ABSTRACT
Many self-reactive lymphocytes are not eliminated in the primary lymphoid organs for two reasons. Firstly, many self antigens are neither present in the primary lymphoid organs nor supplied to them via the bloodstream (e.g., “sequestered antigens” such as lens proteins in the eye), and many self antigens expressed as the result of differentiation of cells and tissues in the major organs of the body are not regulated by AIRE. Thus self-reactive T cells that escape negative selection in the thymus have to be deleted or rendered anergic in the periphery where they come into contact with the majority of self antigens. Secondly, self-antigen receptor specificities may be generated in B cells as the consequence of somatic mutation of antibody genes in cells within the germinal centers of secondary lymphoid organs/tissues (Sections C2, D3, and E4). Unlike B-cell antigen receptors, it is believed that TCRs do not normally mutate. The silencing of self-reactive lymphocytes in the periphery might be due to deletion in some cases. However, it is generally believed that the “silencing” is mainly due to anergy induced during the initial contact of the T cells with self antigen in the periphery.
