Citation

Brunner T, Arnold D, Wasem C, Laissue JA, Mueller C. Expert Opin. Investig. Drugs 1999; 8(9): 1359-1372.

Copyright

(Copyright © 1999, Informa Healthcare)

DOI

10.1517/13543784.8.9.1359

PMID

unavailable

Abstract

In the thymus, based on the reactivity of their T-cell receptor with self-MHC and antigenic peptides, developing immature T-cells undergo positive and negative selection. Cells recognising self-peptides and MHC with high affinity are considered autoreactive, and thus potentially harmful, and are eliminated by induction of apoptotic cell death. Thymic negative selection is, however, only incomplete and autoreactive T-cells escape into the periphery. It is not the presence of autoreactive mature T- and B-lymphocytes as the underlying cause of tissue destruction and development of autoimmune diseases, but their uncontrolled and excessive clonal expansion upon activation by self-antigen. Thus, potent regulatory mechanisms must keep these autoreactive cells under control to avoid their inappropriate activation. Recent evidence indicates that death receptors of the tumour necrosis factor receptor family play a central role in mediating antigen receptor-induced suicide of autoreactive T-lymphocytes. Defects in these apoptosis-inducing regulatory mechanisms may result in the development of autoimmune diseases. Therefore, enhancing the cells own suicide program, offers a most attractive therapeutic target for the treatment of autoimmune diseases.

Language: en

Keywords

Activation-induced cell death; animal cell; apoptosis; Apoptosis; autoantigen; autoimmune disease; Autoimmune disease; B lymphocyte; Bcl-2; Bcl-x(L); bisindolylmaleimide; Caspases; CD95; cell selection; cyclosporin A; Death receptors; Fas; Fas antigen; Fas-associated death domain (FADD); Fas-associated protein-1 (FAP-1); Flice-like inhibitory protein (FLIP); gld; human; human cell; immunoglobulin enhancer binding protein; immunoregulation; Inhibitor of apoptosis (IAP); lpr; major histocompatibility antigen; mouse; nonhuman; Nuclear factor-κb protein kinase C; protein bcl 2; protein bcl x; regulatory mechanism; review; T lymphocyte; T lymphocyte activation; T lymphocyte receptor; T-lymphocytes; tacrolimus; thymus; tissue injury; tumor necrosis factor alpha; tumor necrosis factor receptor; Tumour necrosis factor α