DISEASE OF THE

IMMUNE SYSTEM
The Normal Immune
Response
Normal immune response
Immune system – vital for survival; protects us from infectious pathogens in the
environment
1) Innate immunity – natural or native immunity
● First line of defense
● Mediated by cells and molecules that recognize products of microbes and dead
cells and induce rapid protective host reactions
2) Adaptive immunity – acquired or specific immunity
■ Consists if mechanisms that are stimulated by (“adapt to”) microbes
■ Capable of recognizing microbial and antimicrobial substances
■ Develops later after exposure to microbes and other foreign substances
■ More powerful than innate immunity
■ “immune response”
 Feature Innate Immunity Adaptive Immunity
The body's initial, non-specific defense A highly specific, learned immune response
Definition mechanism against pathogens. triggered after exposure to specific pathogens.
Speed of Response Immediate (within minutes to hours) Delayed (several days to weeks)
Non-specific, recognizes general patterns like
pathogen-associated molecular patterns Highly specific, recognizes unique antigens on
Specificity (PAMPs). pathogens.
No memory, the response is the same upon Immunological memory, more efficient response
Memory repeated exposure. upon re-exposure to the same pathogen.
Neutrophils, macrophages, dendritic cells, T cells (helper, cytotoxic), B cells (plasma cells),
Key Cells Involved natural killer (NK) cells, eosinophils, basophils. memory cells.
Physical barriers (skin, mucous membranes), Antibodies, T-cell receptors (TCRs), MHC
Major Components phagocytes, complement system, cytokines. molecules, antigen-presenting cells (APCs).
Phagocytosis, inflammation, antimicrobial
peptides, complement activation, NK cell Antibody production by B cells, T-cell mediated
Response Mechanism cytotoxicity. cytotoxicity, memory cell formation.
Pattern recognition receptors (PRRs), such as Recognition of specific antigens presented by
Recognition Mechanism Toll-like receptors (TLRs) on immune cells. MHC molecules on infected cells or APCs.

Paul S, Hmar EL, Sharma HK. Strengthening Immunity with Immunostimulants: A Review, Curr Trends Pharm Res, 2020, 7(1): 35-64.
 Feature Innate Immunity Adaptive Immunity
Short-lived response; inflammatory Long-lasting protection due to memory cells;
processes typically resolve once the the response becomes faster and stronger on
Duration of Action pathogen is cleared. subsequent exposures.
Triggered after recognition of specific
Activation of Triggered immediately after infection; no antigens; requires prior exposure for optimal
Response need for prior exposure. response.
Innate immunity includes natural barriers, Adaptive immunity involves humoral
phagocytic cells, complement system, and (antibody-mediated) immunity (B cells) and
Types of Immunity NK cells. cellular (T cell-mediated) immunity.
Inflammation may be present but is more
focused and regulated through cytokines and
Effect on Inflammation Often induces acute inflammation. antibodies.
Cytokines (IL-1, TNF-α, etc.), complement Antibodies (IgG, IgM, IgA), cytokines (IFN-γ,
Key Mediators proteins, antimicrobial peptides. IL-2), TCRs.
Evolutionarily ancient, found in all More recent evolutionary development, found
Evolutionary Origin multicellular organisms. in vertebrates.
Examples of Response to bacterial infections, wound Protection against specific pathogens,
Involvement healing, initial antiviral defense. vaccination response, long-term immunity.
Paul S, Hmar EL, Sharma HK. Strengthening Immunity with Immunostimulants: A Review, Curr Trends Pharm Res, 2020, 7(1): 35-64.
Figure 6.1 The principal components of innate and adaptive
immunity. NK, Natural killer.
Innate Immunity
Innate immunity is always present, ready to provide defense against
microbes and to eliminate damaged cells
Components of Innate Immunity
● Epithelial barriers that block the entry of microbes, phagocytic cells
(mainly neutrophils and macrophages), dendritic cells, natural killer
cells, and several plasma proteins of the complement system
Epithelia of ∙ Provide mechanical barriers to the entry of microbes from the
skin and GIT external environment
∙ Also produce antimicrobial molecules such as defensins, and
lymphocytes located in the epithelial combat microbes at these
sites
Monocytes ∙ Phagocytes in blood; rapidly recruited at sites of infection
and ∙ Macrophages – matured monocytes in tissues; “professional
neutrophils phagocytes”; sense and ingest invaders
o Dominant cells in chronic inflammation

Dendritic cells ∙ Specialized cell population present in epithelia, lymphoid organs,

and most tissues
∙ Capture protein antigens and display peptides for recognition by T
lymphocytes; antigen presenting cells (APCs)
∙ Endowed with receptors that sense microbes and cell damage 🡪
Stim
ulate secretion of cytokines
∙ Involved in initiation of innate immune responses
Natural Killer ∙ Provide early protection against many viruses and intracellular
Cells bacteria
Mast cells ∙ Capable of producing many mediators of inflammation
∙ Also epithelial and endothelial cells
Innate ∙ Cells with the appearance of lymphocytes but w/ features more
lymphoid cells like cells of innate immunity
∙ Contribute to early defense against microbes
Proteins of ∙ Plasma proteins that are activated by microbes using the
complement alternative and lectin pathways in innate immune response
system
∙ In adaptive immunity: activated by antibodies using classical
pathway

∙ Mannose-binding lectin and CRP 🡪 coat microbes and

promote phagocytosis

∙ Lung surfactant – also a component of innate immunity provide

protection against inhaled microbes
Cellular Receptors for Microbes, Products of
Damaged Cells, and Foreign Substances
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 (thus cannot be mutated to allow the microbes to evade the defense
mechanism)
Damaged-associated molecular patterns – where leukocytes recognize molecules
released
· by injured and necrotic cells
Pattern recognition receptors – cellular receptors that recognize these molecules
· Pattern recognition receptors are located in all the cellular compartments where
microbes may be present:
· Plasma membrane receptors detect extracellular microbes
o
· Endosomal receptors detect ingested microbes
· Cytosolic receptors detect microbes in the cytoplasm
Toll-Like Receptors ∙ Best-known of the pattern recognition receptors; Toll was
discovered in Drosophila
∙ 10 TLRs in mammals; present in plasma membrane and
endosomal vesicles
∙ All these receptors signal by a common pathway that
culminates in the activation of two sets of transcription
factors:
o NF-kB – stimulates the synthesis and secretion of
cytokines and the expression of adhesion molecules
o Interferon regulatory factors (IRFs) –
stimulate the production of the antiviral cytokines, type I
interferons
NOD-Like ∙ NLRs – cytosolic receptors; recognize wide variety of substances including:
Receptors o Products of necrotic cells (uric acid, released ATP)
and the o Ion disturbances (loss of K+)
Inflammaso o Microbial products
me ∙ NLRs signal via a cytosolic multiprotein complex called
inflammasome, w/c activates enzyme (caspase-1) that cleaves IL-1 to generate active
form
∙ IL-1 – mediator of inflammation that recruits leukocytes and induce fever

∙ Gain-of-function mutations of NLRs lead to periodic fever

syndromes, called autoinflammatory syndromes

o Respond to treatment w/ IL-1 antagonist

Other ∙ C-type lectin receptors (CLRs) – expressed on the plasma membrane of macropahges
Receptors for and dendritic cells
Microbial o Detect fungal glycans and elicit inflammatory reactions to fungi
Products ∙ RIG-like receptors (RLRs) – located on the cytosol of most cell types and detect nucleic
acids of viruses that replicate in the cytoplasm
∙ These receptors stimulate the production of antiviral cytokines
∙ G protein coupled receptors on neutrophils, macrophage
🡪 recognize short bacterial peptides containing N- formylmethionyl residues
o GPCR enables neutrophils to detect bacterial proteins and stimulate chemotactic
response
∙ Mannose receptors – recognize microbial sugars and induce phagocytosis
 Reactions of Innate Immunity
Innate immune system provides host defense by two
main reactions

Inflammation ∙ Cytokines and products of complement activation are

produced during innate immune reactions and trigger the
vascular and cellular components of inflammation
∙ Recruited leukocytes destroy microbes and ingest and
eliminate damaged cells
Antiviral defense ∙ Type I interferons produced in response to viruses act on cells
and activate enzymes that degrade viral nucleic acids and inhibit
viral replication inducing antiviral state
Others ∙ Innate immunity provides the danger signals that stimulate
more powerful adaptive immune response
Adaptive Immunity
· The adaptive immune system consists of lymphocytes and their
products, including antibodies
· Two types of adaptive immunity:
o Humoral immunity – protects against extracellular microbes and
their toxins
▪ Mediated by B lymphocytes, antibodies or immunoglobulins (Ig)
: bone marrow
o Cell-mediated or cellular immunity – responsible for defense
against intracellular microbes
▪ Mediated by T lymphocytes : timus
Activating and inhibitory receptors of
natural killer (NK) cells. (A) Healthy cells
express self class I major
histocompatibility
complex (MHC) molecules, which are
recognized by inhibitory receptors, thus
ensuring that NK cells do not attack
normal cells. Note that healthy cells may
express ligands for activating
receptors (not shown) or may not
express such ligands (as shown), but
they do not activate NK cells because
they engage the inhibitory receptors. (B)
In infected and stressed cells, class I
MHC expression is reduced so that the
inhibitory receptors are not engaged,
and ligands for activating receptors are
expressed. The result is that NK cells
are activated and the infected cells are
killed.
Cells of the Immune System
Lymphocytes and other cells involved in immune response
constantly circulate among lymphoid and other tissues via blood
and lymphatic circulation
Promotes immune surveillance
∙ Naive cells – mature lymphocytes that have not encountered
the antigen for which they are specific
∙ Effector cells – differentiated lymphocytes after they are
activated by recognition of antigens and other signals; functions
to eliminate microbes

∙ Memory cells – live in a state of heightened awareness; able to

react rapidly and strongly combat the microbe in case it returns
T Lymphocytes
1. Helper T lymphocytes (HTL) – stimulate B lymphocyte to make antibodies and activate
other leukocytes to destroy microbes
2. Cytotoxic T lymphocytes (CTL) – kill infected cells
3. Regulatory T lymphocytes (RTL) – limit immune responses and prevent reaction against
self antigens
∙ T lymphocytes develop in the thymus. Mature T cells are found in the blood (60-70% of
lymphocytes) and in T cell zones of peripheral lymphoid organs
∙ T cell recognize an antigen by antigen-specific TCR
o TCR consist of a disulfide-linked heterodimer made up of α & β polypeptide chain, each
have a variable (antigen-binding) region and constant region
∙ The αβ TCR recognizes peptide antigens that are presented by MHC molecules on the
surfaces of APC
∙ MHC restriction – limiting the specificity of T cells for peptides displayed by cell surface MHC
molecules; ensures that T cells see only cell associated antigens
∙ Each TCR is noncovalently linked to six polypeptide chains, w/c form the CD3
complex and the ζ chain dimer
o CD3 and ζ proteins are invariant or identical in all T cells
o Involve in transduction signals
o Form TCR complex (TCR, CD3 and ζ protein)
∙ Small population of mature T cells express TCR composed of γ and δ polypeptide chains
∙ γδ TCR – recognizes peptides, lipids, and small molecules, w/o a requirement for display by MHC proteins
o γδ T cells – aggregate at epithelial surfaces (skin and mucosa of GIT and
urogenital tracts); these cells are sentinels that protect against microbes that try to enter the epithelia
∙ Another small subset of T cells expresses markers that are also found on NK cells 🡪
called NK-T cells
o NK-T cells – express a very limited diversity of TCRs; recognize
glycolipids displayed by MHC like molecule CD1
∙ T cell express several other proteins that assist the TCR complex in functional responses: CD4, CD8,
CD28
o CD4 and CD8 – expressed on subsets of αβ T cells;
▪ Serve as coreceptors in T-cell activation; recognize part of the same ligand
▪ CD4+ - 60% of mature T cells
▪ CD8+ - 30%
∙ CD4+ T cells – function as cytokine-secreting helper cells that assist macrophages and B cells to combat
infections
o Recognize and respond to antigen displayed only by class II MHC
∙ CD8+ T cells – functions as cytotoxic (killer) T lymphocytes (CTLs) to destroy host cells harbouring
microbes
o Recognize cell-bound antigens only in association with class I MHC molecule
∙ CD4 or CD8 coreceptors initiates signals needed for activation of T cells
∙ Integrins – adhesion molecules that promote the attachment of T-cells to APCs
∙ T cells have to recognize antigen-MHC complexes and signals provided by APC 🡪
CD28
B Lymphocytes
• B lymphocytes are the only cells in the body capable of producing antibody molecules, the
mediators of humoral immunity

• B lymphocytes develop from bone marrow

• Mature B cells – 10-20% of the circulating peripheral lymphocyte
• Also present in peripheral lymphoid tissues such as lymph nodes, spleen, and MALT
• B cells recognize antigen via the B-cell antigen receptor complex
• Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of
• all mature, naive B cells, are the antigen-binding component of the B-cell receptor complex
• After stimulation by Ag and other signals, B cells develop into plasma cells (factories for
antibodies)

• Plasmablasts – antibody-secreting cells detected in human peripheral blood

• B-antigen receptor complex also contains a heterodimer of two invariant proteins called Igα and Igβ
(essential for signal transduction)
• Igα (CD&(a)
• Igβ (CD79Bb)

• B cell also express type 2 complement receptor (CR2, or CD21) 🡪 recognizes complement products
generated during innate immune responses to microbes

• CD40 – receives signals from helper T cells

• CR2 – also used by the EBV as a receptor to enter and infect B cells
Dendritic Cells
∙ Dendritic cells – aka interdigitating dendritic cells; the most important APC for
initiating T-cell responses against protein antigens
o Have numerous fine cytoplasmic processes that resembles dendrites
o Langerhans cells – immature dendritic cells w/in epidermis
∙ Features of dendritic cells as APC:
o (1) Located under the epithelia (common site of entry), and interstitial of all
tissues (where Ag are produced)
o (2) Express many receptors for capturing and responding to microbes, including TLRs and
lectins
o (3) They are recruited to the T-cell zones of lymphoid organs where they function as APC
o (4) They express high levels of MHC and other molecules needed for presenting Ag to
and activating T cells
∙ Follicular dendritic cells– second type of cell w/ dendritic morphology; present in the
germinal centers of lymphoid follicles in spleen and lymph nodes
o Bear Fc receptors for IgG and receptors for C3b
o Can trap antigen bound to antibodies or complement proteins
o Play a rle in humoral immune responses by presenting antigens to B cells
and selecting the B cells that have the highest affinity for the antigen, thus improving the
quality of the antibody produced
Macrophages

∙ Part of the mononuclear phagocyte system

∙ Important functions in the induction and effector phases of adaptive immune
response:
✔ Macrophages that have phagocytosed microbes and protein Ags process the Ags and
present peptide fragments to T cells. Thus, macrophage function as APC in T-cell
activation
✔ Macrophages are key effector cells in certain forms of cell-mediated immunity, the
reaction that serves to eliminate intracellular microbes. In this response, T cells
activate macrophages and enhance their ability to kill ingested microbes
✔ Macrophages participate in the effector phase of humoral immunity. They
phagocytose, and destroy microbes that are opsonized
Natural Killer Cells
∙ The function of NK cells is to destroy irreversibly stressed and abnormal cells, such as virus-infected
cells and tumor cells
∙ 5-10% of peripheral blood lymphocytes
∙ They do not express TCRs or Ig
∙ Larger than lymphocytes and contain abundant azurophilic granules
∙ Have the ability to kill virus-infected cells and tumor cells w/o prior exposure to or activation by these microbes
or tumors
o Early line of defense against viral infections and tumors
∙ CD16 and CD56 – commonly used to identify NK cells
∙ CD16 – is an Fc receptor for IgG; confers on NK cells the ability to lyse IgG-coated target cells 🡪 called
antibody-dependent cell-mediated toxicity (ADCC)
∙ The functional activity of NK cells is regulated by a balance between signals from
activating and inhibitory receptors
∙ NKG2D family – activating receptor; recognize surface molecules induced by various kinds of stress (e.g., infection,
DNA damage)
∙ NK cell inhibitory receptors recognize self class I MHC molecules (in healthy cells)
o Prevent NK cells from killing normal cells
∙ Infection or neoplasm 🡪 enhance expression of activating receptors and reduces
expression of class I MHC molecules 🡪 balance is tilted toward activation and infected or tumor cell is killed
∙ NK cells also secrete cytokines:
o IFN-y – activates macrophages to destroy ingested microbes; thus NK cells provide early defense against
intracellular microbial infections
∙ NK cells activity is regulated by many cytokines:
o IL-2 & IL-5 – stimulate proliferation if NK cells
o IL-12 - activates killing and secretion of IFN-y
Cellular receptors for microbes and
products of cell injury. 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. Major
classes of innate immune receptors are
TLRs, NOD-like receptors (NLRs) in the
cytosol, C-type lectin receptors (CLRs),
RIG-like receptors (RLRs) for viral
nucleic acids, and cytosolic receptors
for DNA (not shown). RIG, retinoic
acid-inducible gene.
Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Microbes

∙ Naive T lymphocytes are activated by Ag and costimualtors in peripheral lymphoid organs and proliferate and
differentiate into effector cells that migrate to site of antigens
∙ Secretion of IL-2 – earliest responses of CD4+ cells and expression of high-affinity receptors for IL-2
∙ IL-2 – growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to increase in
number of antigen-specific lymphocytes
∙ Functions of helper T cells are mediated by the combined actions of CD40L and
cytokines
o When CD4+ helper T cells recognize antigens displayed by macrophage or B cells, the T cells express CD40L w/c
engages CD40 on macrophages or B cells and activates these cells
∙ Some of the activated CD4+ cells differentiate into effector cells that secrete different sets of cytokines and perform
different functions
∙ IFN-y – potent macrophage activator secreted by TH1
o Combination of CD40- and IFN-y mediated activation results in “classical macrophage activation “ 🡪 lead to
destruction of ingested microbes
∙ TH2 produces:
o IL-4 – stimulates B cells to differentiate into Ig-E secreting plasma cells
o IL-5 – activates eosinophils
∙ Eosinophils and mast cells bind to IgE-coated microbes (helminthic parasites) and eliminate
∙ TH2 also induce “alternative pathway” of macrophage activation 🡪 asso.w/ tissue repair and fibrosis
∙ TH17 cells – releases IL-17 w/c recruit neutrophils and monocytes and destroy
extracellular bacteria and fungi, also involved in inflammatory diseases
∙ Activated CD8+ T lymphocytes differentiate into CTLs 🡪 kills microbes in cytoplasm
o CTLs eliminate the reservoirs of infection
The inflammasome.
The inflammasome is a protein
complex that recognizes products
of dead cells and some microbes
and induces the secretion of
biologically active interleukin 1. The
inflammasome consists of a sensor
protein (an example is the
leucine-rich protein NLRP3), an
adapter, and the enzyme
caspase-1, which is converted from
an inactive to an active
form. ATP, Adenosine
triphosphate; IL, interleukin; TLR, T
oll-like receptor.
The principal classes
of lymphocytes and
their functions. B and
T lymphocytes are
the cells of adaptive
immunity. Several
other classes of
lymphocytes have
been identified,
including NK-T cells
and so-called innate
lymphoid cells
(ILCs); the functions
of these cells are not
as well established
as those of B and T
lymphocytes. NK
cells are discussed
earlier.
The T-cell receptor (TCR) complex and
other molecules involved in T-cell
activation. The TCR heterodimer, consisting
of an α and a β chain, recognizes antigen
(in the form of peptide-MHC complexes
expressed on antigen-presenting cells, or
APCs), and the linked CD3 complex and ζ
chains initiate activating signals. CD4 and
CD28 are also involved in T-cell activation.
(Note that some T cells express CD8 and
not CD4; these molecules serve analogous
roles.) The sizes of the molecules are not
drawn to scale. MHC, Major
histocompatibility complex.
Structure of antibodies and the B-cell antigen
receptor. (A) The B-cell antigen receptor complex
is composed of membrane immunoglobulin M
( IgM; or IgD, not shown ), which recognizes
antigens, and the associated signaling proteins Igα
and Igβ. CD21 is a receptor for a complement
component that also promotes B-cell activation.
(B) Crystal structure of a secreted IgG molecule,
showing the arrangement of the variable (V) and
constant (C) regions of the heavy (H) and
light (L) chains.
Morphology of a lymph node.
(A) The histology of a lymph node, with an outer
cortex containing follicles and an inner medulla. (B)
The segregation of B cells and T cells in different
regions of the lymph node, illustrated schematically.
(C) The location of B cells ( stained green, using the
immunofluorescence technique) and T cells (stained
red) in a lymph node.
Major Histocompability
Complex Molecules,
Cytokines, Overview of
Lymphocyte Activation and
Immune Responses
Major Histocompability Complex
• The function → to display peptide fragments of protein antigens for
recognition by antigen- specific T cells.
• In humans → human leukocyte antigens (HLA). The genes encoding HLA
molecules are clustered on a small segment of chromosome 6

• Highly polymorphic
Class I MHC
• All nucleated cells and platelets.
• Heterodimers
• polymorphic α, or heavy, chain (44-kD)
• Nonpolymorphic, noncovalently, smaller
(12-kD) protein β2-microglobulin.
• The α chains are encoded by three genes:
HLA-A, HLA-B, and HLA-C, that lie close to
one another in the MHC locus
• Class I MHC molecules display peptides that
are derived from cytoplasmic proteins →
normal proteins and virus and tumor-specific
antigens, which are all recognized bound to
class I MHC molecules by CD8+ T cells.
 TCR recognizes the MHC-peptide complex
CD8 molecule ( coreceptor) binds to the class
I heavy chain / α3 domain

Cytoplasmic proteins degraded

in proteasomes

peptides transported into the (ER)

Peptides bind to newly synthesized class I molecules

Class II MHC molecules
• Encoded in a region called HLA-D →
three subregions: HLA-DP, HLA-DQ, and
HLA-DR.
• Heterodimer
• Polymorphic, a noncovalently associated α
chain and β chain.
• Class II MHC molecules present
antigens derived from extracellular
microbes and proteins following their
internalization into endosomes or
lysosomes.
• Mainly expressed on cells that present
ingested antigens to T-cell helper
(macrophages, B lymphocytes, and
DCs).
 class II-peptide complex is
Proteins are proteolytically digested, Peptides associate with class II
recognized by CD4+ T cells (β2
producing peptides heterodimers in the vesicles
domain)
Cytokines
• Leukocytes are stimulated and regulated by secreted proteins →
cytokines.
• Cytokines → called interleukins because they mediate communications
between leukocytes and cells other than leukocytes
• Cell communication → signaling molecule
• Autocrine: act on the cells that produce them
• Paracrine: on neighboring cells
• Endocrine: and at a distance (rarely).
Cytokines in immune responses
● Cytokines are produced rapidly after encounter with microbes and other
Innate Immunity stimuli
● Function: to induce inflammation and inhibit virus replication.
● Cytokines: TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines.
● Sources: macrophages, DCs, ILCs, and NK cells, but endothelial and
epithelial cells can also produce them.

• cytokines are produced principally by CD4+ T lymphocytes activated by antigen

Adaptive Immunity and other signals
• Function: promote lymphocyte proliferation and differentiation and to activate
effector cells.
• Cytokines: IL-2, IL-4, IL-5, IL-17, and IFN-γ
• Some cytokines serve mainly to limit and terminate immune responses; these
include TGF-β and IL-10.
Lymphocyte Activation and Immune Responses
1. Display and Recognition of Antigens
2. Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination
of Intracellular Microbes
3. Humoral Immunity: Activation of B Lymphocytes and Elimination of
Extracellular Microbes
4. Decline of Immune Responses and Immunologic Memory
Cell-Mediated Immunity
• In peripheral lymphoid organs: Naïve T
lymphocytes are activated by antigen and
costimulators → proliferate and
differentiate into effector cells
• CD4+ → IL-2 and creates an autocrine loop
→ stimulates T-cell proliferation → increase
in antigen-specific lymphocytes.
• Some activated CD4+ T cells → effector cells
• Activated CD8+ → differentiate into CTLs:
• kill cells harboring microbes in the
cytoplasm
• eliminate the reservoirs of infection
• kill tumor cells by recognizing tumor-
specific antigens.
CD4+ Effector Cells
Humoral Immunity
Decline of Immune Responses and Immunologic
Memory
• 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 resting state.
• The initial activation of lymphocytes also generates long-lived memory
cells, which may survive for many years after the infection
• Memory cells → faster response
Hypersensitivity:
Immunologically Mediated Tissue Injury
Introduction
● Injurious immune reactions, called hypersensitivity, are responsible for the pathology associated
with immunologic diseases.
● Hypersensitivity implies an excessive or harmful reaction to an antigen.
● Several important general features of hypersensitivity disorders:
○ Hypersensitivity reactions can be elicited by exogenous environmental antigens or
endogenous self antigens.
○ Hypersensitivity usually results from an imbalance between the effector mechanisms of
immune responses and the control mechanisms.
○ The development of hypersensitivity diseases is often associated with the inheritance of
particular susceptibility genes.
○ The mechanisms of tissue injury in hypersensitivity reactions are the same as the
mechanisms against infectious pathogens.
Classification of Hypersensitivity Reactions
Table 6.1 Mechanisms of Hypersensitivity Reactions
Type Immune Mechanisms Histopathologic Lesions Prototypical Disorders
Production of IgE antibody →
immediate release of vasoactive Vascular dilation, edema, smooth
Immediate (type I) Anaphylaxis; allergies; bronchial
amines and other mediators from muscle contraction, mucus
hypersensitivity asthma (atopic forms)
mast cells; later recruitment of production, tissue injury, inflammation
inflammatory cells

Production of IgG, IgM → binds to

Phagocytosis and lysis of cells;
antigen on target cell or tissue →
Antibody-mediated (type II) inflammation; in some diseases, Autoimmune hemolytic anemia;
phagocytosis or lysis of target cell by
hypersensitivity functional derangements without cell Goodpasture syndrome
activated complement or Fc
or tissue injury
receptors; recruitment of leukocytes

Deposition of antigen-antibody
complexes → complement activation
Systemic lupus erythematosus; some
Immune complex–mediated → recruitment of leukocytes by Inflammation, necrotizing vasculitis
forms of glomerulonephritis; serum
(type III) hypersensitivity complement products and Fc (fibrinoid necrosis)
sickness; Arthus reaction
receptors → release of enzymes and
other toxic molecules

Activated T lymphocytes → (1)

Perivascular cellular infiltrates;
Cell-mediated (type IV) release of cytokines, inflammation Contact dermatitis; multiple sclerosis;
edema; granuloma formation; cell
hypersensitivity and macrophage activation; (2) T type 1 diabetes; tuberculosis
destruction
cell–mediated cytotoxicity

Ig, Immunoglobulin.
Immediate (Type I) Hypersensitivity
● 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.
● Allergen 🡪 allergy.
Figure 6.13 Phases of immediate hypersensitivity reactions. (A) Kinetics of the immediate and late-phase reactions. The immediate
vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously
sensitized individual), and the late-phase reaction develops 2 to 24 hours later. The immediate reaction (B) is characterized by
vasodilation, congestion, and edema, and the late-phase reaction (C) is characterized by an inflammatory infiltrate rich in
eosinophils, neutrophils, and T cells.
Figure 6.14 Sequence of events in immediate (type I)
hypersensitivity. Immediate hypersensitivity reactions are
initiated by the introduction of an allergen, which
stimulates Th2 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 mediators that are
responsible for the pathologic manifestations of immediate
hypersensitivity.
Immediate (Type I) Hypersensitivity

Figure 6.15 Mast cell mediators. On activation, mast cells

release various classes of mediators that are responsible for
the immediate and late-phase reactions. PAF,
Platelet-activating factor.
Immediate (Type I) Hypersensitivity
● 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.
■ Major basic protein and eosinophil cationic protein 🡪 damage tissue.
■ Galectin-10 🡪 Charcot-Leyden crystals 🡪 Inflammation and enhance Th2 response.

Fig. XX Charcot-leyden crystals seen as purplish-red in the trichrome stain, x400

magnification. Available from:
https://www.medical-labs.net/charcot-leyden-crystals-2-1159/
Immediate (Type I) Hypersensitivity
● Development of allergies
○ Susceptibility to immediate hypersensitivity reaction sis genetically determined.
○ A propensity to develop immediate hypersensitivity = Atopy.
○ ↑ IgE levels and ↑ IL-4 producing Th2 cells.
○ Exposure to environmental pollutants, which is common in industrialized societies, is an
important predisposing factor for allergy.
○ Viral infections of the airways are triggers for bronchial asthma.
○ Twenty percent to 30% om type I hypersensitivity are triggered by non-antigenic stimuli
(temperature extremes and exercise) 🡪 nonatopic allergy.
○ The incidence of many allergic disease has increased in high income countries 🡪 hygiene
hypothesis.
Table 6.2 Examples of Disorders Caused by Immediate Hypersensitivity
Clinical Syndrome Clinical and Pathologic Manifestations
Fall in blood pressure (shock) caused by
Anaphylaxis (may be caused by drugs, bee
vascular dilation; airway obstruction due to
sting, food)
laryngeal edema
Airway obstruction caused by bronchial smooth
Bronchial asthma muscle hyperactivity; inflammation and tissue
injury caused by late-phase reaction
Increased mucus secretion; inflammation of
Allergic rhinitis, sinusitis (hay fever)
upper airways, sinuses
Increased peristalsis due to contraction of
Food allergies
intestinal muscles
Immediate (Type I) Hypersensitivity
● Systemic Anaphylaxis
○ Characterized by vascular shock,
widespread edema, and difficulty in
breathing.
○ Extremely small doses of antigen may
trigger anaphylaxis.

Fig. XX Signs and symptoms of anaphylaxis. Available

from: https://www.physio-pedia.com/Anaphylaxis
Antibody-Mediated (Type II) Hypersensitivity
● Antibodies that react with antigens present on cell surfaces or in the ECM cause disease by
destroying these cells, triggering inflammation, or interfering with normal functions.
Figure 6.16Mechanisms 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.
Table 6.3 Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Disease Target Antigen Mechanisms of Disease Clinicopathologic Manifestations
Red cell membrane proteins (Rh Opsonization and phagocytosis of
Autoimmune hemolytic anemia Hemolysis, anemia
blood group antigens, I antigen) red cells
Autoimmune thrombocytopenic Platelet membrane proteins Opsonization and phagocytosis of
Bleeding
purpura (Gpllb:Illa integrin) platelets
Antibody-mediated activation of
Proteins in intercellular junctions
Pemphigus vulgaris proteases, disruption of Skin vesicles (bullae)
of epidermal cells (desmogleins)
intercellular adhesions
Neutrophil granule proteins,
Neutrophil degranulation and
Vasculitis caused by ANCA presumably released from Vasculitis
inflammation
activated neutrophils
Noncollagenous protein in
Complement- and Fc
Goodpasture syndrome basement membranes of kidney Nephritis, lung hemorrhage
receptor–mediated inflammation
glomeruli and lung alveoli
Streptococcal cell wall antigen;
Inflammation, macrophage
Acute rheumatic fever antibody cross-reacts with Myocarditis, arthritis
activation
myocardial antigen
Antibody inhibits acetylcholine
Myasthenia gravis Acetylcholine receptor binding, down-modulates Muscle weakness, paralysis
receptors
Antibody-mediated stimulation of
Graves disease (hyperthyroidism) TSH receptor Hyperthyroidism
TSH receptors
Neutralization of intrinsic factor,
Intrinsic factor of gastric parietal
Pernicious anemia decreased absorption of vitamin B Abnormal erythropoiesis, anemia
cells
12
ANCA, Antineutrophil cytoplasmic antibodies; TSH, thyroid-stimulating hormone.
Immune Complex-Mediated (Type III)
Hypersensitivity
● Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites
of deposition.
Table 6.4 Examples of Immune Complex–Mediated Diseases
Disease Antigen Involved Clinicopathologic Manifestations
Nephritis, skin lesions, arthritis,
Systemic lupus erythematosus Nuclear antigens
others
Streptococcal cell wall antigen(s);
Poststreptococcal glomerulonephritis may be “planted” in glomerular Nephritis
basement membrane
Hepatitis B virus antigens in some
Polyarteritis nodosa Systemic vasculitis
cases
Reactive arthritis Bacterial antigens (e.g., Yersinia ) Acute arthritis
Various proteins, e.g., foreign serum
Serum sickness protein (horse antithymocyte Arthritis, vasculitis, nephritis
globulin)
Arthus reaction (experimental) Various foreign proteins Cutaneous vasculitis
 Immune Complex-Mediated (Type III)
Hypersensitivity

complex

Figure 6.17 Immune complex disease. The sequential phases in the induction of systemic immune complex–mediated diseases (type III
hypersensitivity).
Immune Complex-Mediated (Type III)
Hypersensitivity
● Local Immune Complex Disease
○ Arthus reaction
■ A localized area of tissue necrosis resulting from acute immune complex vasculitis,
usually elicited in the skin.
■ Intracutaneous injection of antigen in a previously immunized animal that contains
circulating antibodies against the antigen.
Immune Complex-Mediated (Type III)
Hypersensitivity

Fig. XX Arthus reaction following split-dose injection for influenza

vaccine. Available from: Mendez P, Quinonez S, Hajirawala M. A Case
Series of Arthus Reactions Seen in Pediatric Patients Receiving Influenza
and Pneumococcal Vaccines. Ann Allergy Asthma Immunol. 2024
Nov;133(6):S126–7.
T Cell-Mediated (Type IV) Hypersensitivity
• Cell-mediated hypersensitivity
is caused mainly by
inflammation resulting from
cytokines produced by CD4+ T
cells.
• Cell killing by CD8+ cells may
also be involved in some
autoimmune diseases.
Figure 6.18 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. CD4+ Th17 cells contribute to
inflammation by recruiting neutrophils (and, to a
lesser extent, monocytes). (B) In some diseases,
CD8+ cytotoxic T lymphocytes directly kill tissue
cells. APC, Antigen-presenting cell.
Table 6.5 T Cell–Mediated Diseases
Principal Mechanisms of Tissue
Disease Specificity of Pathogenic T Cells Clinicopathologic Manifestations
Injury
Inflammation mediated by Th17
Chronic arthritis with
•Collagen? (and Th1?) cytokines; role of
Rheumatoid arthritis inflammation, destruction of
•Citrullinated self proteins? antibodies and immune
articular cartilage
complexes?

Inflammation mediated by Th1 and Demyelination in CNS with

Protein antigens in myelin (e.g.,
Multiple sclerosis Th17 cytokines, myelin destruction inflammation; paralysis, optic
myelin basic protein)
by activated macrophages neuritis

Antigens of pancreatic islet β cells Insulitis (chronic inflammation in

T-cell–mediated inflammation,
Type 1 diabetes (insulin, glutamic acid islets), destruction of β cells;
destruction of islet cells by CTLs
decarboxylase, others) diabetes

Inflammatory bowel Inflammation mediated by Th1 and Chronic intestinal inflammation,

Enteric bacteria; self antigens?
disease Th17 cytokines obstruction
Inflammation mediated mainly by
Psoriasis Unknown Destructive plaques in the skin
Th17 cytokines
Various environmental chemicals Epidermal necrosis, dermal
Inflammation mediated by Th1
Contact sensitivity (e.g., urushiol from poison ivy or inflammation, causing skin rash
(and Th17?) cytokines
poison oak) and blisters
Examples of human T cell–mediated diseases are listed. In many cases, the specificity of the T cells and the mechanisms of tissue injury are
inferred based on the similarity with experimental animal models of the diseases. CTLs, Cytotoxic T lymphocytes.
T Cell-Mediated (Type IV) Hypersensitivity
● Clinical examples of CD4+ T cell-mediated inflammatory reactions
○ Tuberculin reactions
■ Reddening and induration 8 to 12 hours
■ Peak in 24 to 72 hours
■ Perivascular “cuffing”
Figure 6.19 Delayed type hypersensitivity
reaction in the skin. (A) Perivascular
accumulation (“cuffing”) of mononuclear
inflammatory cells (lymphocytes and
macrophages), with associated dermal
edema and fibrin deposition. (B)
Immunoperoxidase staining reveals a
predominantly perivascular cellular
infiltrate that marks positively with
anti-CD4 antibodies.
Figure 6.20Granulomatous inflammation. A section of a lymph node shows several granulomas, each made
up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows
several multinucleate giant cells.
T Cell-Mediated (Type IV) Hypersensitivity
● Contact dermatitis
○ Urushiol (poison ivy or poison oak).
○ Itchy, vesicular dermatitis.
○ Environmental chemical binds to and structurally modifies self proteins 🡪 recognized by T
cells and elicit the reaction.
○ May also modify HLA molecules.
T Cell-Mediated (Type IV) Hypersensitivity
● CD8+ T Cell-mediated Cytotoxicity
○ CD8+ CTLs kill antigen-expressing target cells
■ Diabetes mellitus type 1
■ Host vs. graft rejection
■ Viral hepatitis
○ Principal mechanisms: Perforins and granzymes in the lysosome-like granules of CTLs.
Autoimmune Disease
• 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
(3) the absence of another well-defined cause of the disease.
•The immune responses are
directed against a single organ
or tissue 🡪 organ-specific
disease
the other end are diseases in
which the autoimmune
reactions are against
widespread antigens 🡪
systemic disease.

Autoimmune
Disease
Immunologic
Tolerance
• Immunologic
tolerance is the
phenomenon of
unresponsiveness
to an antigen
induced by
exposure of
lymphocytes to that
antigen
Central Tolerance
• immature self-reactive T and B lymphocyte clones that
recognize self antigens during their maturation in the central
(primary, or generative) lymphoid organs (the thymus for T
cells and the bone marrow for B cells) are killed or rendered
harmless. In developing lymphocytes, random somatic antigen
receptor gene rearrangements generate diverse antigen
receptors, many of which by chance may have high affinity for
self antigens. The mechanisms of central tolerance eliminate
these potentially dangerous lymphocytes.
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
• Suppression by regulatory T cells
• Deletion by apoptosis
Mechanisms of Autoimmunity: General
Principles
• Autoimmunity arises from a combination of the inheritance
of susceptibility genes, which may contribute to the
breakdown of self-tolerance, and environmental triggers,
such as infections and tissue damage, which promote the
activation of self-reactive lymphocytes.
• Although much remains unknown about the enigma of
autoimmunity, the following abnormalities appear to contribute to its
development:
• Defective tolerance or regulation
• Abnormal display of self antigens
• Inflammation or an initial innate immune response
Phatogenesis of
autoimmunity
• Autoimmunity results
result 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.
Role of Susceptibility
Genes
• Most autoimmune diseases
are complex multigenic
disorders.
• Association of HLA Alleles With
Disease 🡪 the greatest contribution.
• Association of Non-MHC Genes
With Autoimmune Diseases.
Role of Infections
and Other
Environmental
Factors
Systemic Lupus
Erythematosus
(SLE)
• an autoimmune disease
involving multiple organs,
characterized by a vast array
of autoantibodies,
particularly antinuclear
antibodies (ANAs), in which
injury is caused mainly by
deposition of immune
complexes and binding of
antibodies to various cells
and tissues.
Spectrum of Autoantibodies in Systemic Lupus
Erythematosus
• The hallmark of SLE is the production of autoantibodies, several of which
(antibodies to double-stranded DNA and the so-called Smith [Sm] antigen) are
virtually diagnostic.
• ANAs. These are directed against nuclear antigens and can be grouped
into four categories based on their specificity for:
(1) DNA
(2) histones
(3) nonhistone proteins bound to RNA
(4) nucleolar antigens.
Pathogenesis
• The fundamental defect in SLE is a failure of the
mechanisms that maintain self-tolerance. Although what
causes this failure of self-tolerance remains unknown, as is true
of most autoimmune diseases, both genetic and environmental
factors play a role.
Genetic Factors
SLE is a genetically complex disease with contributions from MHC and multiple
non-MHC genes. Many lines of evidence support a genetic predisposition.
• Family members of patients have an increased risk of developing SLE.
• There is a higher rate of concordance (>20%) in monozygotic twins when compared
with dizygotic twins (1% to 3%).
• Studies of HLA associations support the concept that MHC genes regulate
production of particular autoantibodies.
• Some lupus patients have inherited deficiencies of early complement components,
such as C2, C4, or C1q. Lack of complement may impair removal of circulating
immune complexes by the mononuclear phagocyte system, thus favoring tissue
deposition. Knockout mice lacking C4 or certain complement receptors are also
prone to develop lupus-like autoimmunity.
• Genome-wide association studies have identified several genetic loci that may be
associated with the disease.
Immunologic Factors
• Recent studies in animal models and patients have revealed several immunologic
aberrations that collectively may result in the persistence and uncontrolled
activation of self-reactive lymphocytes.
• Failure of self-tolerance in B cells results from defective elimination of
self-reactive B cells in the bone marrow or defects in peripheral tolerance
mechanisms.
• Activation of CD4+ helper T cells specific for nucleosomal antigens that escape
tolerance and help B cells to produce high-affinity pathogenic autoantibodies.
• TLR engagement by nuclear DNA and RNA contained in immune complexes may
activate B lymphocytes.
• Type I interferons play a role in lymphocyte activation in SLE. High levels of
circulating type I interferons and a molecular signature in blood cells suggesting
exposure to these cytokines has been reported in SLE patients and correlates with
disease severity.
Environmental Factors
• Exposure to ultraviolet (UV) light. UV irradiation may induce
apoptosis in cells and may alter the DNA in such a way that its
recognition by TLRs is enhanced.
• The gender bias of SLE is partly attributable to actions of sex
hormones and partly related to unknown genes on the X
chromosome, independent of hormone effects.
• Drugs such as hydralazine, procainamide, and d -penicillamine
can induce an SLE-like response in humans.
Model for patogenesis of
systematic lupus
erythematosus.
The morphologic changes in SLE are
extremely variable
* Up to 50% of SLE patients have clinically
significant renal involvement mainly in the form
of glomerulonephritis and tubulointerstitial
nephritis

* Characteristic erythema affects the face along

the bridge of the nose and cheeks (the “butterfly”
rash) in approximately 50% of patients, and a
similar rash may be seen on the extremities and
trunk. Urticaria, bullae, maculopapular lesions,
and ulcerations also occur.

* Joints. Joint involvement is typically a

nonerosive synovitis with little deformity, which
contrasts with rheumatoid arthritis.
• CNS. No clear morphologic abnormalities
account for the neuropsychiatric symptoms of
SLE.
• Pericarditis and Other Serosal
Cavity. Inflammation of the serosal lining
membranes may be acute, subacute, or
chronic. During the acute phases, the
mesothelial surfaces are sometimes covered
with fibrinous exudate. Later they become
thickened, opaque, and coated with a shaggy
fibrous tissue that may lead to partial or total
obliteration of the serosal cavity. Pleural and
pericardial effusions may be present.

• Cardiovascular System. Involvement may

manifest as damage to any layer of the heart.
Symptomatic or asymptomatic pericardial
involvement is present in up to 50% of
patients.
Clinical Features
• SLE is a multisystem disease that is highly variable in its presentation, and
its diagnosis relies on a constellation of clinical, serologic, and morphologic
changes.
• Chronic Discoid Lupus Erythematosus 🡪 skin manifestations, but systemic
manifestations are rare.
• Subacute Cutaneous Lupus Erythematosus 🡪 Firstly, the skin rash tends
to be widespread, superficial, and nonscarring (though exceptions occur).
Secondly, most patients have mild systemic symptoms consistent with
SLE.
• Drug-Induced Lupus Erythematosus 🡪 hydralazine, procainamide,
isoniazid, and D-penicillamine.
Rheumatoid Arthritis
• Chronic inflammatory disease that primarily affects the joints,
but may also involve extraarticular tissues such as the skin,
blood vessels, lungs, and heart. Abundant evidence supports the
autoimmune nature of the disease.
Sjögren Syndrome
• Chronic disease characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from immunologically
mediated destruction of the lacrimal and salivary
glands.
Pathogenesis
• The characteristic decrease in tears and saliva (sicca syndrome) is the result
of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands.
The infiltrate contains predominantly activated CD4+ helper T cells and
some B cells, including plasma cells.
• 75% of patients have rheumatoid factor (an antibody reactive with self IgG)
whether or not coexisting rheumatoid arthritis is present. ANAs are
detected in 50% to 80% of patients by immunofluorescence assay. A host of
other organ-specific and non–organ-specific antibodies have also been
identified. Most important, however, are antibodies directed against two
ribonucleoprotein antigens, SS-A (Ro) and SS-B (La), which can be
detected in as many as 90% of patients by sensitive techniques. These
antibodies are thus considered serologic markers of the disease. These
autoantibodies are also present in a smaller percentage of patients with SLE
and hence are not entirely specific for Sjögren syndrome.
 (A) Enlargement of yhe salivary gland. (B) Intense
Sjogren syndrome lymphocytic and plasma cell infiltration with ductal
hyperplasia in salivary gland.
Clinical Features
• Sjögren syndrome occurs most commonly in women between 50 and 60
years of age.
• Symptoms result from inflammatory destruction of the exocrine glands.
The keratoconjunctivitis produces blurring of vision, burning, and itching,
and thick secretions accumulate in the conjunctival sac. The xerostomia
results in difficulty in swallowing solid foods, a decrease in the ability to
taste, cracks and fissures in the mouth, and dryness of the buccal mucosa.
Parotid gland enlargement is present in one-half of patients; dryness of the
nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis are other
symptoms. Manifestations of extraglandular disease are seen in one-third
of patients and include synovitis, diffuse pulmonary fibrosis, and peripheral
neuropathy. These are more common in patients with high titers of
antibodies specific for SS-A. In contrast to SLE, glomerular lesions are
extremely rare in Sjögren syndrome. Defects of tubular function, however,
including renal tubular acidosis, uricosuria, and phosphaturia, are often
seen and are associated with tubulointerstitial nephritis.
Systemic Sclerosis
Systemic Sclerosis (Scleroderma)

▪ Characterized by:
1. Chronic inflammation.
2. Damage to small blood vessels.
3. Progressive interstitial and perivascular.

▪ Classifying the disease into two major categories:

1. Diffuse scleroderma.
2. Limited scleroderma.
Pathogenesis
Skin
Alimentary Tract: The alimentary tract is affected in
approximately 90% of patients.
Musculoskeletal System: Inflammation of the synovium,
associated with synovial hypertrophy and hyperplasia, is
common in the early stages; fibrosis later ensues.
Kidneys: Renal abnormalities occur in two-thirds of patients
with systemic sclerosis, most prominently vascular lesions.
Lungs: Pulmonary involvement is seen in more than 50% of
individuals with systemic sclerosis and may manifest as
interstitial fibrosis and pulmonary hypertension.
Heart: Pericarditis with effusion, myocardial fibrosis, and
thickening of intramyocardial arterioles occur in one-third of
patients.
Clinical Features

▪ Systemic sclerosis has a female-to-male ratio of 3 : 1

▪ Cutaneous: edema followed by fibrosis of the skin (chiefly extremities,
face, trunk); telangiectasis; calcinosis; Raynaud’s phenomenon
▪ Arthralgias and/or arthritis
▪ GI: esophageal hypomotility; intestinal hypofunction, gastric antral
vascular ectasia (GAVE)
▪ Pulmonary: interstitial lung disease, pulmonary arterial hypertension,
alveolitis
▪ Cardiac: pericarditis, cardiomyopathy, conduction abnormalities
▪ Renal: hypertension; renal crisis/failure
Inflammatory Myopathies: Uncommon.

Mixed Connective Tissue Disease: The disease is characterized

serologically by high titers of antibodies to U1 ribonucleoprotein.

Polyarteritis Nodosa and Other Vasculitides: Belongs to a

group of diseases characterized by necrotizing inflammation of the walls of
blood vessels and showing strong evidence of an immunologic pathogenic
mechanism.
IgG4-Related Disease: IgG4-RD.
Rejection of Tissue Transplants

Mechanisms of Recognition and Rejection of Allografts

🡪 Rejection is a process in which T lymphocytes and antibodies produced

against graft antigens react against and destroy tissue grafts.

🡪 Grafts between individuals of the same species are called allografts, and
grafts from one species to another are called xenografts.
Recognition of Graft Alloantigens by T and B
Lymphocytes

✔ The major antigenic differences between a donor and recipient that

result in rejection of transplants are differences in HLA alleles.

✔ HLA genes >>> highly polymorphic, there are always some differences
between individuals.
✔ The graft antigens >>> T cells by graft APCs, or the graft antigens are picked up by
host APCs, processed, and presented to host T cells.

✔ These are called the direct and indirect pathways of recognition of alloantigens.

✔ Activation of CD8+ T cells >>> CTLs, and CD4+ T cells 🡪 cytokine-producing

effector cells, mainly Th1 cells.

✔ The direct pathway >>> acute rejection and the indirect pathway >>> chronic
rejection.
Patterns and Mechanisms of Graft Rejection

✔ Graft rejection >>> hyperacute, acute, and chronic, on the basis of

clinical and pathologic features.
✔ Hyperacute rejection >>> preformed antibodies specific for antigens
on graft endothelial cells.
✔ Acute rejection >>> T cells and antibodies that are activated by
alloantigens in the graft.
✔ Chronic rejection >>> indolent form of graft damage that occurs over
months or years, leading to progressive loss of graft function.
Methods of Increasing Graft Survival

• The value of HLA matching between donor and recipient.

• Immunosuppressive therapy >>> steroids (which reduce

inflammation), mycophenolate mofetil (which inhibits lymphocyte
proliferation), and tacrolimus (FK506).
Transplantation of Hematopoietic Stem Cells
(HSCs)
• Use of HSC transplants to treat hematologic malignancies, bone
marrow failure syndromes, and inherited bone marrow disorders ↑
each year.

• Two problems >>> graft-versus-host disease (GVHD) and

immunodeficiency.
• Immunodeficiency is a frequent complication.

• The immunodeficiency >>> myeloablation prior to HSC

transplantation, a delay in the repopulation of the recipient’s immune
system, and an attack on the host’s immune cells by grafted
lymphocytes.

• Infection cytomegalovirus is particularly important 🡪 pneumonitis

can be a fatal complication.
IMMUNODEFICIENCY
DISEASES
 Primary (congenital) Secondary (acquired)
Immunodeficiencies Immunodeficiencies
• Genetic (inherited) • Complication of cancer,
defects that affect the diabetes and other
defense mechanisms of metabolic diseases,
innate immunity malnutrition, chronic
(phagocytes, NK cells, infection, and in persons
or complement) receiving chemotherapy
• The humoral and/or or radiation therapy for
cellular arms of cancer
adaptive immunity • Immunosuppressive
(mediated by B and T drugs to prevent graft
lymphocytes, rejection or to treat
respectively). autoimmune diseases
 Defects in Innate Immunity

Primary Defects in Adaptive

Immunodeficiencies Immunity

Immunodeficiencies
Associated With Systemic
Diseases
 Defects in Innate
Immunity

Deficiencies
Defects in Affecting the
Leukocyte Function Complement
System
 Severe Combined Immunodeficiency

X-Linked Agammaglobulinemia (Bruton

Agammaglobulinemia)

DiGeorge Syndrome (Thymic Hypoplasia)

Other Defects in Lymphocyte Maturation

Defects in Adaptive Hyper-IgM Syndrome

Immunity
Common Variable Immunodeficiency

Isolated IgA Deficiency

X-Linked Lymphoproliferative Disease

Other Defects in Lymphocyte Activation

Severe Combined Immunodeficiency
(SCID)

• a constellation of genetically distinct

syndromes, all having in common
defects in both humoral and
cell-mediated immune responses.

• X-linked SCID 🡪 the most common

form, accounting for 50% to 60% of
cases, is X-linked, and hence SCID is
more common in boys than in girls.
 Immunodeficiencies Associated With Systemic
Diseases

Wiskott-Aldrich Syndrome Ataxia Telangiectasia

An X-linked disease characterized by An autosomal-recessive disorder characterized by

thrombocytopenia, eczema, and a abnormal gait (ataxia), vascular malformations
marked vulnerability to recurrent (telangiectases), neurologic deficits, increased
infection, resulting in early death. incidence of tumors, and immunodeficiency.
Secondary Immunodeficiencies

caused by:
- defective lymphocyte maturation (when the bone marrow is
damaged by radiation or chemotherapy or involved by
tumors, such as leukemias)
- inadequate Ig synthesis (as in malnutrition)
- lymphocyte depletion (from drugs or severe infections)
- the most serious secondary immunodeficiency is AIDS
Secondary Immunodeficiencies
Acquired Immunodeficiency
Syndrome (AIDS)

AIDS is caused by the retrovirus

human immunodeficiency virus
(HIV) and is characterized by
profound immunosuppression that
leads to opportunistic infections,
secondary neoplasms, and
neurologic manifestations.
 Men who have sex with
men

Heterosexual
transmission

Intravenous drug
users

HIV infection of
Epidemiology the newborn

Patients with
hemophilia

Recipients of blood and

blood components

In approximately 5% of cases, the risk

factors cannot be determined.
 Major routes of
transmission

Sexual Parenteral Mother-to-infan

transmission transmission t transmission
 Etiology: the Properties of HIV

HIV is a nontransforming human retrovirus belonging to the lentivirus family.

Structure of HIV
The virus core contains
(1) the major capsid protein p24
(2) nucleocapsid protein p7/p9
(3) two copies
of viral genomic RNA
(4) the three viral enzymes
(protease, reverse
transcriptase, and integrase).
The HIV-1 RNA genome contains the gag, pol, and
env genes, which are typical of retroviruses
 Pathogenesis of HIV Infection and AIDS

• Although HIV can infect many tissues, the major target of HIV infection is the immune system. The
central nervous system (CNS) is also affected.
• Profound immune deficiency, primarily affecting cell mediated immunity, is the hallmark of AIDS.

Active viral replication

HIV enters the body The infection becomes
is associated with more
through mucosal established in lymphoid
infection of cells and
tissues and blood tissues
progression to AIDS

• First infects T cells as well as • Where the virus may remain

DCs and macrophages. latent for long periods.
Life cycle of HIV
Central Nervous System
Involvement

• The clinical syndrome of CNS

abnormalities is called HIV-associated
neurocognitive disorder (HAND).
• Microglia, cells in the CNS that belong
to the macrophage lineage, are the
predominant cell types in the brain
that are infected with HIV.
• HIV is carried into the brain by
infected T cells or monocytes.
Natural History of HIV Infection
Clinical Features of
AIDS
• The final phase is progression to
AIDS, characterized by a
breakdown of host defense, a
dramatic increase in viral load,
and severe, life-threatening
clinical disease.
• Clinical features of AIDS: fever,
weight loss, diarrhea,
generalized lymphadenopathy,
multiple opportunistic
infections,neurologic disease,
and, in many cases, secondary
neoplasms.
Pathogenesis of B-cell lymphomas in HIV infection.
 MORPHOLOGY

Biopsy specimens from The mantle zones that This hyperplasia of B cells
enlarged lymph nodes The follicles are enlarged surround the follicles are is the morphologic
in the early stages of and often take on attenuated, and the reflection of the
HIV infection reveal a unusual, serpiginous germinal centers impinge polyclonal B-cell
marked hyperplasia of shapes. on interfollicular T-cell activation that is seen in
B-cell follicles. areas. HIV-infected individuals.
 The germinal centers may even
With disease progression, The lymph nodes are become hyalinized. These
the frenzy of B-cell depleted of small, atrophic, “burnt-out”
proliferation subsides and lymphocytes, and the lymph nodes may harbor
gives way to a pattern of organized network of numerous opportunistic
severe lymphoid involution. FDCs is disrupted. pathogens, often within
macrophages.

Because of profound
For example,
In the empty-looking lymph immunosuppression,
mycobacteria may not
nodes and in other organs, the inflammatory responses to
evoke granuloma
presence of infectious agents infections, both in the
formation because
may not be readily apparent lymph nodes and at
CD4+ cells are
without special stains. extranodal sites, may be
deficient.
sparse or atypical.

As might be expected, lymphoid involution

is not confined to the nodes; in later
stages of AIDS, the spleen and thymus also
are converted to “wastelands” that are
virtually devoid of lymphocytes.
Amyloidosis

1 2 3
a condition associated with a These abnormal fibrils are The fibrillar deposits bind a
number of inherited and produced by the aggregation wide variety of proteoglycans
inflammatory disorders in of misfolded proteins and glycosaminoglycans🡪
which extracellular deposits deposits staining
of fibrillar proteins are characteristics that were
responsible for tissue damage thought to resemble starch
and functional compromise. (amylose) 🡪 called amyloid
Three most common amyloid:
• Amyloid light chain (AL) protein: associated with certain
plasma cell tumors
• Amyloid-associated (AA) protein : made in liver associated
with chronic inflammation
• β-amyloid (Aβ) protein c : in Alzheimer diasease
Rare Amyloid: Transthyretin (TTR), β2-microglobulin, minority
of cases of prion disease in the CNS
Pathoge
nesis
and
Classifi
Cation
of
Amyloi
dosis
Morphology of amyloidosis in organs

Spleen: Splenomegaly, deposits

Kidney: Size reduction, amyloid Liver: Hepatomegaly, appear
in splenic follicles, tapioca-like
deposit in glomeruli, interstisial first on space of disse then
granules on gross inspection,
peritubular, and artery parenchymal cells and sinusoid
(sago spleen).

Heart: cardiomegaly:, deposits

begin as focal subendocardial
accumulations and myocardium Other: macroglossia, Alzheimer,
muscle fibers. Eventually causes carpal ligament depositions.
pressure atrophy of myocardial
fibers
Clinical manifestations Prognosis: AL
• Weakness, weight loss, amyloidosis have an
lightheadedness, or syncope (non overall median survival
specific)
• renal: nephrotic syndrome,
of 2 years after
progressive CKD, eventually renal diagnosis, and the
failure prognosis is even
• Heart: pericarditis, arrythmia poorer with
• Gastrointestinal: macroglossia, myeloma-associated AL
diarrhea, indigestion
• Vascular: vascular breakdown,
amyloidosis.
eventually bleeding