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NATIONAL CHENG KUNG UNIVERSITY MEDICAL COLLEGE
MEDICAL MICROBIOLOGY COURSE
Monday, February 27, 2006, 1:10-3:00 p.m.
REGULATION OF THE IMMUNE RESPONSE
IMMUNOLOGICAL TOLERANCE
Yee-Shin Lin, Ph.D.
A. BACKGROUND
Factors determining the outcome of an immune response:
1. Antigen: the nature of an antigen, its dose, and the route of administration
2. Antigen-presenting cell: co-stimulation
3. Genetic background of the individual
4. History of previous exposure: cross-reaction
5. Antibody
6. T cells
7. Neuroendocrine modulation
Tolerance mechanisms are needed because the immune system randomly generates a vast diversity of
anti-specific receptors (i.e., surface Ig and TCR) and some of these will be self-reactive. The mechanisms
include:
1. Central thymic tolerance
2. Peripheral or post-thymic tolerance
3. B-cell tolerance
4. Artificially induced tolerance
Reading: Roitt, Brostoff & Male [chapters 11, 12]
Pre-class assigned reading: Page/Column 173 (green box), 175R-178; Fig. 11.4, 11.5, 11.7, 11.11, 11.13,
11.14, 11.15, 11.17, 11.18, 11.21, 11.25; 191 (green box), 196-205; Fig. 12.1-12.3, 12.7-12.9, 12.12-12.16,
12.18, 12.19, 12.23, 12.24; and all bold titles
B. LECTURE SUMMARY
REGULATION OF THE IMMUNE RESPONSE
FACTORS OR CELLS INVOLVED IN THE IMMUNOREGULATION
1. Antigen [p. 173, 174]
2. Antigen-presenting cell
3. Antibody and immune complexes [Fig. 11.4, 11.5, 11.7]
4. Idiotype and anti-idiotype [Fig. 11.14, 11.15]
5. T cells [Fig. 11.8, 11.11, 11.13]
6. NK and NK T cells
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Network theory of regulation: Jerne proposed an idiotype network theory that explained the regulation of
immune response by receptor-anti-receptor (idiotype-anti-idiotype) interaction.
a. Anti-idiotype antibodies may suppress or enhance immune response depending on dose and timing.
b. Anti-idiotypic antibodies have been observed after injection of antigen.
c. Responsible for "fine-tuning" the immune response.
Interactions between the endocrine, nervous and immune systems: [Fig. 11.17]
GENETIC CONTROL OF IMMUNE RESPONSES
MHC-linked immune response genes: MHC genes control immune responsiveness: high, intermediate, and
low responders [Fig. 11.18].
Advantages of MHC polymorphism: Different MHC proteins might be better than others at presenting different
antigens to T cells, and the "perfect pathogen" cannot exist since an organism which evades the immune system
in one individual will not do so in another.
MHC-restriction in cell interaction: The MHC controls interactions between cells of the immune system,
where the cells must share an MHC region (or subregion) to cooperate optimally. These types of interaction are
said to be MHC-restricted.
Most T cell recognize antigen in association with an MHC molecule:
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For induction of TH cells, TH cells recognize antigen in association with class II molecules.
Cytotoxic T cells recognize viral antigens in association with class I molecules. This recognition of MHC
was learnt during ontogeny.
MHC associations and autoimmune disease: [Fig. 11.21]
Non-MHC-linked immune response genes: [p.185-187]
Genetic defects associated with immune deficiency or abnormalities [Fig. 11.25]
IMMUNOLOGICAL TOLERANCE
Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen; it is induced by
prior exposure to that antigen. The most important aspect of tolerance is self-tolerance, which prevents the body
from mounting an immune attack against its own tissues. The self-nonself discrimination is learned during
development. However, it is not the structure of a molecule per se that determines whether it will be
distinguished as self or non-self. Factors other than the structural characteristics of an epitope are also important.
Among these are:
1. The stage of differentiation when lymphocytes first confront the epitopes.
2. The site of the encounter.
3. The nature of the cells presenting epitopes.
4. The number of lymphocytes responding to the epitopes.
Historical background
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1. High dose of antigen in adult life leading to specific nonresponsiveness.
2. Exposure of antigen in embryonic life leading to specific nonresponsiveness.
3. Neonatal mice injected with spleen cells from another mice will later accept skin grafts from the spleen cell
donors. [Fig. 12.1]
Experimental induction of tolerance
1. Transgenic technology has allowed the study of tolerance to authentic self antigens.
2. Four possible ways in which self-reactive lymphocytes may be prevented from responding to self antigens:
clonal deletion, clonal abortion, clonal anergy, and suppression. Which of these fates awaits the self-reactive
lymphocyte depends on numerous factors: the stage of maturity of the cell being silenced, the affinity of its
receptor for the self antigen, the nature of this antigen, its concentration, its tissue distribution, its pattern of
expression, and the availability of co-stimulatory signals.
Central thymic tolerance to self antigens: The thymus selects T cells with receptors that bind to antigen
associated with MHC molecules but deletes cells with over-high avidity for self antigens. [Fig. 12.2, 12.3,
12.7-12.9]
Post-thymic tolerance to self antigens: Potentially self-reactive T cells can sometimes ignore their self antigen
(Sequestration and privileged site), can be tolerized by self antigen on tissue cells (deletion), or silenced by
immunoregulatory cells (immune regulation). [Fig. 12.12-12.16, 12.18]
B-cell tolerance to self antigens [Fig. 12.19]
1. High affinity IgG production is T-cell dependent. The simplest explanation for non-self reactivity by B cells
is a lack of T-cell help.
2. Self-reactive B cells may be deleted or anergized depending on the affinity of the B-cell antigen receptor and
the nature of the antigen. B cells that respond to membrane-bound self antigens are deleted whereas B cells that
can bind soluble antigens become anergic.
Tolerance can be induced artificially by a variety of means, conditions affecting ease of tolerance induction:
1. Immunocompetence of the host, with the help of immunosuppressive regimens (e.g., anti-CD4, CD8, CD28,
CD154). [Fig. 12.23]
2. Tolerance is induced more easily with soluble protein antigens in deaggregated form.
3. Antigens are presented in the absence of costimulator molecules.
4. Tolerance can be mediated by suppressive cytokines.
5. Very low or very high dose of antigen.
Cells involved in the induction of tolerance: [Fig. 12.24]
1. Both T and B cells are susceptible to tolerance induction, usually it is easier to induce tolerance in T cells
than B cells.
2. The dose of tolerance and the time required for T cell tolerance and B cell tolerance are different.
3. The duration of tolerance is shorter in B cells than in T cells.
4. For the T-dependent antigen-induced tolerance in the whole animal, it is generally T-cell-mediated.
Induction of B cell tolerance in adults to T-dependent antigen:
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1. T cell help not available
2. Th cell deleted
3. Th cell tolerized or suppressed
Maintaining tolerance needs the persistence of antigen. Responsiveness returns after the antigen
concentration drops below a certain threshold. If the tolerance results from clonal deletion or permanent anergy,
recovery of responsiveness is related to the time required to generate new immunocompetent cells from their
precursors. The understanding of tolerogenesis could be valuable in promoting tolerance in transplantation or
controlling the untoward immune responses of hypersensitivity or autoimmune disease. It is essential to
determine the mechanisms which induce 'peripheral' tolerance. On the other hand, in the treatment of tumors,
the ability to break peripheral tolerance to a particular self component (such as an oncogene product) might
enable the body to mount an active immune response which could limit tumor growth.
C. ImmunObjectives -- a self assessment
1. Define:
 idiotype network
 MHC-restriction
 clonal deletion or clonal anergy
2. Describe the different factors and cells that regulate the outcome of the immune response.
3. How do antibody and immune complex regulate immune response?
4. How are Th1 cells regulated?
5.
How the self-tolerance and MHC-restriction of T cells are accomplished during thymus education?
6. What are the mechanisms of peripheral (post-thymic) tolerance?
7. If you have B cells reactive against self-antigens such as thyroglobulin, why are they not activated? How
might they be activated?
8.
In some instances it is desirable to turn off the immune system. Why?
9. What are the differences between immunogen and tolerogen?