that serve to normally limit such responses. In fact, in
many hypersensitivity diseases, it is suspected that the underlying cause is a failure of normal regulation.
• The development of hypersensitivity diseases (both allergic and autoimmune) is often
associated with the inheritance of particular susceptibility genes. HLA genes and many non-HLA genes
have been implicated in different diseases; specific examples will be described in the context of the
diseases.
• The mechanisms of tissue injury in hypersensitivity reactions are the same as the effector
mechanisms of defense against infectious pathogens. The problem in hypersensitivity is that these
reactions are poorly controlled, excessive, or misdirected (e.g., against normally harmless environmental
and self-antigens).
Allergic reactions contain in their pathogeny two types of immunological processes –
humoral immunity and cellular immunity. Allergic reactions, which have on the basis humoral immune
reactions, represent the immediate hypersensibility; allergic reactions having on the basis cellular
immune reactions represent late (delayed) hypersensibility. Since both, immune and allergic reactions,
have a common pathogenic substrate, when appreciating the biological essence of these reactions may
appear some difficulties. When differentiating immune reactions and allergic reactions there are some
criteria to be taken into consideration: so, reactions of the body triggered by heterogeneous antigen, that
have the goal to reestablish the antigenic homeostasis and are qualitatively and qualitatively adequate
to antigen and have a protective character represent immune reactions; reactions that are similar to the
immune one, but are inadequate quantitatively and qualitatively to antigen (hyperergic), that overcome
the reasonable measure for protection of the body and lead to cellular injuries, inflammation and necrosis
are called allergic reactions. Briefly we can state that allergic reactions are immune reactions that cause
cellular injuries, inflammation, and necrosis.

ETIOLOGY OF ALLERGY. CHARACTERISTICS OF ALLERGENS.

 Substances of antigenic and hapten nature, that trigger allergic reactions, are called allergens.
Allergens represent the same antigens, but they don’t produce physiological immune reactions but
pathologic allergic reactions. So, all characteristics of antigens refer to allergens too.
Antigens, or immunogens, are substances foreign to the host that can stimulate an immune
response. These foreign molecules are recognized by receptors on immune cells and by proteins, called
antibodies or immunoglobulins that are secreted in response to the antigen. Antigens include bacteria,
fungi, viruses, protozoa, and parasites. Non-microbial agents such as plant pollens, poison ivy resin,
insect venom, and transplanted organs can also act as antigens. Most antigens are macromolecules, such
as proteins and polysaccharides, although lipids and nucleic acids occasionally can serve as antigens.
Antigens, which in general are large and chemically complex, are biologically degraded into
smaller chemical units or peptides. These discrete, immunologically active sites on antigens are called
antigenic determinants, or epitopes. It is the unique molecular shape of an epitope that is recognized by
a specific immunoglobulin receptor found on the surface of the lymphocyte or by an antigen-binding of
a secreted antibody. A single antigen may contain multiple antigenic determinants, each stimulating a
distinct clone of lymphocytes to produce a unique type of antibody. For example, different proteins that
comprise a virus may function as unique antigens, each of which contains several antigenic
determinants. Hundreds of antigenic determinants are found on structures such as the bacterial cell wall.
Smaller substances (molecular masses <10,000 daltons) usually are unable to stimulate an
adequate immune response by themselves. When these low-molecular-weight compounds, known as
haptens (incomplete antibodies), combine with larger protein molecules, they function as antigens. The
proteins act as carrier molecules for the haptens to form antigenic hapten–carrier complexes. An allergic
response to the antibiotic penicillin is an example of a medically important reaction due to hapten–
carrier complexes. Penicillin (molecular mass of approximately 350 daltons) is normally a non-antigenic
molecule. However, in some individuals, it can chemically combine with body proteins to form larger
complexes that can then generate a potentially harmful immune allergic response.

Classification of allergens:
According to their origin there can be recognized:
a. Exogenous allergens –from the environment pass in the organism;
b. Endogenous allergens – substances from bodies composition; endogenic allergens
are also called – auto-allergens.
Exogenous allergens are divided in:
1. house-keeping allergens;
2. industrial allergens;
3. drugs;
4. vegetal allergens;
5. infectious allergens;
6. parasite allergens;

Endogenous allergens are divided in:

1. Native natural allergens – represent normal components of the body, toward which the
organism didn’t produce immune tolerance during ontogenesis;
2. Acquired non-infectious allergens –natural antigens, normal body structures which were
denaturized by physical, chemical factors or combined with other exogenous substances;
3. Acquired infectious allergens – natural antigens proper for the body, associated with
microorganisms, microbial toxins etc.

According to their chemical composition allergens can be divided in:

a) simple proteins;
 b) nucleoproteins;
c) polysaccharides ;
d) lipopolysaccharide;
e) simple organic substances;
f) anorganic substances;
g) chemical elements;
Some of the enumerated allergens are complete, that can produce allergic reactions by
themselves, while others are incomplete (haptens) that can cause allergic reactions only if associated
with the organism’s proteins, forming complex, conjugated antigens.
According to their way of entrance into the body allergens can be:
a. Inhaled allergens, or respiratory allergens (solid aerosols, perfumes etc.) penetrate via the
airways and cause, especially, allergic diseases of the respiratory apparatus (allergic rhinitis, bronchial
asthma etc.);
b. Alimentary allergens – components of alimentary products, penetrating via enteral way,
producing first of all allergic reactions of the GIT, but by protruding the natural barriers they can reach
the internal medium and thus affect other organs;
c. Contact allergens – pass through the teguments, skin and mucosaand produce local allergic
reactions;
d. Iatrogenic, parenteral, injected allergens – substances administrated directly into the internal
medium by subcutaneous, intramuscularly, intravenous route with therapeutic or prophylactic goal.
CLASSIFICATION OF HYPERSENSITIVITY DISEASES
Hypersensitivity diseases can be classified on the basis of the immunologic mechanism that
mediates the disease.
Table 1. Classification of hypersensitivity reactions
(From Robbins and Cotran; Pathologic basis of disease)

This classification is of value in distinguishing the manner in which the immune response causes
tissue injury and disease, and the accompanying pathologic and clinical manifestations. However, it is
now increasingly recognized that multiple mechanisms may be operative in any one hypersensitivity
disease.
 • In immediate hypersensitivity (type I hypersensitivity), the injury is caused by TH2 cells, IgE
antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on vessels and
smooth muscle and pro-inflammatory cytokines that recruit inflammatory cells.
• In antibody-mediated disorders (type II hypersensitivity), secreted IgG and IgM antibodies
injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation.
Antibodies may also interfere with cellular functions and cause disease without tissue injury.
• In immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies
bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and
induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue
damage by release of lysosomal enzymes and generation of toxic free radicals.
• In cell-mediated immune disorders (type IV hypersensitivity), sensitized T lymphocytes (TH1
and TH17 cells and cytotoxic T lymphocytes ( CTLs)) are the cause of the tissue injury. TH2 cells induce
lesions that are part of immediate hypersensitivity reactions and are not considered a form of type IV
hypersensitivity.

GENERAL PATHOGENESIS OF ALLERGIC REACTIONS

In the evolution of all allergic reactions there are several essential processes:
1. Sensibilization = sensitization (immunological stage);
2. Synthesis of allergic mediators (pathochemical stage);
3. Manifestations of allergic reaction (physiopathological stage)
4. Hypo-sensibilization = Decline of Immune Responses and Immunological Memory.

Sensibilization– represents increased body sensibility to allergen (from normal to hyper-

sensibilization) with formation of sensitized immune cells or immunoglobulins.
Sensitization which occurs at the allergen administration is called active sensitization. Active
sensitization is submitted to the same laws as primary immunization: become apparent at low doses of
antigen, depends on the immunogenicity of allergen; The first signs of sensitization (specific antibodies)
occur over 4-5 days after inoculation of antigens, and peak sensitization occurs at 12th - 14th day.
Maximum duration of sensitization is due to immunological memory and can be lifelong. Sensitization
achieved by transfer of immunoglobulins from actively sensitized animal to non-sensitized animals (not
contacted with relevant allergen) is called passive sensitization. Passive sensitization differs from the
active: occurs over 2-4 hours after the transfer of Ig (time necessary to their fixation on mast cells); lasts
up to 2-4 months (the time of transferred-IgE catabolism), does not reappear (lack of immunological
memory).
Synthesis and release of allergic mediators – involves releasing from cells, activation or new
synthesis of biologic active substances with pathogenic role in development of allergic reactions.
Manifestations of allergic reactions – are determined by the action of allergic mediators on
specific cell receptors with subsequent effects.
Decline of immune responses and immunological memory
Hyposensibilization – represents decreased body sensibilization for a specific allergen. Hypo-
sensibilization can be spontaneous (ex: over time when the allergen is absent the intensity of allergic
reaction can be diminished) or induced in cases when there is repeated action of specific allergen in
exaggerated amounts.

The majority of effector lymphocytes induced by an infectious pathogen die by apoptosis after
the microbe is eliminated, thus returning the immune system to its basal resting state, called homeostasis.
The initial activation of lymphocytes also generates long-lived memory cells, which may survive for
years after the infection. Memory cells are an expanded pool of antigen-specific lymphocytes (more
numerous than the naive cells specific for any antigen that are present before encounter with that
antigen), and that respond faster and more effectively when re-exposed to the antigen than do naïve
cells. This is why the generation of memory cells is an important goal of vaccination.

General pathogenesis of immediate hypersensibility - I, II, III allergic reactions (which

develop on the basis of humoral immune reactions).
According to pathologic mechanisms, the evolution of immediate allergic reaction has several
stages:
1. Immunologic stage (stage of sensitization);
2. Pathochemical stage, (release of biological active substances);
3. Pathophysiologic stage (clinical manifestations).

Immunologic stage in immediate hypersensibility involves the following sequence of

processes and is identical in all types of allergy reactions (similar in I, II and III types):
1. Primary penetration of exoallergen into the organism or formation of endoallergens;
2. Allergen contact with histiophagocytic system cells, or other antigen-presenting cells
(macrophages, dendritic cells), followed by the allergen processing, and their presentation to T-
lymphocytes (CD4+ helper 2 (Fig.1);
3. B-cell activation by T lymphocytes, with blast-transformation, proliferation and formation of
an immune clone of B-lymphocyte stimulated by antigen;
4. B-lymphocyte differentiation into plasma cells that synthesize IgE and IgG4 in reactions of
type I or IgM and IgG in type II and III;
5. Ig association with Fc receptors of basophiles and mast cells in allergic reactions type I, or
free circulation in type II and III.
In other words, during the stage of sensitization there is recognition and display of antigens with
activation of B cells to differentiate into plasma cell which will produce antibodies against specific
allergens. More detailed this can be represented as follows.
Microbes and their protein antigens are captured by dendritic cells that are resident in epithelia
and tissues. These cells carry their antigenic cargo to draining lymph nodes. Here the antigens are
processed and displayed complexed with MHC II molecules on the cell surface. This complex is
presented to T lymphocytes which will be activated and will secrete a series of cytokines that will
activate the B lymphocytes. Upon activation, B lymphocytes proliferate and then differentiate into
plasma cells that secrete different classes of antibodies with distinct functions. Many polysaccharide
and lipid antigens have multiple identical antigenic determinants (epitopes) that are able to engage many
antigen receptor molecules on each B cell and initiate the process of B-cell activation. B cells can work
as antigen-presenting cells by ingesting protein antigens into vesicles, degrading them, and displaying
peptides bound to MHC II molecules for recognition by helper T cells. The helper T cells express CD40L
and secrete cytokines, which work together to activate the B cells.
 Fig. 1. Processing and display of antigen in immediate hypersensibility
(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)

Most circulating IgG antibodies have half-lives of about 3 weeks. Some antibody-secreting
plasma cells migrate to the bone marrow and live for years, continuing to produce low levels of
antibodies.
Sensibilization is increasing of the normal reaction to the allergen (the primary contact) to
exacerbated (from repeated contact). In this context, during immediate type allergic reactions, sensitized
body is different from the non-sensitized only by the presence of allergen-specific immunoglobulins,
which are fixed on mast cells and basophils or are in free circulation.Sensitization is the period of allergy
latency, because, until the repeated contact with the same allergen, it does not manifest clinically. Only
by serological reactions can be detected specific antibodies for free circulation, or those fixed on
basophils and mast cells. This latency period will last until the body's repeated contact with the same
allergen which caused sensitization.
II.Pathochemical stage – release, activation or synthesis of chemical mediators from altered
cells or immune cells as a result of interaction between antigen and antibody.
III.Physiopathologic stage – the stage of clinical manifestation, physiopathologic effects
launched by the mediators action on specific reactive structures in the tissues of the body.
On the contrary to sensitization stage, pathochemical and physiopathologic stages have different
mechanisms for each reaction separately.

Immediate (Type I) hypersensitivity

Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring in a previously
sensitized individual that is triggered by the binding of an antigen to IgE antibody on the surface of mast
cells. Immediate hypersensitivity may occur as a systemic disorder or as a local reaction. The systemic
reaction most often follows injection of an antigen into a sensitized individual (e.g., by a bee sting), but
can also follow antigen ingestion (e.g., peanut allergens). Sometimes, within minutes the patient goes
into a state of shock, which may be fatal. Local reactions are diverse and vary depending on the portal
of entry of the allergen. They may take the form of localized cutaneous rash or blisters (skin allergy,
hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial
asthma, or allergic gastroenteritis (food allergy). Many local type I hypersensitivity reactions have two
well-defined phases. The immediate reaction is characterized by vasodilation, vascular leakage, and
depending on the location, smooth muscle spasm or glandular secretions. These changes usually become
evident within minutes after exposure to an allergen and tend to subside in a few hours. In many
instances (e.g., allergic rhinitis and bronchial asthma), a second, late-phase reaction sets in 2 to 24 hours
later without additional exposure to antigen and may last for several days. This late-phase reaction is
characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+
T cells, as well as tissue destruction typically in the form of mucosal epithelial cell damage.

Stages of immediate (Type I) hypersensitivity

Activation of TH2 cells and production of IgE antibody (sensitization).The first step in the
generation of TH2 cells is the presentation of the antigen to naive CD4+ helper T cells, probably by
dendritic cells that capture the antigen from its site of entry. For reasons that are still not understood,
only some environmental antigens elicit strong TH2 responses and thus serve as allergens. In response
to antigen and other stimuli, including cytokines such as IL-4 produced at the local site, the T cells
differentiate into TH2 cells. The newly minted TH2 cells produce a number of cytokines upon subsequent
encounter with the antigen; as mentioned earlier, the signature cytokines of this subset are IL-4, IL-5,
and IL-13. IL-4 acts on B cells to stimulate class switching to IgE and promotes the development of
additional TH2 cells. IL-5 is involved in the development and activation of eosinophils, which are
important effectors of type I hypersensitivity. IL-13 enhances IgE production and acts on epithelial cells
to stimulate mucus secretion. In addition, TH2 cells (as well as mast cells and epithelial cells) produce
chemokines that attract more TH2 cells, as well as other leukocytes, to the reaction site.
Sensitization and activation of mast cells. Mast cells are bone marrow–derived cells that are
widely distributed in the tissues. They are abundant near blood vessels and nerves and in subepithelial
tissues, which explains why local immediate hypersensitivity reactions often occur at these sites. Mast
cells have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators.
Mast cells (and their circulating counterpart, basophils) are activated by the cross-linking of high-
affinity IgE Fc receptors; in addition, mast cells may also be triggered by several other stimuli, such as
complement components C5a and C3a (called anaphylatoxins because they elicit reactions that mimic
anaphylaxis), both of which act by binding to receptors on the mast cell membrane. Basophils are similar
to mast cells in many respects, including the presence of cell surface IgE Fc receptors as well as
cytoplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues
but rather circulate in the blood in extremely small numbers. Similar to other granulocytes, basophils
can be recruited to inflammatory sites.
Mast cells and basophils express a high-affinity receptor, called FcεRI, which is specific for the
Fc portion of IgE and therefore avidly binds IgE antibodies. IgE-coated mast cells subsequent encounter
with the specific antigen. When a mast cell, armed with IgE antibodies previously produced in response
to an antigen, is exposed to the same antigen, the cell is activated, leading eventually to the release of
an arsenal of powerful mediators responsible for the clinical features of immediate hypersensitivity
reactions. In the first step in the sequence of mast cell activation, the antigen binds to the IgE antibodies
previously attached to the mast cells. The underlying Fcε receptors are brought together, and this
activates signal transduction pathways from the cytoplasmic portion of the receptors. These signals lead
to the production of mediators that are responsible for the initial, sometimes explosive, symptoms of
immediate hypersensitivity, and they also set into motion the events that lead to the late-phase reaction.
 Figure 2. Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity
reactions are initiated by the introduction of an allergen, which stimulates TH 2 responses and IgE production in genetically
susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates
the mast cells to secrete the mediatorsthat are responsible for the pathologic manifestations of immediate hypersensitivity.
(from Robbins and Cotran; Pathologic basis of disease)

Mast cell activation leads to degranulation, with the discharge of preformed (primary) mediators
that are stored in the granules, and de novo synthesisorsecondary mediators, including lipid products
and cytokines.
Preformed mediators. Mediators contained within mast cell granules are the first to be released
and can be divided into three categories:
• Vasoactive amines. The most important mast cell-derived amine is histamine. Histamine causes
intense smooth muscle contraction, increased vascular permeability, and increased mucus secretion by
nasal, bronchial, and gastric glands.
• Enzymes. These are contained in the granule matrix and include neutral proteases (chymase,
tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of
kinins and activatedcomponents of complement (C3a) by acting on their precursor proteins.
• Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate.
The proteoglycans serve to package and store the amines in the granules.

Other mediators which are release in the result of mast cell degranulation are: chemotactic factor
for neutrophils, chemoattractant factor for eosinophils, beta-glucosaminidase. Chemoattractantfactor
for neutrophils which trigger chemotaxis of neutrophils and their accumulation at the site of injury and
chemotactic factor for eosinophils – chemotaxis of eosinophils with inflammatory infiltration of the
tissues. In the result of neutrophils and eosinophils accumulation in the tissue and their activation, there
will be release of mediators from these inflammatory cells like: arylsulphatase, phospholipase,
histaminase, cationic proteins, that will additionally harm the tissues.

Lipid mediators. The major lipid mediators are arachidonic acid–derived products (eicosanoids
system). Reactions in the mast cell membranes lead to activation of phospholipase A2, an enzyme that
converts membrane phospholipids to arachidonic acid. This is the parent compound from which
leukotrienes and prostaglandins are produced by the lipoxygenase and cyclooxygenase pathways,
respectively (see mediators of inflammation).
• Leukotrienes. Leukotrienes C4 and D4 are the most potent vasoactive and spasmogenic agents
known. On a molar basis, they are several thousand times more active than histamine in increasing
vascular permeability and causing bronchial smooth muscle contraction. Leukotriene B 4 is highly
chemotactic for neutrophils, eosinophils, and monocytes.
• Prostaglandin D2. This is the most abundant mediator produced in mast cells by the
cyclooxygenase pathway. It causes intense bronchospasm as well as increased mucus secretion.
• Platelet-activating factor (PAF). PAF is a lipid mediator produced by some mast cell
populations but it is not derived from arachidonic acid. It causes platelet aggregation, release of
histamine, bronchospasm, increased vascular permeability, and vasodilation. Its role in immediate
hypersensitivity reactions is not well established.

Figure 3. Mast cell mediators. Upon activation, mast cells release various classes of mediators that are
responsible for the immediate and late-phase reactions. PAF, Platelet-activating factor. (from Robbins and Cotran; Pathologic
basis of disease)

Cytokines. Mast cells are sources of many cytokines, which may play an important role at several
stages of immediate hypersensitivity reactions. The cytokines include: TNF, IL-1, and chemokines,
which promote leukocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the TH2
response; and numerous others. The inflammatory cells that are recruited by mast cellderived TNF and
chemokines are additional sources of cytokines and of histamine-releasing factors that cause further
mast cell degranulation.
 These mediators are responsible for the manifestations of immediate hypersensitivity reactions.
Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and are
responsible for the intenseimmediate reactions characterized by edema, mucus secretion, and smooth
muscle spasm; others, exemplified by cytokines, including chemokines, set the stage for the latephase
response by recruiting additional leukocytes. Not only do these inflammatory cells release additional
waves of mediators (including cytokines), but they also cause epithelial cell damage. Epithelial cells
themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as
chemokines.

Late-phase reaction
In the late-phase reaction, leukocytes are recruited that amplify and sustain the inflammatory
response without additional exposure to the triggering antigen. Eosinophils are often an abundant
leukocyte population in these reactions. They are recruited to sites of immediate hypersensitivity by
chemokines, such as eotaxin, and others that may be produced by epithelial cells, TH 2 cells, and mast
cells. The TH2 cytokine IL-5 is the most potent eosinophil-activating cytokine known. Upon activation,
eosinophils liberate proteolytic enzymes as well as two unique proteins called major basic protein and
eosinophil cationic protein, which damage tissues. It is now believed that the late-phase reaction is a
major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma. Therefore,
treatment of these diseases requires the use of broad-spectrum antiinflammatory drugs, such as steroids,
rather than anti-histamine drugs, which are of benefit in the immediate reaction as occurs in allergic
rhinitis (hay fever).
Susceptibility to immediate hypersensitivity reactions is genetically determined. An increased
propensity to develop immediate hypersensitivity reactions is called atopy. Atopic individuals tend to
have higher serum IgE levels and more IL-4–producing TH2 cells than does the general population. A
positive family history of allergy is found in 50% of atopic individuals.
Environmental factors are also important in the development of allergic diseases. Exposure to
environmental pollutants, which is common in industrialized societies, is an important predisposing
factor for allergy. In fact, it is known that dogs and cats diverged from humans about 95 million years
ago and chimpanzees only about 4-5 million years ago, suggesting that chimps share more genes with
us than do dogs and cats. Nevertheless, dogs and cats, who live in the same environment as humans,
develop allergies and chimps do not. This simple observation suggests that environmental factors may
be more important in the development of allergic disease than genetics. Viral infections of the airways
are important triggers for bronchial asthma, an allergic disease affecting the lungs. Bacterial skin
infections are strongly associated with atopic dermatitis. It is estimated that 20% to 30% of immediate
hypersensitivity reactions are triggered by non-antigenic stimuli such as temperature extremes and
exercise, and do not involve TH2 cells or IgE; such reactions are sometimes called non-atopic allergy
(pseudoallergy). It is believed that in these cases mast cells are abnormally sensitive to activation by
various non-immune stimuli.
 Table 2. Examples of disorders caused by immediate hypersensitivity
(from Robbins and Cotran; Pathologic basis of disease)

The incidence of many allergic diseases is increasing in developed countries, and seems to be
related to a decrease in infections during early life. These observations have led to an idea, sometimes
called the hygiene hypothesis, that early childhood and even prenatal exposure to microbial antigens
educates the immune system in such a way that subsequent pathologic responses against common
environmental allergens are prevented. Thus, too much hygiene in childhood may increase allergies later
in life. This hypothesis, however, is difficult to prove, and the underlying mechanisms are not defined.
With this consideration of the basic mechanisms of type I hypersensitivity, we turn to some clinically
important examples of IgE-mediated disease. These reactions can lead to a wide spectrum of injury and
clinical manifestations

Systemic anaphylaxis
Systemic anaphylaxis is characterized by vascular shock, widespread edema, and difficulty in
breathing. It may occur in sensitized individuals in hospital settings after administration of foreign
proteins (e.g.,antisera), hormones, enzymes, polysaccharides, and drugs (e.g., the antibiotic penicillin),
or in the community setting following exposure to food allergens (e.g., peanuts, shellfish) or insect
toxins (e.g., those in bee venom). Extremely small doses of antigen may trigger anaphylaxis, for
example, the tiny amounts used in skin testing for various forms of allergies. Because of the risk of
severe allergic reactions to minute quantities of peanuts, U.S. agencies are considering a ban on peanut
snacks served in the confined quarters of commercial airplanes. Within minutes after exposure, itching,
hives, and skin erythema appear, followed shortly thereafter by a striking contraction of respiratory
bronchioles and respiratory distress. Laryngeal edema results in hoarseness and further compromises
breathing. Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow, and the patient may
go into shock and even die within the hour.
The risk of anaphylaxis must be borne in mind when certain therapeutic agents are administered.
Although patients at risk can generally be identified by a previous history of some form of allergy, the
absence of such a history does not preclude the possibility of an anaphylactic reaction.

Local immediate hypersensitivity reactions

About 10% to 20% of the population suffers from allergies involving localized reactions to
common environmental allergens, such as pollen, animal dander, house dust, foods, and the like.
Specific diseases include urticaria, allergic rhinitis (hay fever), bronchial asthma, and food allergies.
 Antibody-mediated (Type II) hypersensitivity
Antibodies that react with antigens present on cell surfaces or in the extracellular matrix cause
disease by destroying these cells, triggering inflammation, or interfering with normal functions. The
antibodies may be specific for normal cell or tissue antigens (autoantibodies) or for exogenous antigens,
such as chemical or microbial proteins, that bind to a cell surface or tissue matrix. These reactions are
the cause of several important diseases.
Immunological stage of this reaction is similar to the mechanisms of sensitization described
above, which is general for all allergic reaction which rely of humoral immune response. Involved
antibodies are IgG and IgM.

Mechanisms of tissular injuries and inflammation

(Pathochemical and physiopathological stages).

Opsonization and phagocytosis

Phagocytosis is largely responsible for depletion of cells coated with antibodies. Cells opsonized
by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions of
some IgG subclasses. In addition, when IgM or IgG antibodies are deposited on the surfaces of cells,
they may activate the complement system by the classical pathway. Complement activation generates
by-products, mainly C3b and C4b (opsonins), which are deposited on the surfaces of the cells
(opsonization) and are recognized by phagocytes that express receptors for these proteins. The net result
is phagocytosis of the opsonized cells (by macrophages and neutrophils) and their destruction.
Complement activation on cells surface also leads to the formation of the membrane attack complex
(MAC), which disrupts membrane integrity by “drilling holes” through the lipid bilayer, thereby causing
osmotic lysis of the cells. This mechanism of killing is probably effective only with cells that have thin
cell walls, such as Neisseria bacteria. Antibody-mediated destruction of cells may occur by another
process called antibody-dependent cellular cytotoxicity (ADCC). Cells that are coated with IgG antibody
are killed by a variety of effector cells, mainly NK cells (natural killer lymphocytes) and macrophages,
which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without
phagocytosis, but by release of perforins. Clinically, antibody-mediated cell destruction and
phagocytosis occur in the following situations: (1) transfusion reactions, in which cells from an
incompatible donor react with and are opsonized by preformed antibody in the host; (2) hemolytic
disease of the newborn (erythroblastosis fetalis), in which there is an antigenic difference between the
mother and the fetus, and IgG anti-erythrocyte antibodies from the mother cross the placenta and cause
destruction of fetal red cells; (3) autoimmune hemolytic anemia, agranulocytosis, and
thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are then
destroyed ; and (4) certain drug reactions, in which a drug acts as a “hapten” by attaching to plasma
membrane proteins of red cells and antibodies are produced against the drug-protein complex.

Inflammation
When antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix,
the resultant injury is due to inflammation. The deposited antibodies activate complement by classical
pathway, generating by-products, including chemotactic agents (mainly C5a), which direct the
migration of polymorphonuclear leukocytes and monocytes, and anaphylatoxins (C3a and C5a), which
increase vascular permeability. The leukocytes are activated by engagement of their C3b and Fc
receptors. This results in the production of other substances that damage tissues (released from activated
leucocytes), such as lysosomal enzymes, including proteases capable of digesting basement membrane,
collagen, elastin, and cartilage, and reactive oxygen species (O2-, H2O2, OH-).
 Finally, we can conclude that mediators of type II allergic reaction are: compliment system,
lysosomal enzymes and reactive oxygen species.
Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms
of glomerulonephritis, vascular rejection in organ grafts, and other disorders.

Cellular dysfunction
In some cases, antibodies directed against cell surface receptors impair or dysregulate function
without causing cell injury or inflammation. For example, in myasthenia gravis, antibodies reactive with
acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission
and therefore cause muscle weakness. The converse (i.e., antibody-mediated stimulation of cell
function) is the basis of Graves disease. In this disorder, antibodies against the thyroid-stimulating
hormone (TSH) receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Figure 4.Mechanisms of antibody-mediated injury.A, Opsonization of cells by antibodies and

complement components and ingestion by phagocytes. B, Inflammation induced by antibody binding to Fc receptors of
leukocytes and by complement breakdown products. C, Antireceptor antibodies disturb the normal function of receptors. In
these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and
antibodies against the thyroid stimulating hormone (TSH) receptor activate thyroid cells in Graves disease. (from Robbins
and Cotran; Pathologic basis of disease).

Examples of antibody-mediated diseases (Type II hypersensitivity)

 (from Robbins and Cotran; Pathologic basis of disease)

Immune complex–mediated (Type III) hypersensitivity

Immunological stage of this reaction is similar to the mechanisms of sensitization described
above, which is general for all allergic reaction which rely of humoral immune response. Involved
antibodies are IgG and IgM.
Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites
of deposition. The pathologic reaction is usually initiated when antigen combines with antibody in the
circulation, creating immune complexes that typically deposit in vessel walls. Less frequently, the
complexes may be formed at sites where antigen has been “planted” previously (called in situ immune
complexes). The antigens that form immune complexes may be exogenous, such as a foreign protein
that isinjected or produced by an infectious microbe, or endogenous, if the individual produces antibody
against self antigens (autoimmunity). Immune complex–mediated diseases tend be systemic, but often
preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels
(vasculitis), all of which are common sites of immune complex deposition.
• Systemic immune complex disease. Acute serum sickness is the prototype of a systemic
immune complex disease; it was once a frequent sequela to the administration of large amounts of
foreign serum (e.g., serum from immunized horses used for protection against diphtheria). In modern
times the disease is infrequent, and usually seen in individuals who receive antibodies from other
individuals or species. Nevertheless, it is an informative model that has taught us a great deal about
systemic immune complex disorders.
The pathogenesis of systemic immune complex disease can be divided into three phases.
1. Formation of immune complexes. The introduction of a protein antigen triggers an immune
response that results in the formation of antibodies (sensitization), typically about a week after the
injection of the protein. These antibodies are secreted into the blood, where they react with the antigen
still present in the circulation and form antigen-antibody complexes.
 2. Deposition of immune complexes. In the next phase the circulating antigen-antibody
complexes are deposited in various tissues. The factors that determine whether immune complex
formation will lead to tissue deposition and disease are not fully understood, but the major influences
seem to be the characteristics of the complexes and local vascular alterations. In general, complexes that
are of medium size, formed in slight antigen excess, are the most pathogenic. Organs where blood is
filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune
complexes become concentrated and tend to deposit; hence, immune complex disease often affects
glomeruli and joints.
3. Inflammation and tissue injury. Once immune complexes are deposited in the tissues, they
initiate an acute inflammatory reaction. During this phase (approximately 10 days after antigen
administration), clinical features such as fever, urticaria, joint pains (arthralgias), lymph node
enlargement, and proteinuria appear. Wherever complexes deposit the tissue damage is similar. The
resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it
occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.
High pathogenic role in development of injuries and inflammation in this type of allergy have:
activation of the compliment system by classical pathway, activation of Hageman factor (Factor XIIa)
triggered by injuries of endothelial cells by deposition of immune complexes. The important role of
complement in the pathogenesis of the tissue injury is supported by the observations that complement
proteins can be detected at the site of injury and, during the active phase of the disease, consumption of
complement leads to a decrease in serum levels of C3. In fact, serum C3 levels can in some cases, be
used to monitor disease activity. Complement activation leads to release of anaphylatoxins (fraction
C3a, C5a) which have proinflammatory effects (vasodilation, increase vessel permeability,
chemoattractants) and formation of membrane attack complex (fraction C5-C9). Active Hageman factor
will in turn activate the clotting system (formation of thrombin which possesses pro-inflammatory
effects) and development of microthrombi at the sites of injury with ischemia that will amplify the
injuries. As well, there will be activation of kinin system with release of bradykinin, fibrinolytic system
with formation of plasmin and degradation of fibrin with release of fibrin-splitting products (see
inflammation; plasma derived mediators). Anaphylatoxins, bradykinin due to their chemoattractant
functions lead to migration at the site of injury of other inflammatory cells (recruitment of neutrophils,
monocytes etc.) which additionally will harm the tissue by releasing of lysosomal enzymes, reactive
oxygen species.
Such, in conclusion, mediators of type III allergic reaction are: complement system, clotting
system, kinin system, fibrinolytic system, lysosomal enzymes, reactive oxygen species.
If the disease results from a single large exposure to antigen, such as acute serum sickness, the
lesions tend to resolve as a result of catabolism of the immune complexes. A form of chronic serum
sickness results from repeated or prolonged exposure to an antigen. This occurs in several diseases, such
as systemic lupus erythematosus (SLE), which is associated with persistent antibody responses to
autoantigens. In many diseases, the morphologic changes and other findings suggest immune complex
deposition but the inciting antigens are unknown. Included in this category are membranous
glomerulonephritis and several vasculitides.
 Figure 5. Immune complex disease.
The sequential phases in the induction of systemic immune complex–mediated diseases (type III
hypersensitivity). (from Robbins and Cotran; Pathologic basis of disease).
• Local immune complex disease (Arthus reaction)
The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex
vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous
injection of antigen in a previously immunized animal that contains circulating antibodies against the
antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large
immune complexes are formed locally. These complexes precipitate in the vessel walls and cause
fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury.
Examples of immune complex–mediated diseases
(From Robbins and Cotran; Pathologic basis of disease)
 General pathogenesis of type IV allergic reactions (delayed allergic
reaction= late hypersensibility)
In the evolution of delayed allergic reactions (Type IV) there can be distinguished three stages:
• Immunologic stage during which there is:
1. Primary entrance of exoallergen into the organism or formation of endoallergen;
2. Allergen contact with histiophagocytic system cells or other antigen-presenting cells,
processing of allergen and presenting to T-cells;
3. T-cells activation by allergen – blast-transformation, proliferation and formation of
immunologic clone of T-cells activated by antigen (CD4+ H1 or H17, CD8+) which are marked by specific
receptors for this allergen (Fig.6);

Fig. 6. Recognition, display of antigen and effector cells in cell mediated hypersensibility.
Dendritic cells (DCs) capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During
this process, the DCs mature, and express high levels of MHC II molecules and costimulators. Naive T cells recognize MHC-
associated peptide antigens displayed on DCs. The T cells are activated to proliferate and to differentiate into effector and
memory cells (CD4+ H1 or H17, CD8+), which migrate to sites of infection and serve various functions in cell-mediated
immunity. CD4+ effector T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes, and activate
the phagocytes to kill the microbes. CD4+ T cells also induce inflammation. CD8+ cytotoxic T lymphocytes (CTLs) kill
infected cells harboring microbes in the cytoplasm. Some activated T cells differentiate into long-lived memory cells. APC,
antigen-presenting cell. (from Robbins and Cotran; Pathologic basis of disease)

Naive T lymphocytes are activated by antigen and costimulators in peripheral lymphoid organs,
and proliferate and differentiate into effector cells that migrate to any site where the antigen (microbe)
is present. One of the earliest responses of CD 4+ helper T cells is secretion of the cytokine IL-2 and
expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes
and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes.
Activated CD8+ lymphocytes differentiate into CTLs that kill cells harboring microbes in the cytoplasm.
By destroying the infected cells, CTLs eliminate the reservoirs of infection.
Lymphocytes bearing specific receptors are called sensitized lymphocytes and constitute the
cellular substrate of delayed allergic reactions. The sequence of processes listed here is the phenomenon
of sensitization of the body to the allergen and consist in increased reaction to allergen - from normal
(the primary contact) to exacerbated (from repeated contact). Thus, the sensitized body differs from the
non-sensitized only by the presence of sensitized T lymphocytes, which bear on the outer surface
specific receptors for allergen.
II. Pathochemical stage start up at the repeated contact of the sensitized organism with the
allergen and consists of release, activation or synthesis of chemical mediators by sensitized
lymphocytes.
III. Physiopathologic stage – clinical manifestations – physiopathologic effects launched by
mediator release in pathochemical stage.

T Cell–mediated (Type IV) hypersensitivity

The cell-mediated type of hypersensitivity is caused by inflammation resulting from cytokines
produced by CD4+ T cells and cell killing by CD8+ T cells. CD4+ T cell–mediated hypersensitivity
induced by environmental and self antigens is the cause of many chronic inflammatory diseases,
including autoimmune diseases. CD8+ cells may also be involved in some of these autoimmune diseases
and may be the dominant effector cells in certain reactions, especially those that follow viral infections.

CD4+ T Cell–mediated inflammation

In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced by the T cells induce
inflammation that may be chronic and destructive. The prototype of T cell–mediated inflammation is
delayed-type hypersensitivity (DTH), a tissue reaction to antigens given to immune individuals. In this
reaction, an antigen administered into the skin of a previously immunized individual results in a
detectable cutaneous reaction within 24 to 48 hours (hence the term delayed, in contrast to immediate
hypersensitivity). Both TH1 and TH17 cells contribute to organ-specific diseases in which inflammation
is a prominent aspect of the pathology. The inflammatory reaction associated with TH 1 cells is
dominated by activated macrophages, and that triggered by TH 17 cells has a greater neutrophil
component. The inflammatory reactions stimulated by CD 4+ T cells can be divided into sequential
stages.
Activation of CD4+ T cells. As described earlier, naive CD4+ T cells recognize peptides displayed
by dendritic cells and secrete IL-2, which functions as an autocrine growth factor to stimulate
proliferation of the antigen responsive T cells. The subsequent differentiation of antigen-stimulated T
cells to TH1 or TH17 cells is driven by the cytokines produced by APCs at the time of T-cell activation.
In some situations the APCs (dendritic cells and macrophages) produce IL-12, which induces
differentiation of CD4+T cells to the TH1 subset. IFN-γ produced by these effector cells promotes further
TH1 development, thus amplifying the reaction. If the APCs produce inflammatory cytokines such as
IL-1, IL-6, these stimulate differentiation of T cells to the TH 17 subset. Some of the differentiated
effector cells enter the circulation and may remain in the memory pool of T cells for long periods,
sometimes years.
 Figure 7. Mechanisms of T cell–mediated (type IV) hypersensitivity reactions.
A, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate
inflammation and activate phagocytes, leading to tissue injury. CD 4+ TH17 cells contribute to inflammation by recruiting
neutrophils (and, to a lesser extent, monocytes). B, In some diseases, CD 8+ cytotoxic T lymphocytes (CTLs) directly kill
tissue cells. APC, Antigen presenting cell. (from Robbins and Cotran; Pathologic basis of disease)

Responses of differentiated effector T cells. Upon repeat exposure to an antigen, TH1 cells secrete
cytokines (lymphotoxin, inhibitory factor for macrophage migration, chemoattractant factors, IFN-γ).
One of the most important from this is IFN-γ, which activates the macrophages. IFN-γ-activated
macrophages (“classically activated”) are altered in several ways: their ability to phagocytose and kill
microorganisms is markedly augmented; they express more class II MHC molecules on the surface, thus
facilitating further antigen presentation; they secrete TNF, IL-1, and chemokines, which promote
inflammation; and they produce more IL-12, thereby amplifying the TH1 response. Thus, activated
macrophages serve to eliminate the offending antigen; if the activation is sustained, continued
inflammation and tissue injury result. Activated TH17 cells secrete IL-17, IL-22, chemokines, and
several other cytokines. Collectively, these cytokines recruit neutrophils and monocytes to the reaction,
thus promoting inflammation. TH17 cells also produce IL-21, which amplifies the TH17 response.
Clinical examples of CD4+ T cell–mediated inflammatory reactions. The classic example of DTH
is the tuberculin reaction, which is produced by the intracutaneous injection of purified protein
derivative (PPD, also called tuberculin), a protein-containing antigen of the tubercle bacillus. In a
previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a
peak in 24 to 72 hours, and thereafter slowly subside. Morphologically, delayed-type hypersensitivity
is characterized by the accumulation of mononuclear cells, mainly CD 4+ T cells and macrophages,
around venules, producing perivascular “cuffing”. In fully developed lesions, the venules show marked
endothelial hypertrophy, reflecting cytokine-mediated endothelial activation. With certain persistent or
non-degradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, the infiltrate is
dominated by macrophages over a period of 2 or 3 weeks. With sustained activation, macrophages often
undergo a morphologic transformation into epithelioid cells, large epithelium-like cells with abundant
cytoplasm. A microscopic aggregation of epithelioid cells, usually surrounded by a collar of
lymphocytes, is referred to as a granuloma. This pattern of inflammation, called granulomatous
inflammation, is typically associated with strong TH 1-cell activation and high-level production of
cytokines such as IFN-γ. It can also be caused by indigestible foreign bodies, which activate
macrophages without eliciting an adaptive immune response.
 Figure 8. Granulomatous inflammation.
The events that give rise to the formation of granulomas in type IV hypersensitivity reactions, illustrating the role of TH 1
cytokines. In some granulomas (e.g., in schistosomiasis), TH2 cells contribute to the lesions. The role of TH17 cells in
granuloma formation is not known. (from Robbins and Cotran; Pathologic basis of disease)

Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may
be evoked by contact with urushiol, the antigenic component of poison ivy or poison oak, and presents
as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and
structurally modifies some self-proteins and peptides derived from these modified proteins are
recognized by T cells and elicit the reaction. Chemicals may also modify HLA molecules, making them
appear foreign to T cells. The same mechanism is responsible for most drug reactions, among the most
common immunologic reactions of humans. In these reactions, the drug (often a reactive chemical) alters
self proteins, including MHC molecules, and the “neoantigens” are recognized as foreign by T cells,
leading to cytokine production and inflammation. These often manifest as skin rashes. CD 4+ T cell–
mediated inflammation is the basis of tissue injury in many organ-specific and systemic autoimmune
diseases, such as rheumatoid arthritis and multiple sclerosis, as well as diseases probably caused by
uncontrolled reactions to bacterial commensals, such as inflammatory bowel disease.

T Cell–mediated diseases
 (from Robbins and Cotran; Pathologic basis of disease)

CD8+ T cell–mediated cytotoxicity. In this type of T cell–mediated reaction, CD8+ CTLs kill
antigen-expressing target cells. Tissue destruction by CTLs may be an important component of some T
cell–mediated diseases, such as type 1 diabetes. CTLs directed against cell surface histocompatibility
antigens play an important role in graft rejection, to be discussed later. They also play a role in reactions
against viruses. In a virus-infected cell, viral peptides are displayed by class I MHC molecules and the
complex is recognized by the TCR of CD8+T lymphocytes. The killing of infected cells leads to the
elimination of the infection, but in some cases it is responsible for cell damage that accompanies the
infection (e.g., in viral hepatitis). Tumor-associated antigens are also presented on the cell surface, and
CTLs are involved in the host response to transformed cells. The principal mechanism of T cell–
mediated killing of targets involves perforins and granzymes, preformed mediators contained in the
lysosome-like granules of CTLs. CTLs that recognize the target cells secrete a complex consisting of
perforin, granzymes, and other proteins which enters target cells by endocytosis. In the target cell
cytoplasm, perforin facilitates the release of the granzymes from the complex. Granzymes are proteases
that cleave and activate caspases, which induce apoptosis of the target cells. Activated CTLs also express
Fas ligand, a molecule with homology to TNF, which can bind to Fas expressed on target cells and
trigger apoptosis. CD8+T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory
reactions resembling DTH, especially following virus infections and exposure to some contact
sensitizing agents.

Rejection of tissue transplants

Transplant rejection is discussed here because it involves several of the immunological reactions
that underlie immune-mediated inflammatory diseases. A major barrier to transplantation is the process
ofrejection, in which the recipient's immune system recognizes the graft as being foreign and attacks it.
Mechanisms of recognition and rejection of allografts
Rejection is a complex process in which both cell-mediated immunity and circulating antibodies
play a role; moreover, the contributions of these two mechanisms are often reflected in the histologic
features of the rejected organs.

• T Cell–mediated reactions
 The critical role of T cells in transplant rejection has been documented both in humans and in
experimental animals. T cellmediated graft rejection is called cellular rejection, and it involves
destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated
CD4+ helper cells. The major antigenic differences between a donor and recipient that result in
rejectionof transplants are differences in highly polymorphic HLA alleles. The recipient's T cells
recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways,
called direct and indirect.
• In the direct pathway, T cells of the transplant recipient recognize allogeneic (donor) MHC
molecules on the surface of APCs in the graft. It is believed that dendritic cells carried in the donor
organs are the most important APCs for initiating the antigraft response, because they not only express
high levels of class I andII MHC molecules but also are endowed with costimulatory molecules (e.g.,
B7-1 and B7-2). The T cells ofthe host encounter the donor dendritic cells either within the grafted organ
or after the dendritic cells migrateto the draining lymph nodes. CD 8+ T cells recognize class I MHC
molecules and differentiate into active CTLs, which can kill the graft cells by mechanisms already
discussed. CD4+ helper T cells recognize allogeneic class II molecules and proliferate and differentiate
into TH1 (and possibly TH17) effector cells.Cytokines secreted by the activated CD4+ T cells trigger a
delayed hypersensitivity reaction in the graft, resulting in increased vascular permeability and local
accumulation of mononuclear cells (lymphocytes andmacrophages), and graft injury caused by the
activated macrophages.
• In the indirect pathway of allorecognition, recipient T lymphocytes recognize MHC antigens
of the graft donor after they are presented by the recipient's own APCs. This process involves the uptake
and processing of MHC and other foreign molecules from the grafted organ by host APCs. The peptides
derivedfrom the donor tissue are presented by the host's own MHC molecules, like any other foreign
peptide. Thus,the indirect pathway is similar to the physiologic processing and presentation of other
foreign (microbial) antigens. The indirect pathway generates CD 4+ T cells that enter the graft and
recognize graftantigens being displayed by host APCs that have also entered the graft, and the result is
a delayedhypersensitivity type of reaction. However, CD 8+ CTLs that may be generated by the indirect
pathwaycannot directly recognize or kill graft cells, because these CTLs recognize graft antigens
presented by thehost's APCs. Therefore, when T cells react to a graft by the indirect pathway, the
principal mechanism ofcellular rejection may be T-cell cytokine production and delayed
hypersensitivity. It is postulated that thedirect pathway is the major pathway in acute cellular rejection,
whereas the indirect pathway is more important in chronic rejection. However, this separation is by no
means absolute.
 Fig. 9.Recognition and rejection of organ allografts.
In the direct pathway, donor class I and class II MHC antigens on antigen-presenting cells in the graft (along with
costimulators, not shown) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively. CD4+
cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed hypersensitivity
reaction. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells. In the indirect pathway
graft antigens are picked up, processed, and displayed by host APCs and activate CD4+ T cells, which damage the graft by
a local delayed hypersensitivity reaction and stimulate B lymphocytes to produce antibodies.
(from Robbins and Cotran; Pathologic basis of disease)

• Antibody-mediated reactions in transplant rejection

Although T cells are pivotal in the rejection of organ transplants, antibodies produced against
alloantigens in the graft are also important mediators of rejection. This process is called humoral
rejection, and it can take two forms. Hyperacute rejection occurs when preformed anti-donor
antibodiesare present in the circulation of the recipient. Such antibodies may be present in a recipient
who has previously rejected a kidney transplant. Multiparous women who develop anti-HLA antibodies
againstpaternal antigens shed from the fetus may have preformed antibodies to grafts taken from their
husbands or children, or even from unrelated individuals who share HLA alleles with the husbands.
Prior blood transfusions can also lead to pre-sensitization, because platelets and white blood cells are
rich in HLA antigens and donors and recipients are usually not HLA-identical. With the current
practiceof cross-matching, that is, testing recipient's serum for antibodies against donor's cells, hyper-
acuterejection is no longer a significant clinical problem.
In recipients not previously sensitized to transplantation antigens, exposure to the class I and
class II HLA antigens of the donor graft may evoke antibodies. The antibodies formed by the recipient
may cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation,
andantibody-dependent cell-mediated cytotoxicity. The initial target of these antibodies in rejection
seemsto be the graft vasculature. Thus, antibody-dependent acute humoral rejection is usually
manifested bya vasculitis, sometimes referred to as rejection vasculitis
 AUTOIMMUNE DISEASES

Immunologic tolerance
Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes
to that antigen. Self-tolerance refers to lack of responsiveness to an individual’s own antigens, and it underlies our ability
to live in harmony with our cells and tissues. Because the antigen receptors of lymphocytes are generated by somatic
recombination of genes in a random fashion, lymphocytes with receptors capable of recognizingself-antigens are generated
constantly, and these cells have to be eliminated or inactivated as soon as they recognize self-antigens, to prevent them from
causing harm. The mechanisms of self-tolerance can be broadly classified into two groups: central tolerance and peripheral
tolerance (Fig. 6-21). Each of these is considered briefly.
Central Tolerance In this process, immature self-reactive T and B lymphocyte clones that recognize self antigens
during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B
cells) are killed or rendered harmless. The mechanisms of central tolerance in T and B cells show some similarities and
differences.
• In developing T cells, random somatic gene rearrangements generate diverse TCRs. Such antigen-independent
TCR generation produces many lymphocytes that express high-affinity receptors for self-antigens. When immature
lymphocytes encounter the antigens in the thymus, many of the cells die by apoptosis. This process, called negative selection
or deletion, is responsible for eliminating self-reactive lymphocytes from the T-cell pool. A wide variety of autologous
protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic
antigen-presenting cells in association with self MHC molecules and can, therefore, be recognized by potentially self-reactive
T cells. A protein called AIRE (autoimmune regulator) stimulates expression of some “peripheral tissue-restricted” self-
antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens. Mutations in the AIRE
gene are the cause of an autoimmune polyendocrinopathy. In the CD4+ T-cell lineage, some of the cells that see self-antigens
in the thymus do not die but develop into regulatory T cells (described later).
• When developing B cells strongly recognize self-antigens in the bone marrow, many of the cells reactivate the
machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens.
This process is called receptor editing; it is estimated that a quarter to half of all B cells in the body may have undergone
receptor editing during their maturation. If receptor editing does not occur, the self-reactive cells undergo apoptosis, thus
purging potentially dangerous lymphocytes from the mature pool. Central tolerance, however, is imperfect. Not all self
antigens may be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery.
There is similar “slippage” in the B-cell system. Self-reactive lymphocytes that escape negative selection can inflict tissue
injury unless they are deleted or muzzled in the peripheral tissues.

Peripheral tolerance
Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues; these are best defined for T
cells. These mechanisms include the following:
• Anergy. Lymphocytes that recognize self-antigens may be rendered functionally unresponsive, a phenomenon
called anergy. We discussed earlier that activation of antigen-specific T cells requires two signals: recognition of peptide
antigen in association with self MHC molecules on the surface of APCs and a set of costimulatory signals (“second signals”)
from APCs. These second signals are provided by certain T cell-associated molecules, such as CD28, that bind to their
ligands (the costimulators B7-1 and B7-2) on APCs. If the antigen is presented to T cells without adequate levels of
costimulators, the cells become anergic. Because costimulatory molecules are not expressed or are weakly expressed on
resting dendritic cells in normal tissues, the encounter between autoreactive T cells and their specific self-antigens displayed
by these dendritic cells may lead to anergy. Several mechanisms of T-cell anergy have been demonstrated in various
experimental systems. One of these, which has clinical implications, is that T cells that recognize self-antigens receive an
inhibitory signal from receptors that are structurally homologous to CD28 but serve the opposite functions. Two of these
inhibitory receptors are CTLA-4, which (like CD28) binds to B7 molecules, and PD-1, which binds to two ligands that are
expressed on a wide variety of cells. Because CTLA-4 has higher affinity for B7 molecules than does CD28, CTLA-4 may
be preferentially engaged when the levels of B7 are low, as when APCs are presenting self-antigens. Conversely, microbial
products elicit innate immune reactions, during which B7 levels on APCs increase and the low-affinity receptor CD28 is
engaged more. Thus, the affinities of the activating and inhibitory receptors and the level of expression of B7 may determine
the outcome of T cell antigen recognition. The importance of these inhibitory mechanisms has been established by the finding
that mice in which the gene encoding CTLA-4 or PD-1 is knocked out develop autoimmune diseases. Furthermore,
polymorphisms in the CTLA4 gene are associated with some autoimmune endocrine diseases in humans. Interestingly, some
tumors and viruses may use the same pathways of immune regulation to evade immune attack. This realization has led to the
development of antibodies that block CTLA-4 and PD-1 for tumor immunotherapy—by removing the brakes on the immune
response, these antibodies promote responses against tumors. Anergy also affects mature B cells in peripheral tissues. It is
believed that if B cells encounter self-antigen in peripheral tissues, especially in the absence of specific helper T cells, the B
cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting
in their death. B lymphocytes also express inhibitory receptors that may play a role in limiting their activation and preventing
responses to self-antigens.
• Suppression by regulatory T cells. A population of T cells called regulatory T cells functions to prevent immune
reactions against self-antigens. Regulatory T cells develop mainly in the thymus, as a result of recognition of self-antigens
(Fig. 9), but they may also be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that
express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3.
Both IL-2 and FOXP3 are required for the development and maintenance of functional CD 4+ regulatory T cells. Mutations
in FOXP3 result in severe autoimmunity in humans and mice; in humans these mutations are the cause of a systemic
autoimmune disease called IPEX (an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked). In
mice knockout of the gene encoding IL-2 or the IL-2 receptor α or β chain also results in severe multi-organ autoimmunity,
because IL-2 is essential for the maintenance of regulatory T cells. Recent genome-wide association studies have revealed
that polymorphisms in the CD25 gene are associated with multiple sclerosis and other autoimmune diseases, raising the
possibility of a regulatory T-cell defect contributing to these diseases. The mechanisms by which regulatory T cells suppress
immune responses are not fully defined, but their inhibitory activity may be mediated in part by the secretion of
immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions.
Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T
cells via CD28.

Mechanisms of immunologic tolerance to self-antigens.

The principal mechanisms of central and peripheral self-tolerance in T and B cells are illustrated. APC, Antigen-presenting
cell. (from Robbins and Cotran; Pathologic basis of disease)

Regulatory T cells may play a role in the acceptance of the fetus. Placental mammals face a unique challenge
because the developing fetus expresses paternal antigens that are foreign to the mother yet have to be tolerated. There is
emerging evidence that regulatory T cells prevent immune reactions against fetal antigens that are inherited from the father
and therefore foreign to the mother. In line with this idea, during evolution, placentation appeared simultaneously with the
ability to stably express the Foxp3 transcription factor. Experiments in mice have shown that fetal antigens induce long-lived
Foxp3+ regulatory T cells, and depletion of these cells results in fetal loss. There is great interest in determining the
contribution of regulatory T cells in human pregnancy and possible defects in these cells as the basis for recurrent
spontaneous abortions.
• Deletion by apoptosis. T cells that recognize self-antigens may receive signals that promote their death by
apoptosis. Two mechanisms of deletion of mature T cells have been proposed, based mainly on studies in mice. It is
postulated that if T cells recognize self-antigens, they may express a pro-apoptotic member of the Bcl family, called Bim,
without anti-apoptotic members of the family like Bcl-2 and Bcl-x (whose induction requires the full set of signals for
lymphocyte activation). Unopposed Bim triggers apoptosis by the mitochondrial pathway. A second mechanism of
activation-induced death of CD4+ T cells and B cells involves the Fas-Fas ligand system. Lymphocytes as well as many other
cells express the death receptor Fas (CD95), a member of the TNF-receptor family. Fas ligand (FasL), a membrane protein
that is structurally homologous to the cytokine TNF, is expressed mainly on activated T lymphocytes. The engagement of
Fas by FasL induces apoptosis of activated T cells (Chapter 2). It is postulated that if self-antigens engage antigen receptors
of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas mediated apoptosis. Self-
reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells. The importance of this mechanism in
the peripheral deletion of autoreactive lymphocytes is highlighted by two mice that are natural mutants of Fas or FasL. These
mice develop an autoimmune disease somewhat resembling human SLE, associated with generalized lymphoproliferation.
In humans a similar disease is caused by mutations in the FAS gene; it is called the autoimmune lymphoproliferative
syndrome (ALPS). Some antigens are hidden (sequestered) from the immune system, because the tissues in which these
antigens are located do not communicate with the blood and lymph. As a result, self-antigens in these tissues fail to elicit
immune responses and are essentially ignored by the immune system. This is believed to be the case for the testis, eye, and
brain, all of which are called immune-privileged sites because it is difficult to induce immune responses to antigens
introduced into these sites. If the antigens of these tissues are released, for example, as a consequence of trauma or infection,
the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated
mechanism for post-traumatic orchitis and uveitis.

AUTOIMMUNITY. GENERAL PRINCIPLES.

The immune system normally exists in an equilibrium in which lymphocyte activation, which is
required for defense against pathogens, is balanced by the mechanisms of tolerance, which prevent
reactions against self-antigens. The underlying cause of autoimmune diseases is the failure of tolerance,
which allows responses to develop against self-antigens. Understanding why tolerance fails in these
diseases is an important goal of immunologists.
Immune reactions against self-antigens – autoimmunity - are an important cause of certain
diseases in humans, estimated to affect at least 1% to 2% of the US population. A growing number of
diseases have been attributed to autoimmunity. It should be noted, however, that the mere presence of
autoantibodies does not indicate an autoimmune disease exists. Autoantibodies can be found in the
serum of apparently normal individuals, particularly in older age groups. Furthermore, innocuous
autoantibodies are sometimes produced after damage to tissues and may serve a physiologic role in the
removal of tissue breakdown products. How, then, does one define pathologic autoimmunity? Ideally,
at least three requirements should be met before a disorder is categorized as truly caused by
autoimmunity: (1) the presence of an immune reaction specific for some self-antigen or self-tissue; (2)
evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance;
and (3) the absence of another well-defined cause of the disease. Similarity with experimental models
of proven autoimmunity is also often used to support this mechanism in human diseases. Disorders in
which chronic inflammation is a prominent component are sometimes grouped under immune-mediated
inflammatory diseases; these may be autoimmune, or the immune response may be directed against
normally harmless microbes such as gut commensal bacteria.
The clinical manifestations of autoimmune disorders are extremely varied. On one end are
conditions in which the immune responses are directed against a single organ or tissue, resulting in
organ-specific disease, and on the other end are diseases in which the autoimmune reactions are against
widespread antigens, resulting in systemic or generalized disease. Examples of organ-specific
autoimmune diseases are type 1 diabetes mellitus, in which the autoreactive T cells and antibodies are
specific for β cells of the pancreatic islets, and multiple sclerosis, in which autoreactive T cells react
against central nervous system myelin. The best example of systemic autoimmune disease is SLE, in
which a diversity of antibodies directed against DNA, platelets, red cells, and protein-phospholipid
complexes result in widespread lesions throughout the body. In the middle of the spectrum falls
Goodpasture syndrome, in which antibodies to basement membranes of lung and kidney induce lesions
in these organs. It is obvious that autoimmunity results from the loss of self-tolerance, and the question
arises as to how this happens.
 Autoimmune diseases
(From Robbins-Cotran; Pathological basis of disease)

General features of autoimmune diseases

Diseases caused by autoimmunity have some important general features.
• Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the
damage is often progressive. One reason for the chronicity is that the immune system contains many
intrinsic amplification loops that allow small numbers of antigen-specific lymphocytes to accomplish
their task of eradicating complex infections. When the response is inappropriately directed against self-
tissues, the same amplification mechanisms exacerbate and prolong the injury. Another reason for the
persistence and progression of autoimmune disease is the phenomenon of epitope spreading, in which
an immune response against one-self antigen causes tissue damage, releasing other antigens, and
resulting in the activation of lymphocytes by these newly encountered epitopes.
• The clinical and pathologic manifestations of an autoimmune disease are determined by the
nature of the underlying immune response. Some of these diseases are caused by autoantibodies, whose
formation may be associated with dysregulated germinal center reactions. Most chronic inflammatory
diseases are caused by abnormal and excessive TH1 and TH17 responses; examples of these diseases
include psoriasis, multiple sclerosis, and some types of inflammatory bowel disease. CD8+ CTLs
contribute to killing of cells, such as islet β cells in type 1 diabetes. In some autoimmune diseases, such
as rheumatoid arthritis, both antibodies and T cell–mediated inflammation may be involved.

MECHANISMS OF AUTOIMMUNE DISEASES

It is obvious that autoimmunity results from loss of self–tolerance. Just how this happens
is largely unknown, but both inheritance of susceptibility genes that contributes to the maintenance of
self–tolerance and environmental factors, such as infections that promote the activation of self–reactive
lymphocytes, are clearly important. Gender may also play a role in the development of autoimmune
disorders. A number of autoimmune disorders such as SLE occur more commonly in women than men,
suggesting that estrogens may play a role in the development of autoimmune disease. Evidence suggests
that estrogens stimulate and androgens suppress the immune response. For example, estrogen stimulates
a DNA sequence that promotes the production of interferon-γ which is thought to assist in the induction
of an autoimmune response. Because of the complexity of the immune system, it seems unlikely that
autoimmune disorders arise from a single defect. It is thought that susceptibility genes and
environmental triggers induce a number of changes that contribute to the development of autoimmunity.
Heredity
Genetic factors can increase the incidence and severity of autoimmune diseases, as shown by the
familial clustering of several autoimmune diseases and the observation that certain inherited HLA types
occur more frequently in persons with a variety of immunologic and lymphoproliferative disorders. For
example, 90% of persons with ankylosing spondylitis carry the HLA-B27 antigen, compared with 7%
of persons without them disease. Other HLA-associated diseases are Reiter syndrome and HLA-B27,
rheumatoid arthritis and HLA-DR4, and SLE and HLA-DR3. The molecular basis for these associations
is unknown. Because autoimmunity does not develop in all persons with genetic predisposition, it
appears that other factors such as a “trigger event” interact to precipitate the altered immune state. The
event or events that trigger the development of an autoimmune response are unknown. It has been
suggested that the “trigger” may be a virus or other microorganism, a chemical substance, or a
selfantigen from a body tissue that has been hidden from the immune system during development.

Figure10. Pathogenesis of autoimmunity.

Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and
environmental triggers (such as infections, tissue injury, and inflammation) that promote lymphocyte entry into tissues,
activation of self-reactive lymphocytes, and tissue damage. (from Robbins and Cotran; Pathologic basis of disease)

Environmental factors
Although environmental factors, such as infectious agents, appear to be involved in the
pathogenesis of autoimmune disorders, their precise role in initiating or perpetuating the autoreactive
response is largely unknown.
Among the proposed mechanisms involved in loss of self-tolerance are breakdown of T-cell
anergy, release of sequestered antigens, molecular mimicry, and superantigens.
• Breakdown in T-cell anergy
 Anergy is a state of unresponsiveness to antigen. It involves the prolonged or irreversible
inactivation of lymphocytes, such as that induced by an encounter with self-antigens. Activation of
antigen-specific CD4+ T cells requires two signals: (1) recognition of the antigen in association with
class II MHC molecules on the surface of an antigen-presenting cell and (2) a set of costimulatory
signals provided by the antigen-presenting cell. If the second costimulatory signal is not delivered, the
T cell becomes anergic. Most normal tissues do not express the costimulatory molecules and thus are
protected from autoreactive T cells. However, this protection can be broken if the normal cells that do
not normally express the costimulatory molecules are induced to do so. Some inductions can occur after
an infection or in situations where there is tissue necrosis and local inflammation. For example,
upregulation of the costimulator molecule B7-1 has been observed in the central nervous system of
persons with multiple sclerosis, in the synovium of persons with rheumatoid arthritis, and in the skin of
persons with psoriasis.
• Release of sequestered antigens
Normally the body does not produce antibodies against self-antigens. Thus, any self-antigen that
was completely sequestered during development and then reintroduced to the immune system is likely
to be regarded as foreign. Among the sequestered tissues that could be regarded as foreign are
spermatozoa, thyroglobulin and ocular antigens such as those found in uveal tissue. Posttraumatic uveitis
and orchiditis after vasectomy may fall into this category. Changes in antigen structure or release of
hidden antigens may also account for the persistence of autoimmune disorders. Infections, and even the
initial autoimmune episode, may expose self-antigens that have been hidden from the immune system.
The result is continued activation of new lymphocytes that recognize the previously hidden epitopes.
• Molecular mimicry
Many autoimmune diseases are associated with infections, and clinical flare-ups are often
preceded by infectious processes. One proposed link between infections and autoimmunity is molecular
mimicry, in which a microbe shares an immunologic epitope with the host. In rheumatic fever and acute
glomerulonephritis, for example, a protein in the cell wall of group A, β-hemolytic streptococci has
considerable similarity with antigens in heart and kidney tissue, respectively. After infection, antibodies
directed against the microorganism cause a classic case of mistaken identity, which leads to
inflammation of the heart or kidney. Not everyone exposed to group Aβ-hemolytic streptococci has an
autoimmune reaction. The reason that only certain persons are targeted for autoimmune reactions to a
particular self-mimicry molecule may be determined by differences in HLA types. The HLA type
determines exactly which fragments of a pathogen are displayed on the cell surface for presentation to
T cells. One individual’s HLA may bind self-mimicry molecules for presentation to T cells, and
another’s HLA type may not. In the spondyloarthropathies, particularly Reiter syndrome and reactive
arthritis, there is a clear relationship between arthritis and a prior bacterial infection, combined with the
inherited HLA-B27 antigens.
 Figure 11. Postulated role of infections in autoimmunity.
Infections may promote activation of self-reactive lymphocytes by inducing the expression of
costimulators (A), or microbial antigens may mimic self antigens and activate self-reactive lymphocytes
as a cross-reaction (B); (from Robbins and Cotran; Pathologic basis of disease)
• Superantigens
Superantigens are a family of related substances, including staphylococcal and streptococcal
exotoxins, that can short-circuit the normal sequence of events in an immune response, leading to
inappropriate activation of CD4+ helper T cells. Superantigens do not require processing and
presentation of antigen by APCs to induce a T-cell response. Instead, they are able to interact with a T-
cell receptor outside the normal antigenbinding site. This distinctive mode of activation, together with
the ability of superantigens to bind to a wide variety of MHC class II molecules, leads to activation of
large numbers of T cells regardless of their MHC/peptide specificity. Superantigens are involved in
several diseases, including food poisoning and toxic shock syndrome. Recently, a bacterial superantigen
was isolated that may be important in the pathogenesis of Chron disease.

IMMUNODEFICIENCY DISEASE
Immunodeficiency can be defined as an abnormality in one or more branches of the immune
system that renders a susceptible to diseases normally prevented by an intact system. Four major
categories of immune mechanisms defend the body against infectious or neoplastic disease: humoral or
antibody-mediated immunity (B lymphocytes), cell-mediated immunity (T lymphocytes), the
complement system, and phagocytosis (neutrophils and macrophages). Humoral and cell-mediated
immunodeficiencies represent disorders of adaptive or specific immunity; and complement and
phagocytic immunodeficiencies, disorders of innate or nonspecific immunity.
Immunodeficiency states can be classified as primary (congenital or inherited) or secondary
(acquired later in life). Secondary immunodeficiency can be the result of malnutrition, infection (
acquired immunodeficiency syndrome [AIDS]), neoplastic disease (lymphoma), or immunosuppressive
therapy (corticosteroids or transplant rejection medications). Regardless of the cause, primary and
secondary deficiencies can produce the same spectrum of disease. The severity and symptomatology of
the various immunodeficiencies depend on the disorder and extent of immune system involvement.

HUMORAL (B-CELL) IMMUNODEFICIENCIES

 Humoral immunodeficiencies involve B-cell function and immunoglobulin or antibody
production. Defects in humoral immunity increase the risk for recurrent pyogenic infections, including
those caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gram-
negative organisms such as Pseudomonas species. Humoral immunity usually is not as important in
defending against intracellular bacteria (mycobacteria), fungi, and protozoa. Viral infections, with the
exception of the enteroviruses that cause gastrointestinal infections, rely on cell-mediated immunity and
usually are handled normally.
Primary humoral immunodeficiency disorders
Primary humoral immunodeficiency disorders are genetic disorders of the B lymphocytes. They
are the most frequent type of primary immunodeficiencies, accounting for 70% of all primary
immunodeficiency disorders. Immunoglobulin production depends on the differentiation of stem cells
to mature B lymphocytes and the generation of immunoglobulin-producing plasma cells. This
maturation cycle initially involves the production of surface IgM, migration from the marrow to the
peripheral lymphoid tissue, and switching to the specialized production of IgG, IgA, IgD, IgE, or IgM
antibodies after antigenic stimulation. Primary humoral immunodeficiency disorders can interrupt the
production of one or all of the immunoglobulins.
Secondary humoral immunodeficiency disorders
Secondary deficiencies in humoral immunity can develop as a consequence of selective loss of
immunoglobulins through the gastrointestinal or genitourinary tracts. Such is the case in persons with
nephrotic syndrome who, because of abnormal glomerular filtration, lose serum IgA and IgG in their
urine. Because of its larger molecular size, IgM is not filtered into the urine, and serum levels remain
normal.

Transient hypogammaglobulinemia of infancy

During the first few months of life, infants are protected from infection by immunoglobulin G
(IgG) class antibodies that have been transferred from the maternal circulation during fetal life. IgA,
IgM, IgD, and IgE do not normally cross the placenta. The presence of elevated levels of IgA or IgM in
the infant cord blood suggests premature antibody production in response to an intrauterine infection.
An infant’s level of maternal IgG gradually declines over a period of approximately 6 months.
Concomitant with the loss of maternal antibody, the infant’s immature humoral immune system
begins to function, and between the ages of 1 and 2 years, the child’s antibody production reaches adult
levels. Any abnormality that blocks or prevents the maturation of B lymphocyte stem cells can produce
a state of immunodeficiency. For example, certain infants may experience a delay in the maturation
process of B cells that leads to a prolonged deficiency in IgG levels (IgM and IgA levels are normal)
beyond 6 months of age. The total number and antigenic response of circulating B cells is normal, but
the chemical communication between B and T cells that leads to clonal proliferation of antibody-
producing plasma cells seems to be reduced. This condition is referred to as transient
hypogammaglobulinemia of infancy. The result of this condition usually is limited to repeated bouts of
upper respiratory and middle ear infections. This condition usually resolves by the time the child is 2 to
4 years of age.

X-Linked agammaglobulinemia. X-linked or Bruton’s agammaglobulinemia is a recessive

trait that affects only males. As the name implies, persons with this disorder have essentially
undetectable levels of all serum immunoglobulins. Therefore, they are susceptible to meningitis and
recurrent otitis media and to sinus and pulmonary infections with encapsulated organisms such as S.
pneumoniae, H. influenzae type b, S. aureus, and Neisseria meningitidis. Many boys with this disorder
have severe tooth decay. The central defect in this syndrome is a genetic mutation that blocks the
differentiation of pre-B cells, creating an absence of mature circulating B cells and plasma cells. T
lymphocytes, however, are normal in number and function. Symptoms of the disorder usually coincide
with the loss of maternal antibodies. A clue to the presence of the disorder is the failure of an infection
to respond completely and promptly to antibiotic therapy.Diagnosis is based on demonstration of low
or absent serum immunoglobulins. Therapy consists of prophylaxis with intravenous immunoglobulin
and prompt antimicrobial therapy for suspected infections.

Common variable immunodeficiency. Another disorder of B-cell maturation, which is similar

to X-linked agammaglobulinemia, is a condition called common variable immunodeficiency. In this
syndrome, the terminal differentiation of mature B cells to plasma cells is blocked. The result is
markedly reduced serum immunoglobulin levels, normal numbers of circulating B lymphocytes, and a
complete absence of germinal centers and plasma cells in lymph nodes and the spleen.
The symptomatology of common variable immunodeficiency is similar to that of X-linked
agammaglobulinemia (i.e., recurrent otitis media and sinus and pulmonary infections with encapsulated
organisms), but the onset of symptoms occurs much later, usually between the ages of 15 and 35 years,
and distribution of disease between the sexes is equal. Persons with late-onset hypogammaglobulinemia
also have an increased tendency toward development of chronic lung disease, autoimmune disorders,
hepatitis, gastric carcinoma, and chronic diarrhea with associated intestinal malabsorption.

X-linked hypogammaglobulinemia
Selective IgA deficiency. Selective IgA deficiency is the most common type of immunoglobulin
deficiency, affecting 1 in 400 to 1 in 1000 persons. The syndrome is characterized by moderate to
marked reduction in levels of serum and secretory IgA. Its likely caused by a block in the pathway that
promotes terminal differentiation of mature B cells to IgA-secreting plasma cells. The occurrence of
IgA deficiency in both males and females and in members of successive generations within families
suggests autosomal inheritance with variable expressivity. The disorder has also been noted in persons
treated with certain drugs (e.g., phenytoin, sulfasalazine), suggesting that environmental factors may
trigger the disorder. Approximately two thirds of persons with selective IgA deficiency have no overt
symptoms, presumably because IgG and IgM levels are normal and compensate for the defect. At least
50% of affected children overcome the deficiency by the age of 14 years. Persons with markedly reduced
levels of IgA often experience repeated upper respiratory and gastrointestinal infections and have
increased incidence of allergic manifestations, such as asthma, and autoimmune disorders. Persons with
IgA deficiency also can develop antibodies against IgA, which can lead to severe anaphylactic reactions
when blood components containing IgA are given. Therefore, only specially washed erythrocytes from
normal donors or erythrocytes from IgA-deficient donors should be used. There is no treatment available
for selective IgA deficiency unless there is a concomitant reduction in IgG levels. Administration of IgA
immunoglobulin is of little benefit because it has a short half-life and is not secreted across the mucosa.
There also is the risk for anaphylactic reactions associated with IgA antibodies in the immunoglobulin.
Immunoglobulin G Subclass Deficiency. An IgG subclass can affect one or more of IgG subtypes,
despite normal levels or elevated serum concentrations of IgG. IgG immunoglobulins can be divided
into four subclasses (IgG1 through IgG4) based on structure and function. Most circulating IgG belongs
to the IgG1 (70%) and IgG2 (20%) subclasses. In general, antibodies directed against protein antigens
belong to the IgG1 and IgG3 subclasses, and antibodies directed against carbohydrate and polysaccharide
antigens are primarily IgG2 subclass. As a result, persons who are deficient in IgG2 subclass antibodies
can be at greater risk for development of sinusitis, otitis media, and pneumonia caused by
polysaccharide-encapsulated microorganisms such as S. pneumoniae, H. influenzae type b, and N.
meningitidis. Children with mild forms of the deficiency can be treated with prophylactic antibiotics to
prevent repeated infections. Intravenous immune globulin can be given to children with severe
manifestations of this deficiency. The use of polysaccharide vaccines conjugated to protein carriers
rather than the protein conjugated to protein carriers that would stimulate an IgG1 response can provide
protection against some of these infections.
 CELL-MEDIATED (T-CELL) IMMUNODEFICIENCIES
Unlike the B-cell lineage or immunodeficiency, in which a well-defined series of differentiation
steps ultimately leads to the production of immunoglobulins, mature T lymphocytes are composed of
distinct subpopulations whose immunologic assignments are diverse. T cells can be functionally divided
into two subtypes (CD4+ helper and CD8+ cytotoxic T cells). Collectively, T lymphocytes protect against
fungal, protozoan, viral, and intracellular bacterial infections; control malignant cell proliferation; and
are responsible for coordinating the overall immune response.

Primary cell-mediated immunodeficiency disorders

In general, persons with cell-mediated immunodeficiency disorders have infections or other
clinical problems that are more severe than antibody disorders. Children with defects in this branch of
the immune response rarely survive beyond infancy or childhood. For children with fatal forms of T-
cell defects, transplantation of thymic tissue or major histocompatibility complex (MHC) – compatible
bone marrow is currently the treatment of choice. Stem cell transplantation, an alternative to bone
marrow transplantation, has also proved useful in treating some disorders. The major risk to recipients
of bone marrow transplantation is that of graft-versus-host disease. Gene replacement therapy remains
a distant goal for most immunodeficiencies at present. The main obstacles to this type of therapy are
purifying self-renewing stem cells, which are the ideal target for introduction of the replacement gene,
and lack of methods for introducing the genes into the stem cell.

Secondary cell-mediated immunodeficiency disorders

Secondary deficiencies of T-cell function are more common than primary deficiencies and have
been described in conjunction with acute viral infections (measles virus, cytomegalovirus) and with
certain malignancies such as Hodgkin’s disease and other lymphomas. In the case of viruses, direct
infection of specific T-lymphocyte subpopulations (helper cells) by lymphotropic viruses such as the
human immunodeficiency virus (HIV) and human herpes virus type 6 can lead to loss of cellular
function and selective subtype depletion with a concomitant loss of immunologic function associated
with that subtype.
Persons with neoplastic disorders can have impaired T-cell function based on unregulated
multiplication or dysfunction of one particular subclone of T cells. The outward expression of this may
be an increased susceptibility to infections caused by normally harmless pathogens (i.e., opportunistic
infections) or failure to generate delayed type hypersensitivity reactions (anergy). Persons with anergy
have a diminished or absent reaction to a battery of skin test antigens, including Candida and the
tuberculin test, even when infected with Mycobacterium tuberculosis. In persons with anergy, a negative
skin test result for tuberculosis can mean a true lack of exposure to tuberculosis or indicate the person’s
inability to mount an appropriate T-cell response.

DiGeorge syndrome. DiGeorge syndrome stems from an embryonic developmental defect. The
defect is thought to occur before the 12th week of gestation, when the thymus, parathyroid gland, and
parts of the head, neck, and heart are developing. The disorder affects both sexes. Because familial
occurrence is rare, it seems unlikely that the disorder is inherited. Formerly thought to be caused by a
variety of factors, including extrinsic teratogens, this defect has been traced to microdeletion of a gene
on chromosome 22 (22q11).
Infants born with this defect have partial or complete failure of development of the thymus and
parathyroid glands and have congenital defects of the head, neck, and heart. The extent of immune and
parathyroid abnormalities is highly variable, as are the other defects. Occasionally, a child has no heart
defect. In some children, the thymus is not absent but is in an abnormal location and is extremely small.
These infants can have partial DiGeorge syndrome, in which hypertrophy of the thymus occurs with
development of normal immune function. The facial disorders can include hypertelorism (i.e., increased
distance between the eyes); micrognathia (i.e., fish mouth); low-set, posteriorly angulated ears; split
uvula; and higharched palate. Urinary tract abnormalities also are common. The most frequent
presenting sign is hypocalcemia and tetany that develops in the first 24 hours of life. It is caused by the
absence of the parathyroid gland and is resistant to standard therapy.
Children who survive the immediate neonatal period may have recurrent or chronic infections
because of impaired T-cell immunity. Children also may have an absence of immunoglobulin
production, caused by a lack of helper T-cell function. For children who do require treatment, thymus
transplantation can be performed to reconstitute T-cell immunity. Bone marrow transplantation also has
been successfully used to restore normal T-cell populations. If blood transfusions are needed, as during
corrective heart surgery, special processing is required to prevent graft-versus-host disease.

COMBINED T-CELL AND B-CELL IMMUNODEFICIENCIES

Disorders that affect both B and T lymphocytes, with resultant defects in both humoral and cell-
mediated immunity, fall under the broad classification of combined immunodeficiency syndrome
(CIDS). A single mutation in any one of the many genes that influence lymphocyte development or
response, including lymphocyte receptors, cytokines, or major histocompatibility antigens, can lead to
combined immunodeficiency. Regardless of the affected gene, the net result is a disruption in the normal
communication system of B and T lymphocytes and deregulation of the immune response. The spectrum
of disease resulting from combined immunodeficiency disorders ranges from mild to severe to
ultimately fatal forms.
Severe combined immunodeficiency. The most pronounced form of the combined
immunodeficiencies often is referred to as severe combined immunodeficiency syndrome (SCIDS).
SCIDS is caused by diverse genetic mutations that lead to absence of all immune function and, in some
cases, a lack of natural killer (NK) cells. Affected infants have a disease course that resembles AIDS,
with failure to thrive, chronic diarrhea, and opportunistic infections that usually lead to death by the age
of 2 years. If recognized at birth or within the first 3 months of life, 95% of infants can be successfully
treated with bone marrow or stem cell transplantation.
Ataxia-telangiectasia. Ataxia-telangiectasia is a complex syndrome of neurologic,
immunologic, endocrinologic, hepatic, and cutaneous abnormalities. It is an autosomal recessive
disorder that is thought to result from the mutation of a single gene located on the long arm of
chromosome 11 (11q22–23). As the name implies, this syndrome is heralded by worsening cerebellar
ataxia (i.e., poor muscle coordination) and the appearance of telangiectases (i.e., lesions consisting of
dilated capillaries and arterioles) on skin and conjunctival surfaces. The ataxia usually goes unnoticed
until the toddler begins to walk; the telangiectases develop thereafter, especially on skin surfaces
exposed to the sun. The ataxia progresses slowly and relentlessly to severe disability. Intellectual
development is normal at first but seems to stop at the 10-year level in many of these children. Children
with ataxia-telangiectasia have deficiencies in both cellular and humoral immunity, including reduced
levels of IgA, IgE, and IgG2, absolute lymphopenia, and a decrease in the ratio of CD4+ helper T cells
to CD8+ suppressor T cells. Approximately 70% have an IgA deficiency, and approximately half also
have an IgG subclass deficiency. There is increased susceptibility to recurrent upper and lower
respiratory tract infections (particularly those caused by encapsulated bacteria) and an increased risk for
the development of malignancies. Death from malignant lymphoma is common.

Wiskott-Aldrich Syndrome. Wiskott-Aldrich syndrome is an X-linked recessive disorder that

becomes symptomatic during the first year of life. Infants with this syndrome are plagued by eczema,
low platelet counts, and susceptibility to bacterial infections. Bleeding episodes or symptoms due to
infection usually begin within the first 6 months of life. Abnormalities of humoral immunity include
decreased serum levels of IgM and markedly elevated serum IgA and IgE concentrations. T-cell
dysfunction initially is mild but progressively deteriorates, and patients become increasingly susceptible
to the development of malignancies of the mononuclear phagocytic system, including Hodgkin’s
lymphoma and leukemia. Children with Wiskott-Aldrich syndrome typically are unable to produce
antibody to polysaccharide antigens and therefore are susceptible to infections caused by encapsulated
microorganisms. They also are prone to septicemia and meningitis with these organisms. Varicella
infection can be lethal to children with this condition.
Bone marrow transplantation has been successful in children with Wiskott-Aldrich syndrome.
Splenectomy may be used to control the thrombocytopenia in situations in which bone marrow
transplantation cannot be done.

DISORDERS OF THE COMPLEMENT SYSTEM

The complement system is an integral part of the innate or nonspecific immune response. The
activation of the complement network through the classic, lectin-mediated, or alternative pathways
promotes chemotaxis, opsonization, and phagocytosis of invasive pathogens, bacteriolysis, and
anaphylactic reactions. Thus, alterations in normal levels of complement or the absence of a particular
complement component can lead to enhanced susceptibility to infectious diseases and immune-mediated
disorders such as hemolytic anemia and collagen vascular disorders. As with B- and T-cell deficiencies,
complement disorders can be classified as primary if the deficiency is inherited or secondary if the
condition develops because of another disease process.

Primary disorders of the complement system

Most primary disorders of the complement system are transmitted as autosomal recessive traits
and can involve one or more complement components (the complement components are designated by
“C” and enzyme subcomponents by “q,” “r,” and “s”). Deficiencies of C1r, C1rs, C4, C2, C3, C5, C6, C7,
C8, and C9 are transmitted as autosomal co-dominant traits, in which each parent transmits a gene that
codes for half the serum level of the component. Because 50% activity is sufficient to prevent disease,
persons who are heterozygous and have one normally functioning gene seldom have problems.
In general, persons with deficiencies in factors C1 (C1q, r, and s) and C4 are not necessarily at
increased risk for recurrent infections because the lectin-mediated and alternative pathways can be
activated normally through C3. However, many of them acquire autoimmune diseases, particularly
lupus-like syndromes. Persons with primary deficiency of C1q have a high incidence of systemic lupus
erythematosus (SLE), an SLE-like syndrome without typical SLE serology, a chronic rash with
underlying vasculitis on biopsy, or membrano-proliferative glomerulonephritis. Like persons with C1q
deficiency, persons with C1r, C1r/C1s, C4, C2, and C3 deficiencies have a high incidence of vasculitis
syndromes, especially SLE or SLE-like syndrome.
A C2 deficiency causes a susceptibility to multiple and potentially life-threatening infections
caused by encapsulated bacteria, especially S. pneumoniae. Similarly, persons with C 3 deficiency are
predisposed to infections that trigger the lectin-mediated or alternate pathway (e.g., those caused by
encapsulated bacteria and S. aureus) because of their inability to opsonize and lyse bacteria. Although
persons with deficiencies in the terminal components of complement (C5 through C9) are susceptible to
repeated episodes of meningitis and sepsis caused by N. meningitides or systemic gonococcal disease,
they are less likely to have autoimmune disorders than persons with other complement deficiencies.

Only supportive measures are available for treatment of primary disorders of the complement
system. Measures to prevent bacterial infections are important. The affected person and close contacts
should be immunized with vaccines for S. pneumoniae, H. influenzae, and N. meningitidis.

Secondary disorders of the complement system

Secondary complement deficiencies also can occur in persons with functionally normal
complement systems because of rapid activation and turnover of complement components (as is seen in
immune complex disease) or reduced synthesis of components, as would be the case in chronic cirrhosis
of the liver or malnutrition.

Hereditary angioneurotic edema. Hereditary angioneurotic edema is a particularly interesting

form of complement deficiency. Persons with this disorder do not produce a functional C1 inhibitor.
Activation of the classic complement pathway is uncontrolled, leading to increased breakdown of C 4
and C2 with concomitant release of C-kinin, a vasodilator. This causes episodic attacks of localized
edema the face, neck, joints, abdomen, and sites of trauma. Swelling of the subcutaneous tissues,
especially of the face, can be disfiguring, and swelling of the gastric mucosa causes nausea, vomiting,
and diarrhea. If the trachea or larynx is involved, the episode can prove fatal. The attacks associated
with this inherited disease usually begin before the age of 2 years and become progressively worse with
age. Symptoms can last from 1 to 4 days, and most persons with the disorder have more than one attack
a month.

DISORDERS OF PHAGOCYTOSIS
The phagocytic system is composed primarily of polymorphonuclear leukocytes (neutrophils
and eosinophils) and mononuclear phagocytes (circulating monocytes and tissue and fixed [spleen]
macrophages). The primary purpose of phagocytic cells is to migrate to the site of infection
(chemotaxis), aggregate around the affected tissue (adherence), envelope invading microorganisms or
foreign substances (phagocytosis), and generate microbicidal substances (enzymes or byproducts of
metabolism) to kill the ingested pathogens. A defect in any of these functions or a reduction in the
absolute number of available cells can disrupt the phagocytic system. Persons with phagocytic disorders
are particularly prone to infections by bacteria and often by Candida species and filamentous fungi,
although the types of pathogens vary with different disorders. As with other alterations in immune
function, defects in phagocytosis can be primary or secondary disorders.

Primary disorders of phagocytosis

The best known of the primary disorders of phagocytosis is chronic granulomatous disease
(CGD). CGD represents a group of inherited disorders that greatly reduce or inactivate the ability of
phagocytic cells to produce the so-called respiratory burst that results in the generation of toxic
derivatives of oxygen (superoxide anion and hydrogen peroxide). These oxygen species participate in
creating an intracellular environment that kills ingested microorganisms. Recurrent infections, along
with granulomatous lesions, in persons with CGD are thought to be due to persistence of viable
microorganisms in impaired phagocytic cells. Other aspects of phagocyte function, such as engulfment
of microorganisms, are normal. Children with CGD are subject to chronic and acute infections of the
skin, liver, lung, and other soft tissues despite aggressive antibiotic therapy. Severe facial acne and
painful inflammation of the nares are common. Organisms responsible for the infections include S.
aureus, Serratia marcescens, Pseudomonas cepacia, Escherichia coli, Candida albicans, and Aspergillus
species. These infections usually begin during the first 2 years of life. The disorder is diagnosed by
examining the ability of a person’s phagocytes to reduce a yellow dye to a blue compound during active
respiration. Bone marrow transplantation is the only known cure for CGD. Supportive care includes the
use of recombinant interferon-γ and prophylactic antibiotic therapy.

Secondary disorders of phagocytosis

Secondary deficiencies of the phagocytic system can be caused by a number of circumstances,
such as deficiencies of opsonins, which coat the surface of a foreign substance and enhance
phagocytosis, and deficiencies of chemotactic factors (antibody and complement), which coat the
surface of microorganisms and promote increased migration of phagocytes to the site of infection and
stimulate phagocytosis. Deficiencies of either of these factors reduce the overall effectiveness of
phagocytes. Drugs that impair or prevent inflammation and T-cell function, such as corticosteroids or
cyclosporine, also alter phagocytic response through modulation of cytokines.
Persons with diabetes mellitus also demonstrate poor phagocytic function, primarily because of
altered chemotaxis. The reason for this dysfunction is not understood, but it is unrelated to the person’s
age or the severity of the metabolic disorder. Apparently, this is a separate genetic disorder that is co-
inherited at a higher frequency among persons with diabetes and among family members. HIV infection
and AIDS represent another form of acquired or secondary deficiency of phagocytic function. However,
in this case, the deficiency is due to direct infection and destruction of helper T cells and monocytes–
macrophages by the virus.

BIBLIOGRAPHY

1. ROBBINS and COTRAN. Pathological basis of disease, 9th edition, 2015, pag. 186-217

2. CAROL MATTSON PORTH. Pathophysiology. Concepts of Altered Health States; 9th

edition, 2014; pag 329-349 and 353-355

3. STEFAN SILBERNAGL and FLORIAN LANG. Color Atlas of Pathophysiology. 3rd edition,
2016, pag. 56-61