Abstract: Series 99, Lecture 5

The Harvey Lectures Series 99 (2003—2004)

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Lecture #5: Thursday, March 25, 2004 — Time and Location

Defective Learning of Immunological “Self” by T Cells in the Thymus Underlies Autoimmune Disease

Diane Mathis, PhD

Head, Section on Immunology and Immunogenetics
Joslin Diabetes Center

Harvard Medical School

Boston, Massachusetts

The major function of the immune system is to ward off microbial challenges. In order to do so optimally, it keys on the recognition of microbial antigens by a diversity of antigen-specific receptors displayed on the surface of T and B cells. This diversity is generated through random rearrangement of chromosomal segments encoding the receptors. Since this is a random process, some receptors capable of recognizing body constituents (self-antigens) are generated. In order to avoid the pathological state of autoimmune disease, the organism needs to somehow eliminate or silence lymphocytes displaying receptors reactive to self-antigens. Several mechanisms for “purging” self-reactive cells have been identified, some operative in the thymus or bone marrow during maturation, others impinging on fully mature cells in the periphery. The relative importance of these diverse mechanisms has been the topic of energetic discussion. In this presentation, the contribution of clonal deletion of self-reactive T cells in the thymus will be discussed. The focus will be on two systems wherein defective thymic clonal deletion results in overt autoimmune disease. The first is AIRE (aire)-deficient humans (or mice) which have a defect in clonal deletion that has been attributed to lack of transcription of genes encoding “peripheral” tissue-restricted antigens in a small subset of thymic stromal cells. The second is NOD mice, currently the most popular animal model of type-1 diabetes, which exhibit very inefficient clonal deletion due to a genetic lesion.