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IMMUNOLOGIC

TOLERANCE
AND
AUTOIMMUNITY.
.

Immunolgic tolerance
B

Cell Tolerance
T Cell Tolerance
Clonal Deletion
Clonal Anergy
Immunogen vs Tolerogen
Mechanism of breaking B and T Cell
Tolerance (autoimmunity)

B or T CELL TOLERANCE
is a process that involves the faillure of B or T cell to respond
to self antigens (normal) or foreign antigens (abnormal)
CLONAL DELETION
This process involved the elimination of immature B or
T cells after antigen binds to their receptor.
CLONAL ANERGY
This process involves the inability of mature B or T cells
to respond to antigen even after it binds to
its receptor.
IMMUNOGEN
The antigen is called an immunogen if it induces
activation of a B or T cell

TOLEROGEN
The antigen is called tolerogen if it does not activate
a B or T cell (Its induce B or T cell clonal anergy).

B CELL TOLERANCE

Stem Cell

Pro-B

Pre-B

Bone Marrow

Immature B Mature B Effector B


Peripheral lymphoid
organ or tissue

No antigen dependence
RAG-1 and RAG-2

Receptor Editing

IgM,IgD

Self antigen Foreign antigen

Selection

Clonal Deletion
(apoptosis)

CentralTolerance

Performance
Effector function.

Clonal anergy
Clonal deletion

Peripherial Tolerance

T CELLS TOLERANCE


TCR

Stem Cell Pro-T Pre-T Immature T Mature T Naive mature T


BM

Periphery

Thymus
No respon to antigen

Pos&Neg selection (self ant)

activation by
Foreign ant

RAG 1 & RAG 2 expression


Clonal Deletion
(apoptosis)

T cell regulator Clonal anergy

CentralTolerance

Clonal deletion

Peripherial Tolerance

Figure 11-3 Central T cell tolerance. Recognition of self antigens by immature T cells in the
thymus may lead to death of the cells (negative selection, or deletion) or the development
of regulatory T cells that enter peripheral tissues.
2005 Elsevier

Contribution of different mechanism to the


generation of diversity in Ig and TCR genes.
V segments

85(heavy chain), 35()


64(TCR),67(TCR)
D segments
27(heavy chain), 0()
0(TCR),2(TCR)
N region diversifcation
V-D,D-J(heavy chain),None()
V-J(TCR),V-D,D-J(TCR)
J segments
6(heavy chain), 5()
61(TCR),4(TCR)
Total potential repertoire
~1011 (Ig), ~1016 (TCR)

Central and peripheral tolerance to self antigens.

Figure 11-2 Central and peripheral


tolerance to self antigens. Immature
lymphocytes specific for self antigens may
encounter these antigens in the generative
lymphoid organs and are deleted, change
their specificity (B cells only), or (in the
case of CD4+ T cells) develop into
regulatory lymphocytes (central
tolerance). Some self-reactive
lymphocytes may mature and enter
peripheral tissues and may be inactivated
or deleted by encounter with self antigens
in these tissues, or are suppressed by the
regulatory T cells (peripheral tolerance).
(Note that T cells recognize antigens
presented by antigen-presenting cells,
which are not shown.)

FATES OF LYMPHOCYTES AFTER ENCOUNTER WITH ANTIGEN.

Figure 11-1 Fates of lymphocytes after encounter with antigens. In a normal immune response, microbes
stimulate the proliferation and differentiation of antigen-specific lymphocytes. (Microbial antigens are
typically recognized by lymphocytes in the presence of costimulators and innate immune responses,
which are not shown.) Self antigens may induce functional unresponsiveness or death of antigenspecific lymphocytes or a change in the specificity of the receptors, making these cells incapable of
responding to the antigen (self-tolerance). Some antigens elicit no response (ignorance), but the
lymphocytes are able to respond to subsequent antigen challenge (not shown). This illustration depicts B
lymphocytes; the same general principles apply to T lymphocytes.

2005 Elsevier

Postulated mechanisms of autoimmunity

Figure 18-6 Postulated mechanisms of autoimmunity. In this proposed model of an organspecific T cell-mediated autoimmune disease, various genetic loci may confer
susceptibility to autoimmunity, in part by influencing the maintenance of self-tolerance.
Environmental triggers, such as infections and other inflammatory stimuli, promote the
influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in
tissue injury.
Downloaded from: StudentConsult (on 20 November 2007 06:33 AM)
2005 Elsevier

Susceptibility loci for autoimmune diseases

Figure 18-7 Susceptibility loci for autoimmune diseases. The chromosomal loci associated with some
autoimmune diseases are shown. The location of candidate genes of immunologic interest are indicated
as ovals on the left of the chromosomes. These ovals are color coded to indicate the diseases to which
the genes are linked. SLE, systemic lupus erythematosus; AITD, autoimmune thyroid disease; RA,
rheumatoid arthritis; T1D, type 1 diabetes. (Modified from Yamada R and K Ymamoto. Recent findings on
genes associated with inflammatory diseases. Mutation Research 573:136-151, Copyright 2005 with
permission from Elsevier.)
2005 Elsevier

HLA link immunolgic Diseases


Disease
Rheumatoid Arthritis
Insulin-Dep Diabetes

Multiple sclerosis
SLE
Pemphigus vulgaris
Ankylosing Spondylitis

HLA allele
DR4
DR3
DR4
DR3/DR4
DR2
DR2/DR3
DR4
B27

RR
4
5
5
25
4
5
14
90-100

Postulated mechanisms of autoimmunity

Figure 18-6 Postulated mechanisms of autoimmunity. In this proposed model of an organspecific T cell-mediated autoimmune disease, various genetic loci may confer
susceptibility to autoimmunity, in part by influencing the maintenance of self-tolerance.
Environmental triggers, such as infections and other inflammatory stimuli, promote the
influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in
tissue injury.
Downloaded from: StudentConsult (on 20 November 2007 06:33 AM)
2005 Elsevier

MECHANISM FOR BREAKING


B AND T CELL TOLERANCE

MOLECULAR MIMICRY
POLYCLONAL
B CELL ACTIVATION
POLYCLONAL
T CELL ACTIVATION
EXPOSURE OF HIDDEN
SELF ANTIGEN

THE ROLE OF INFECTION IN THE


DEVELOPMENT OF AUTOIMMUNITY :

MOLECULAR MIMICRY
IgD

IgM

Streptococcus
Antigen (epitop)

B
Cross
Reaction

epitop on
heart cells

Streptococcus
antibody

Destruction of heart tissue


RHEUMATIC FEVER

B CELL TOLERANCE
SELF ANTIGENS

IgM
B

IgD
Th

Immature

IgM
B

Th

Mature

CLONAL ANERGY
Polyclonal activation

CLONAL DELETION

ACTIVATED CLONE

DEATH
AUTOIMMUNE

THE ROLE OF INFECTION IN THE


DEVELOPMENT OF AUTOIMMUNITY :

POLYCLONAL STIMULANT
LIPOPOLISACHARIDE (LPS)

IgD

IgM

IgD

IgM

Self Antigen
(heart,Kidney,
Insulin,Lung)

Th

ANERGIZED B CELLS

Stimulatory signal
Cytokine
ACTIVATED B CELLS
Anti heart Antibody
Anti kidney Antibody
Anti Insulin Antibody
Anti Lung Antibody

Anti LPS Antibody

THE ROLE OF INFECTION IN THE


DEVELOPMENT OF AUTOIMMUNITY :

POLYCLONAL STIMULANT
SUPERANTIGEN OF BACTERIA

IgD

IgM

Self Antigen
(heart,Kidney,
Insulin,Lung)

APC

Th

ANERGIZED B CELLS

Stimulatory signal
Cytokine
ACTIVATED B CELLS
Anti heart Antibody
Anti kidney Antibody
Anti Insulin Antibody
Anti Lung Antibody

Figure 18-8 Role of infections in the development of autoimmunity. A. Normally, encounter of a mature self-reactive T cell with a self antigen presented by a costimulatordeficient resting tissue antigen-presenting cell (APC) results in peripheral tolerance by anergy. (Other possible mechanisms of self-tolerance are not shown.) B. Microbes
may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant. C.
Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for
self antigens.

ROLE OF INFECTIONS IN THE


DEVELOPMENT OF AUTOIMMUNUTY

Downloaded from: StudentConsult (on 20 November 2007 06:33 AM)


2005 Elsevier

AUTOIMMUNE DISEASES
Rheumatoid Arthritis (antinuclear antibody)
Rheumatic Fever (antistreptococcus antibody)
Goiter(antibody against thyroid epithelial cells)
Diabetes Mellitus type I (antibody against
materials of cytoplasm/cell membrane of
pancreas cell, cytotoxicity of T cell to cell).
Chronic Thyroiditis (Hashimoto), (B and T cell
infiltration)
Scleroderma (antinuclear antibody)
Systemic Lupus Erythematosus (Antinuclear
antibody, anti DNA antibody)

CONCLUSIONS
All normal individuals are tolerant of their own
(self) antigens (self tolerance)
Two mechanism of self tolerance are central
tolerance and peripheral tolerance
Central tolerance consist of clonal deletion,
receptor editing (B cell) and Regulatory T cell.
Peripheral tolerance consist of Clonal Anergy,
clonal deletion, and Regulatory T Cell.
Autoimmune diseases result from the faillure of
self tolerance due to the activation of clonal
anergy or the lack function of Regulatory T cell.
Multiple factors contribute to autoimmunity,
including immunologic abnormality,
susceptibility genes, and infections.