A Central Role for Central Tolerance

Abstract

Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…Indeed, MHC class II expression directs positive and negative selection processes that shape the specificity of the T-cell receptor repertoire of the CD4 þ T-cell population during its development in the thymus. 2 It is, therefore, perhaps not surprising to find that the human MHC class II gene region holds the largest number, and some of the longest recognized, associations with autoimmune diseases of any similar-sized region across the genome (Table 1). Early associations based on serological typing were established for multiple sclerosis, 3,4 type I diabetes 5,6 and celiac disease 7,8 which were subsequently resolved to specific human leukocyte antigen (HLA)-DR/DQ haplotypes.…”

NKT cell development in the absence of the autoimmune regulator gene (Aire)

“…This helps to establish immune tolerance toward TSA because thymocytes that respond strongly to antigens in the thymus are normally purged from the repertoire or rendered innocuous [2,3]. In the absence of Aire, T cells responsive to Aire-dependent TSA are not tolerized in the thymus, instead escaping to the periphery where they can precipitate the onset of autoimmunity against a wide array of tissues and organs [1,4,5].…”

La protéine matricielle CYR61/CCN1 stimule la production de lymphocytes T

“…Le fonctionnement du thymus repose fortement sur le stroma thymique, un réseau conjonctif dont les principales composantes sont les cellules épithéliales thymiques (TEC). Les cellules stromales fournissent un microenvironnement propice au recrutement des cellules souches hémato-poïétiques circulant dans le sang et à leur différentiation en lymphocytes T [1,2]. Malheureusement, l'atrophie du thymus, liée à l'âge ou consécutive à des infections ou une chimiothérapie, résulte en une diminution du nombre de cellules épithéliales et donc une alté-ration de l'architecture du thymus.…”