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88
CHAPTER 12
SELECTED CYTOKINES AND THEIR ACTIVITY
TABLE
12-1
Cytokine
Producing Cell
Target Cell
Activity
IL-1
Monocytes
T cells
Activation of T cells
Macrophages
B cells
Maturation and proliferation of B cells
B cells
Endothelial cells
Increased cell adhesion
Dendritic cells
CNS
Fever, sickness behavior
Hepatocytes
Synthesis and release of acute phase proteins
IL-2
T cells
T cells
Proliferation and differentiation of T cells
B cells
Proliferation and differentiation of B cells
NK cells
Proliferation and activation of NK cells
IL-4
Th2 cells
T cells
Proliferation of T cells
Mast cells
B cells
Isotype switch to IgE by B cells
Macrophages
Inhibits IFN-
activation
IL-6
Th2 cells
B cells
Differentiation into plasma cells
Macrophages
Plasma cells
Stimulation of antibody secretion
Bone marrow
Hepatocytes
Synthesis and release of acute phase proteins
stromal cells
Hemopoietic cells
Differentiation of hemopoietic cells
Dendritic cells
IL-8
Macrophages
All immune cells
Chemotaxis of all migratory immune cells
Endothelial cells
Endothelial cells
Activation and chemotaxis of neutrophils
Inhibition of histamine release by basophils
Inhibition of IgE production by B cells
Promotion of angiogenesis
TNF-
Th1 cells
Virtually all cells in
Proinflammatory actions
Macrophages
the body
Proliferation of cells
Dendritic cells
Differentiation of cells
NK cells
Cytotoxic for transformed cells
Mast cells
TGF-
T cells
Monocytes
Chemotaxis of monocytes
Monocytes
Macrophages
Chemotaxis of macrophages and promotion of
B cells
IL-1 synthesis
Various cells of the
Promotion of IgA synthesis
body
Proliferation of various cells of the body
IFN-
Th1 cells
T cells
Development of Th1 cells and proliferation of
Cytotoxic T cells
B cells
Th2 cells
NK cells
Macrophages
Isotype switch to IgG by B cells
Activation and expression of MHC by
macrophages
MCP
Endothelial cells
Monocytes
Chemotaxis of monocytes
Fibroblasts
T cells
Chemotaxis of T cells
Smooth muscle cells
NK cells
Chemotaxis of NK cells
Macrophages
Activation of macrophages
Basophils
Promotion of histamine release
Eosinophils
Activation of eosinophils
MIP
Macrophages
Neutrophils
Chemotaxis of neutrophils
T cells
Chemotaxis of T cells
Hematopoietic
Inhibition of hematopoiesis
precursor cells
GM-CSF
Th cells
Granulocytes
Proliferation and differentiation of granulocytes
Monocytes
Proliferation and differentiation of monocytes
Hematopoietic
Proliferation of hematopoietic precursor cells
precursor cells
MCP
monocyte chemotactic protein; MIP macrophage inflammatory protein; GM-CSF granulocyte-macrophage colony-
stimulating factor; Th
T helper cells; IL interleukin; IFN interferon.
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89
Clonal selection is the most widely accepted theory that
explains the immune system and contains four major points as follows:
A. B cells and T cells of all antigen specificities develop before exposure to antigen.
B. Each B cell carries an immunoglobulin on its surface for only a single antigen; each
T cell carries a T-cell receptor on its surface for only a single antigen.
C. B cells and T cells can be stimulated by antigen to give rise to progeny cells with iden-
tical antigen specificity, that is, clones.
D. B cells and T cells that are reactive with “self” antigens are eliminated (perhaps through
apoptosis) or somehow inactivated so that an autoimmune reaction does not occur.
A. IMMUNOGLOBULIN (Ig) STRUCTURE (Figure 13-1). An immunoglobulin consists
of four protein subunits: two heavy chains and two light chains that are arranged in a
Y-shaped pattern.
Molecular Biology of the
Immune System
● Figure 13-1 Immunoglobulin Struc-
ture.
2.
Light chains
a.
(Kappa) chain. The chain gene segments are located on chromosome 2
and include
200 variable segments (V
), 5 joining segments (J
), and 1 con-
stant segment (C
). The V
, J
, and C
gene segments undergo gene re-
arrangement to contribute to immunoglobulin diversity.
b.
(Lambda) chain. The chain gene segments are located on chromosome 22
and include
100 variable segments (V
), 6 joining segments (J
), and 6 con-
stant segments (C
). The V
, J
, and C
gene segments undergo gene re-
arrangement to contribute to immunoglobulin diversity.
1.
Heavy chains.
The heavy chain gene seg-
ments are located on chromosome 14 and
include 200 variable segments (V
H
), 50
diversity segments (D
H
), 6 joining seg-
ments ( J
H
), and 5 constant segments
(C
H
). The 5 C
H
segments are named
(mu; M),
(delta; D), (gamma; G),
(epsilon; E), and
(alpha; A). The 5 C
H
segments define the 5 immunoglobulin
classes called IgM, IgD, IgG, IgE, and IgA.
The V
H
, D
H
, J
H
, and C
H
gene segments
undergo gene rearrangement to contribute
to immunoglobulin diversity.
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CHAPTER 13
3.
The diagram demonstrates immunoglobulin structure. The location of heavy chain
and light chain gene segments on chromosomes 14, 2, and 22 are indicated. The
heavy and light chain gene segments are organized into various V, D, J, and C gene
segments which undergo gene rearrangement, transcription, splicing, and transla-
tion to form an immunoglobulin protein. An immunoglobulin protein consists of
either two
light chains or two light chains (never a mixture of one light chain
and one
light chain). V variable, D diversity, J joining, C constant.
B. IMMUNOGLOBULIN DIVERSITY (Figure 13-2). For years, the fundamental mystery
of the immune system was immunoglobulin diversity: How could B cells (i.e., plasma
cells) of the immune system synthesize a million different immunoglobulins, one for
each of the million different antigens? If each immunoglobulin was encoded by its own
gene, then the human genome would consist almost exclusively of genes dedicated to
immunoglobulin synthesis. This is not the case. The answer to this fundamental mys-
tery lies in a number of processes which include the following:
4.
Somatic cell mutations
whereby V gene segments mutate during the life of a B cell.
5.
Random assortment of heavy and light chains.
6.
The diagram demonstrates immunoglobulin diversity. The gene rearrangement us-
ing heavy chain gene segments as an example is shown. The un-rearranged heavy
chain gene segments consisting of 200 V
H
segments, 50 D
H
segments, 6 J
H
seg-
ments, and 5 C
H
segments undergo gene rearrangement whereby particular seg-
ments (V
125
, D
27,
and J
5
, for example) are brought together while the intervening
segments are excised and degraded. The rearranged heavy chain gene segments
undergo transcription to form a primary RNA transcript. The primary RNA tran-
script undergoes splicing to form mRNA (V
125
, D
27,
J
5,
and
). The mRNA under-
goes translation to form a heavy chain polypeptide with a unique amino acid se-
quence that corresponds to the V
125
, D
27,
J
5,
and
gene segment codons. The gene
rearrangement contributes to immunoglobulin diversity. Black segments of the im-
munoglobulin represent the portion that binds antigen.
C. IMMUNOGLOBULIN PROPERTIES (Table 13-1)
1.
IgM
a.
IgM may exist as a monomer or pentamer structure.
b.
The IgM monomer is synthesized by B cells and retained on the cell membrane
of B cells as a B-cell receptor which is specific for a single antigen.
c.
The IgM monomer is designated as
2
2
or
2
2
.
d.
Later in the immune response, the IgM pentamer is synthesized and secreted
by plasma cells. The IgM pentamer is designated as (
2
2
)
5
or (
2
2
)
5
whereby five monomeric IgMs are held together by the J chain.
e.
The IgM monomer is a B-cell receptor for antigen.
● Figure 13-2 Immunoglobulin Diversity.
1.
Gene rearrangement.
The process of
gene rearrangement where V, D, J, and C
gene segments of the heavy and light
chains are randomly rearranged in a mil-
lion combinations that code for a million
different immunoglobulins.
2.
Junctional diversity
whereby DNA dele-
tions occur during gene rearrangement that
leads to amino acid changes.
3.
Insertional diversity
whereby a short se-
quence of nucleotides in inserted during
gene rearrangement that leads to amino
acid changes.
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91
MOLECULAR BIOLOGY OF THE IMMUNE SYSTEM
f.
The IgM pentamer is the earliest immunoglobulin to appear after antigenic
stimulus; activates complement avidly; and does not cross the placenta.
2.
IgD.
IgD exists as a monomer.
a.
IgD is synthesized by B cells and retained on the cell membrane of B cells as a
B-cell receptor which is specific for a single antigen.
b.
IgD is designated as
2
2
or
2
2
.
c.
Later in the immune response, IgD is synthesized and secreted by plasma cells.
d.
IgD is a B-cell receptor for antigen and an early immunoglobulin to appear af-
ter antigenic stimulus; does not activate complement; and does not cross the
placenta.
3.
IgG
a.
IgG exists as a monomer.
b.
IgG is synthesized by plasma cells.
c.
IgG is designated as
2
2
or
2
2
.
d.
IgG is cleaved into three fragments by papain (cleaves above the disulfide bond
joining the
chains) which include two Fab (fragment; antigen binding) frag-
ments each containing one reactive site for an antigenic epitope (monovalent)
and therefore cannot precipitate or agglutinate antigen; one F
C
(fragment;
crystallizable) fragment which activates complement, controls catabolism of
IgG, fixes IgG to cells via an F
C
receptor on the cell surface, and mediates pla-
cental transfer.
e.
IgG is cleaved into one fragment by pepsin which is the F(ab
)2 fragment
which contains two reactive sites for an antigenic epitope (bivalent) and there-
fore can precipitate or agglutinate antigen; the F
C
portion of IgG is extensively
digested by pepsin.
f.
IgG binds to the F
C
receptors on neutrophils and macrophages thereby stimu-
lating phagocytosis; activates complement; and crosses the placenta thereby
transferring maternal antibodies to the fetus.
4.
IgE
a.
IgE exists as a monomer.
b.
IgE is synthesized by plasma cells.
c.
IgE is designated as
2
2
or
2
2
.
d.
IgE is unstable at 56
C and is called reagin.
e.
IgE binds to IgE antibody receptors on eosinophils, basophils, and mast cells
and thereby participates in parasitic infections and Type I hypersensitivity ana-
phylactic reactions; does not activate complement; and does not cross the pla-
centa.
5.
IgA
a.
IgA exists as a monomer, dimer, or dimer with a secretory piece (called se-
cretory IgA).
b.
The IgA monomer is synthesized by plasma cells and is found in the serum
(little is known about the function of IgA in the serum). The IgA monomer is
designated
2
2
or
2
2
.
c.
The IgA dimer is synthesized by plasma cells and is found in the intestinal
mucosa. The IgA dimer is designated as (
2
2
)
2
or (
2
2
)
2
whereby two
monomeric IgAs are held together by the J chain.
d.
The IgA dimer with secretory piece is an IgA dimer with a secretory piece
(which is a portion of the poly-Ig receptor complex found on intestinal ep-
ithelial cells) attached to it.
i.
The IgA dimer synthesized by plasma cells within the lamina propria of
the intestinal tract binds to the poly-Ig receptor on the basal surface of the
enterocytes to form an IgA dimer
poly-Ig receptor complex.
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CHAPTER 13
ii. The IgA dimer
poly-Ig receptor complex is endocytosed and transported
across the enterocyte to the apical or luminal surface.
iii. At the apical surface, the complex is cleaved such that IgA dimer is released
into the intestinal lumen joined with the secretory piece of the poly-Ig re-
ceptor (called secretory IgA). The secretory piece protects IgA dimer from
proteolysis.
e.
The IgA dimer is found in high concentrations in external secretions like
saliva, mucus, tears, sweat, gastric fluid, and colostrum/milk (provides the
neonate with a major source of intestinal protection against pathogens) and
works by blocking bacteria, viruses, and toxins from binding to host cells; does
not activate complement; and does not cross the placenta.
f.
If all the production of IgA from various sources is taken into account, IgA is
the major immunoglobulin in terms of quantity.
D. IMMUNOGLOBULIN FUNCTION. Clearly, the production of immunoglobulins is an
important aspect of the immune system. However, the question as to what are the gen-
eral functions of immunoglobulins that make them so vital needs to be fully under-
stood. The functions of immunoglobulins include the following:
1.
Agglutination.
Agglutination is a process whereby immunoglobulins bind to free
antigens to form aggregates that undergo phagocytosis and also reduce the amount
of free antigen.
2.
Opsonization.
Opsonization is a process whereby immunoglobulins bind to anti-
gens on the surface of bacteria (for example) which stimulates phagocytosis by
neutrophils and macrophages.
3.
Neutralization.
Neutralization is a process whereby immunoglobulins bind to
antigen on viruses or bacteria which blocks their adhesion to host cells and inacti-
vates toxins.
4.
Cytotoxicity.
Cytotoxicity is a process whereby immunoglobulins (e.g., IgE) bind
to antigen on parasitic worms (e.g., Schistosoma) and elicit the eosinophils to re-
lease major basic protein, eosinophil cationic protein, histaminase, and peroxidase
to kill the worm.
5.
Complement activation.
Complement activation is a process whereby im-
munoglobulins bind to antigen on the surface of bacteria (for example) which then
binds the proenzyme C
1 of the complement system. This activates the comple-
ment cascade resulting in bacterial lysis.
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