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1. Basic Components of the Immune System

John B. Zabriskie, M.D.

INTRODUCTION response to a given antigen, and these anti-

bodies are proteins, have similar structures,
This chapter is not a comprehensive review and can be divided into various classes of
of immunology but rather a condensed immunoglobulins. Cellular responses are
version of those aspects of immunology established by cells and can only be trans-
that have particular relevance to clinical ferred by cells. (See the Bibliography for
immunology. Refer to the Bibliography for the extraordinary beginnings of the con-
a more extensive discussion of the role of cept of a cellular arm of the immune sys-
each component. tem.) Up to the 1940s the general dogma
It is generally believed that the immune held that only antibodies were involved in
system evolved as the host’s defense against the immune response. Dr. Merrill Chase,
infectious agents, and it is well known that who began his experiments in a labora-
patients with deficiencies in the immune tory devoted primarily to the humoral
system generally succumb to these infec- response, clearly showed in a series of ele-
tious diseases. However, as we shall see, it gant experiments that immunity was not
may well play a larger role in the elimina- just humoral but that a cellular response
tion of other foreign substances, including by the lymphocytes could also produce
tumor antigens or cells and antibodies that immunity. Some of the best examples of
attack self. the power of cellular immunity may be
An immune response may be conve- found in the many experiments in which
niently divided into two parts: (1) a specific transfer of cells can induce autoimmune
response to a given antigen and (2) a more disease in animals and humans as well as
nonspecific augmentation to that response. rejection of an organ graft in both animals
An important feature of the specific and humans by cells.
response is that there is a quicker response The separation of human and cellular
to the antigen during a second exposure to immunity was further advanced by the
that antigen. It is the memory of the initial study of immunodeficient humans and
response that provides the booster effect. animals. For example, thymectomized or
For convenience, the specific immune congenitally athymic animals as well as
response may be divided into two parts: humans cannot carry out graft rejection,
(1) the humoral response and (2) the cellu- yet they are capable of producing some
lar response to a given antigen. As we shall antibody responses. The reverse is also
see, however, both responses are medi- true. Children (and animals) who have an
ated through the lymphocyte. Humoral immune deficit in the humoral response
responses are antibodies produced in do not make antibodies but can reject

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grafts and appear to handle viral, fungal, Several types of molecules play a vital
and some bacterial infections quite well. role in the immune response, and we will
An extraordinary finding by Good and deal with each in detail. Antigens, both
colleagues in studying the cloacal lym- foreign and self, are substances that may
phoid organ in chickens revealed that, or may not provoke an immune response.
with removal of the bursa Fabricius, these Both T cells and B cells have receptors that
animals lost their ability to produce anti- recognize these antigens. In the case of B
bodies and yet retained the ability to reject cells, antibodies on the surface are a major
grafts. source (but not the only one) of antigen rec-
Out of these and many other contribu- ognition, and once activated, they differen-
tions, a clearer picture of the division of tiate into plasma cells that produce large
efforts by lymphocytes begins to emerge. quantities of antibodies that are secreted
Since cellular immune responses require an into blood and body fluids to block the
intact thymus, cellular immune responses harmful effects of the antigen.
are mediated through the T lymphocytes T cells have similar receptors known
(thymus), while antibody-producing cells, as T-cell receptors (TCR), and in the con-
which are dependent on the bone mar- text of the major histocompatibility com-
row (the bursa equivalent), are known as plex (MHC) molecules provide a means of
B (bursa) cells. The pathways of both cell self-recognition and T-lymphocyte effector
types are depicted in Figure 1.1. functions. Often these effector functions

Lymphocyte Development Peripheral Effector Cells

Thymus
TH1
T
TH
Pre-T
Tc TH2
Self reactive
cells deleted
CLP
T memory
Pre-B

Bone
marrow
Plasma cell

Pre-B B
Pluripotential
stem cell
B memory

Myeloid cell
CMP

Premonocyte Monocyte
Macrophage

CLP – Cell Lymphocyte Progenitor

CMP – Cell Myeloid Progenitor

Dendritic cell

Figure 1.1 Development and differentiation of lymphocytes from pluripotential stem cells.

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are carried out by messages transmitted IgM and IgG2 antibodies and do not stimu-
between these cells. These soluble messen- late long-lasting memory cells. Most bac-
gers are called interleukins or cytokines. terial polysaccharides (found in bacterial
cell walls) fall into this category. Certain
polysaccharides, such as LPS (lipopoly-
ANTIGENS saccharide), not only induce specific B-cell
activation but also can act as a polyclonal
Antigens are any substances that are B-cell stimulant.
capable, under appropriate conditions, of
inducing the formation of antibodies and
reacting specifically with the antibodies ANTIBODY
so produced. They react with both T-cell
recognition receptors and with antibodies. The basic structure of the antibody mol-
These antigenic molecules may have sev- ecule is depicted in Figures 1.2A and B. It
eral antigenic determinants, called epitopes, consists of a four-chain structure divided
and each epitope can bind with a specific into two identical heavy (H) chains with
antibody. Thus, a single antigen can bind a molecular weight of 25 kDa. Each chain
to many different antibodies with different is composed of domains of 110 amino acids
binding sites. and is connected in a loop by a disulfide
Some low-molecular-weight mol- bond between two cysteine residues in the
ecules called haptens are unable to evoke chain.
an immune response but can react with The amino acid N-terminal domains of
existing antibodies. These molecules need the heavy and light chains include the anti-
to be coupled to a carrier molecule to be gen-binding site. The amino acids of these
antigenic. variable domains vary between different
For some molecules such as drugs, the antibody molecules and are thus known as
molecule needs to be conjugated to a car- the variable (V) regions. Most of these dif-
rier. The carrier may be a host protein. The ferences reside in the hypervariable areas of
tertiary structure of the molecule as well the molecule and are usually only six to
as the amino acid sequence is important ten amino acid residues in length. When
in determining antigenicity. Certain struc- the hypervariable regions in each chain
tures such as lipids and DNA are generally come together along with the counterparts
poor antigens. on the other pair of H and L chains, they
Most antigens are either thymus- form the antigen-binding site. This part
dependent or thymus-independent anti- of the molecule is unique to the molecule
gens. Thymus-dependent antigens require and is known as the idiotype determinant.
T-cell participation: Most proteins and In any individual, 106 to 107 different anti-
foreign red cells are examples of these body molecules can be composed from
molecules. Thymus-independent antigens 103 different heavy and light chains of the
do not require T-cell participation for anti- variable regions. The part of the molecule
body production. Instead, they directly next to the V region is called the constant
stimulate specific B lymphocytes by cross- (C) region made up of one domain in the
linking antigen receptors on the surface of light chain (C1) and three or four in a heavy
B cells. These molecules produce primarily chain (CH). A Cl chain may consist of either

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S
S

S
S S
S S

Light chain Heavy chain

Figure 1.2A Heavy and light chains of an IgG antibody. An IgM

antibody would be a pentameric structure of an IgG molecule.

two kappa (κ) or two lambda (λ) chains but tion. This activation permits the segment
never one of each. Of all the human anti- removal of antigen–antibody complement
body molecules, approximately 60%, are κ complexes via complement receptors on
chains and 40% contain λ chains. Although phagocytic cells or complement-mediated
there are no known differences in the func- lysis of the organism. However, in contrast
tional properties of κ and λ chains, there are to the IgG molecule, it has relatively low
several different types of the CH domain. affinity binding to the antigen in question.
These differences are reflected in determin- Second, because of its size, it does not usu-
ing the class (isotype) of the antibody and ally penetrate into tissues.
thereby the physiological function of a par- In contrast, IgG is a smaller molecule
ticular antibody molecule. that penetrates easily into tissues. There
The IgM molecule is the oldest class of are four major classes of IgG: IgG1 and
immunoglobulins, and it is a large mol- IgG3 activate complement efficiently and
ecule consisting of five basic units held clear most protein antigens, including the
together by a J chain. The major role IgM removal of microorganisms by phago-
plays is the intravascular neutralization of cytic cells. In contrast, IgG2 and IgG4 react
organisms, especially viruses. The reason mostly with carbohydrate antigens and are
for this important physiological role is that relatively poor opsonins. This is the only
it contains five complement-binding sites, molecule that crosses the placenta to pro-
resulting in excellent complement activa- vide immune protection to the neonate.

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Antigen-
binding antigen
site

Fab domain

Fc domain

Figure 1.2B Antigen-binding sites and antigen binding in an IgG antibody.

Hinge region allows for rotational and lateral movements of the two antigen-
binding sites.

The major mucosal immunoglobulin, important role in allergic reactions and

IgA, consists of two basic units joined by a J expelling intestinal parasites, which is
chain. The addition of a secretion molecule accomplished by increasing vascular per-
prevents its digestion by enzymes present meability and inducing chemotactive fac-
in mucosal and intestinal secretions. Thus, tors following mast cell degranulation.
IgA2 is the major IgA molecule in secretions Given this extraordinary ability to gen-
and is quite effective in neutralizing anti- erate large numbers of antibody molecules,
gens that enter via these mucosal routes. how does the immune system recognize
IgA1, the main IgA molecule in serum, is, all pathogens, including past, present,
however, susceptible to inactivation by and future? This diversity is achieved by
serum proteases and is thus less active for the way in which the genetics of antibody
defense. Its function is unclear at present. production is arranged (see Figure 1.3).
Two other classes are worthy of note. The light and heavy chains are carried on
IgD is synthesized by antigen-sensitive B different chromosomes. The heavy chain
cells and is involved in the activation of genes are carried on chromosome 14. These
these cells by antigen. IgE is produced by genes are broken up into coding systems
plasma cells and binds to specific IgE recep- called exons with intervening segments of
tors on most cells and basophiles. This mol- silent segments called entrons. The exons
ecule (see Chapter 9) plays an extremely represent the central region of the heavy

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Chromosome ‘Silent’ area = Intron

(V)n D J Cµ Cδ Cγ1 Cγ1 Cα1 Cγ2 Cγ4 Cε Cα2

14 H

VHCµ, = an lgM heavy chain with

a particular variable region
VDJCµ Final
product
(V)n J Cκ lgMκ
2 κ or
lgMλ
VJCκ

(V)n J Cλ
22 λ

VJCλ

Figure 1.3 The genetics of antibody production.

chain and a large number of V regions. in sequence while using the same variable
Between the V and D genes are two small regions (see Figure 1.4). The heavy chain
sets of exons called the D and J. With each gene recombinations are controlled by two
single B cell, one V gene is joined to one D recombination activity genes called RAG1
and J in the chromosome. The product, the and RAG2. If these genes are eliminated by
VH domain, is then joined at the level of “knock-out” techniques in mice, profound
RNA processing to Cu and the B cell makes immunodeficiency status occurs in these
an IgM molecule. By omitting the Cu gene animals, characterized by absent mature B
and joining VHDJ to a Cλ an IgG molecule is and T cells.
produced. This enormous versatility allows Thus, the diversity of antigen bind-
the cell to make IgM, IgD, IgG, IgA, or IgE ing is achieved by the large number of V

Rearranged
VDJ Region Constant Region
Mature B-cell µ δ γ3 γ1 γ2b γ2a ε α
Primary response
Functional gene
Producing lgM

Class Switching

Mature B-cell γ1 γ2b γ2a ε α

Secondary response
Functional gene
Producing lgG1

Figure 1.4 Recombination events necessary for generation of class and subclass switching.

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genes available and their combination with the cell-surface complex or at the level of
different D and L genes to provide differ- the kinases may result in various forms of
ent antibodies. Furthermore, the inherited immunodeficiency. Two other important
set of genes may be increased by somatic antigens present on TCR2 cells recognize
mutation during multiple divisions of lym- histocompatibility antigens and will be
phoid cells, thereby increasing the number discussed later. The genes for TCR chains
of antibody specificities to 1014, which far are on different chromosomes with the β
exceeds the number of B cells (1010) in the and α molecules on chromosome 7, while
body. the α and δ are on chromosome 14. As seen
Once a given B cell is preselected to pro- in Figure 1.5, the four chains are made up
duce a particular VH and VL domain, all the of a variable region and a constant region
ensuing progeny of that B cell will produce similar to those observed with the immu-
the same VH or VL domain. The sequence noglobulins. The variable regions are also
of events is as follows: initially, the B cell numerous and joined at D and J regions
produces intracellular antigen-specific by RAG1 and RAG2. This permits a diver-
IgM, which becomes bound to the cell sur- sity of antigen recognition similar to that
face. The B cell is now antigen responsive observed with immunoglobulin, but addi-
with exposure to a given antigen. The com- tional somatic mutation is not involved in
mitted B cell begins producing a certain T cells. These similarities have led to the
isotype or class of immunoglobulins and concept that genes for antigen-specific T
begins dividing, and all the progeny will cells evolved in the same manner as immu-
produce the identical immunoglobulin mol- noglobulin from a parent gene, and both
ecules. These B cells will later mature into are members of a superantigen family.
either plasma cells or long-term memory The TCR complex recognizes small
B cells. peptides presented to it by the MHC class
I and II and depends on the type of T cell.

T CELLS AND THEIR RECEPTORS

Each T cell is also committed to a given α or γ chain β or δ chain

antigen and recognizes it by one of two
TCRs. They may have TCR2s composed of
gamma (γ) and delta (δ) chains or TCR2s Variable region
composed of another heterodimer of alpha
(α) and beta (β) chains. These TCR2s are
associated with a group of transmem-
Constant region
brance proteins on the CD3 molecule,
which takes the antigen recognition sig-
nal inside the cell. Signal transduction via
the CD3 complex is regulated by a series Plasma membrane

of kinases, which are associated with the

tails of the CD3–TCR complex and regulate
phosphorylation. Deficiencies or blocks Figure 1.5 Diagram of the structure of a T-cell
in the T-cell signaling pathways either at receptor.

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Helper T cells (CD4) recognize class II anti- Figure 1.6). This extensive polymorphism
gens while suppressor cytotoxic T cells is important when viewed in the context of
(CD8) recognize class I antigens. Because an immune system that needs to cope with
of the rather low affinity of the reactions, an ever-increasing range of pathogens.
recognition of processed antigen alone is These pathogens in turn are extremely
not sufficient to activate T cells. Soluble adept at evading the immune system.
interleukins are needed to complete the Thus, the battle between invading microbe
picture and are generated during the anti- and immune recognition is constant and
gen processing. ever changing. Recognition of antigen by
T cells is MHC restricted. Therefore, any
given individual is only able to recognize
MAJOR HISTOCOMPATIBILITY antigen as part of a complex of antigenic
COMPLEX peptide and self.
The importance of this concept is under-
Human histocompatibility antigens are scored by the experiments of Dougherty
also known as human leucocyte antigens and Zinkernagel. Using virus-specific
(HLA), a term that is synonymous with (virus 1) cytotoxic T cells, Figure 1.7 illus-
the MHC complex. These antigens are cell- trates their remarkable discovery. If anti-
surface glycoproteins classified as type I gen-presenting cells (APCs) of mouse
or type II. They can produce genetic poly- A are mixed with T cells of mouse A in
morphism with multiple alleles at each the context of virus 1 peptides, the T cell
site, thus permitting a great deal of genetic responds and kills the virus. If the MHC
variability between given individuals (see complex is from mouse B and the T cells

Peptide binding groove

α1 α2 α1 β1

CHO CHO CHO

CHO

β2m s s s s
s s s s

α3 α2 β2
Plasma
membrane

Class I Class II

Figure 1.6 Diagrammatic representation of class I and II MHC antigens with

B2 microglobulins and CHO carbohydrate side chains.

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MHC MHC MHC

type a type b type a
Ag1 Ag1 Ag2
TcR TcR TcR

T cell T cell T cell

Response No Response No Response

Figure 1.7 MHC restriction of antigen recognition by T cells. If APC and

T cell are of the same genetic lineage as virus I, the T cell responds and
kills the virus. If APC and T cell are of different lineage, no response occurs.
If APC and T cell are of same lineage but virus 2 is present, no response
occurs.

are from mouse A, no killing occurs. groups of class II antigens: namely, HLA-
Finally, if MHC and T cells are both from DP, HLA-DQ, and HLA-DR.
mouse A but virus 2 is unrelated to virus Depending on the nature of the anti-
1, no response will occur. gen (endogenous or exogenous), the MHC
The MHC class I antigens are divided response is different. For example, endog-
into three groups (A, B, and C), and each enous antigens (including viral antigens)
group belongs on a different gene locus on are presented by MHC class I antigen cells
chromosome 6. The products of all three exclusively to CD8 cells. The endogenous
loci are similar and are made up of a heavy antigen is first broken down into small pep-
chain (45 kDa) and associated β2 micro- tides and transported by shuttle proteins
globulin molecule (12 kDa) gene, which called Tap I and Tap II to the endoplasmic
resides on chromosome 12. The MHC class reticulum. There they complex with MHC
I antigen differences are due to variations class I molecules and are delivered to the
in the α chains, the β2 microglobulin being cell surface for further processing to the
constant. X-ray crystallography studies CD8 cells.
have shown that as few as nine amino In contrast, MHC class II molecules
acids can be tightly bound in the α chain are held in the endoplasmic reticulum and
groove. are protected from binding to peptides in
MHC class II antigens also exhibit a the lumen (not human) by a protein called
similar structure with the groove being MHC class II associated invariant chain.
formed by the α1 and β1 chains. Unlike Finally, there are class III antigens, such
class I antigens present on most nucleated as complement components C4 and C2,
cells, the class II antigens are restricted to a plus certain inflammatory proteins, such
few types: macrophages, B cells, and acti- as tumor necrosis factor (TNF), which are
vated T cells. In humans, there are three encoded in adjacent areas.

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ADHESION MOLECULES designated by three separate prefixes:

E (endothelial), P (platelet), and L (leu-
In spite of the known MHC complex cocyte). The letters denote the cells on
consisting of binding of a TCR to the pro- which they were first observed. These
cessed antigen, which in turn is bound to groups of selectins bind avidly to car-
the class II molecule of APCs, this is not bohydrate molecules on leucocytes and
enough for T-cell activation. One must endothelial cells.
have additional stimuli that are provided c. Immunoglobulin superfamily: The
by a series of adhesion molecules on the molecules in this family are so called
two cell surfaces. because they contain a common
These molecules are composed of a immunoglobulin-like structure. They
diverse set of cell-surface glycoproteins and strengthen the interaction between the
play a pivotal role in mediating cell-to-cell T cells and APCs. They include some
adhesion. Adhesion molecules are divided of the most powerful molecules in the
into four major groups, (a) integrins, (b) immune system, such as the CD4, CD8,
selectins, (c) immunoglobulin superfamily, CD2, lymphocyte function antigen
and (d) caherins. (LFA-3 or CD58), and the intercellular
adhesion molecules such as ICAM-1
a. Integrins are heterodimers: These through 3.
are divided into α and β subunits. d. Cadherins: These molecules are
Depending on the substructure of the calcium-dependent adhesion mole-
β unit, there are five families, but for cules and are mainly important in
convenience β1 and β2 integrins are establishing molecular connections
involved in leucocyte–endothelial inter- between epithelial cells. Their particular
actions. β1 integrins, also known as very importance is during embryonic devel-
late activation proteins, are so named opment.
because they appear on lymphocytes
several days after antigenic stimula-
tion and are composed of a common β CYTOKINES
chain (CD29) paired with a different α
chain. They mediate lymphocyte and This group of soluble molecules plays an
monocyte binding to the endothelium extremely important role in clinical immu-
receptors called vascular adhesion mol- nology. They are secreted by macrophages
ecule. β2 integrins also have a common and may act as stimulatory or inhibi-
β chain (CD18), which pairs with dif- tory signals between cells. Cytokines that
ferent α chains (CD11 a, b, c) to form initiate chemotaxis of leucocytes are called
a number of separate molecules. These chemokines.
two sets of integrins mediate strong Among the group of cytokines, there
binding of leucocytes to the endothe- are a few of particular interest because
lial cell while β3–β5 are concerned with of their stimulatory activity. Interleu-
binding to extracellular matrix proteins kins 1 (IL-1) and 2 (IL-2) are of particu-
such as fibronectin and vitronectin. lar importance secondary to their role in
b. Selectins: These molecules are com- amplifying the immune response. IL-1
posed of three glycoproteins and are acts on a wide range of cells including T

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