SECTION 20

TOLERANCE AND AUTOIMMUNITY

CONTACT INFORMATION

Abul Abbas, MD (Email)

READING

Basic Immunology: Functions and Disorders of the Immune System. Abbas, Abul K., and Andrew H. Lichtman. -- Chapter 9

OBJECTIVES

• To understand the concept of immunological toler-ance and its importance

• To understand the difference between central and pe-ripheral tolerance

• To describe the role of negative selection and the AIRE protein in central tolerance

• To understand the mechanisms of peripheral toler-ance affecting T lymphocytes, specifically anergy, apoptosis and suppression by regulatory T cells.

• To describe the properties and functions of regulatory T cells.

• To summarize the roles of the following selected pro-teins in the maintenance of self-tolerance: CTLA-4, Fas, FoxP3.

• To understand how genetic and environmental fac-tors may contribute to the development of autoimmu-nity

• To describe some of the genetic loci that might alter susceptibility to autoimmune diseases

KEY WORDS:

• IMMUNOLOGICAL TOLERANCE

• AUTOIMMUNITY

• AUTOIMMUNE DISEASE

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• CENTRAL TOLERANCE

• PERIPHERAL TOLERANCE

• ANERGY

• REGULATORY T CELLS

• DELETION

MAIN IDEAS:

Lymphocytes with receptors for self antigens are gener-ated in all individuals, and have to be killed or con-trolled in order to prevent autoimmunity. The failure of lymphocytes to respond to an antigen after encounter-ing that antigen is called tolerance (and is the oppo-site of activation).

Central tolerance: many of the immature lympho-cytes that see self antigens in the central (generative) lymphoid organs (thymus, bone marrow) are killed.

Peripheral tolerance: lymphocytes that recognize self antigens in peripheral tissues are shut off, sup-pressed by regulatory T lymphocytes, or kille.

Failure in the mechanisms of tolerance to self antigens results in autoimmunity. The major factors in the devel-opment of autoimmunity are the inheritance of suscep-

tibility genes and environmental factors, such as infec-tions.

Tolerance: unresponsiveness to an antigen induced by prior exposure to that antigenSignificance:

- self-tolerance is a fundamental property of the im-mune system; it is induced when self-reactive lym-phocytes encounter self antigens; its failure leads to autoimmunity

- strategies for inducing tolerance may be useful for treating allergic and autoimmune diseases, and for preventing graft rejection and immune responses in gene therapy and stem cell therapy

Mechanisms of immunological tolerance: the principal mechanisms are divided into central toler-ance and peripheral tolerance. At times, the immune system may fail to recognize or react against some self antigens; this phenomenon is called "ignorance".

Central tolerance: immature lymphocytes recognize, with high affinity, antigen in generative lymphoid or-gans (typically self antigens); this results in death of the lymphocytes by apoptosis, also called negative selec-tion.

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The thymus expresses many self antigens thought to be restricted to peripheral tissues, thus providing an im-munological representation of self. The expression of some of these tissue antigens in the thymus is medi-ated by a transcription factor called AIRE. Other mechanisms of central tolerance render self-reactive lymphocytes harmless: receptor editing (B cells), gen-eration of regulatory T cells (CD4+ T cells)

Peripheral tolerance: mature lymphocytes recog-nize antigens in peripheral tissues in ways that lead to unresponsiveness or cell death.

In T cells:

- anergy (functional unresponsiveness); results from antigen recognition without costimulation, or en-gagement of inhibitory receptors of lymphocytes (e.g. CTLA-4)

- suppression (by regulatory T cells)

- deletion (apoptosis)

In B cells:

- anergy; exclusion from lymphoid follicles and death

Understanding the mechanisms of peripheral tolerance is leading to new strategies for shutting off harmful im-mune responses and restoring the normal balance of lymphocyte activation and tolerance. Many trials of these therapeutic strategies are under way.

Development of autoimmunity is a consequence of the failure of self-tolerance; usually results from a combination of genetic susceptibility and environ-mental triggers (e.g. infections).

Genetic susceptibility

Multiples genes influence susceptibility to autoimmune disease; MHC (HLA in humans) is the most important. Many non-MHC genes are known to be involved. Re-cent genetic analyses are beginning to reveal some of the polymorphic genes that are associated with autoim-mune diseases, but it has proved difficult to use this ge-netic information to better understand the diseases, or to develop novel therapies, or to predict who will get a particular disease and how it will progress.

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Environmental triggers

Infections usually trigger and/or exacerbate autoimmu-nity; likely mechanisms include induction of costimula-tors on APCs, and "molecular mimicry" of foreign anti-gens with self.

Surprisingly, some infections appear to protect indi-viduals from certain autoimmune diseases; the mecha-nisms are not known. Despite our growing knowledge of the mechanisms of self-tolerance, the etiologies of human autoimmune diseases are still not established, and this remains one of the major challenges in Immu-nology.

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