Cellular basis of T-cell autoreactivity in autoimmune diseases.
There is no doubt that T cells play a key role in the pathogenesis of autoimmune diseases (AD) both as effector and regulatory cells. Despite spectacular progress in the understanding of natural tolerance to self, owing particularly to transgenic technology, important questions remain open regarding the pathogenesis of AD, the conditions favoring the transition from benign or 'physiological' autoimmunity to deleterious autoimmunity, and the precise effector mechanisms. This review on the cellular basis of T-cell-mediated AD begins with an enumeration of the main arguments in favor of direct T-cell involvement, special emphasis being given to two animal models which have been most extensively investigated: experimental allergic encephalomyelitis, and the nonobese diabetic mouse. The question as to whether pathogenic T cells use a restricted repertoire of V beta genes is examined in the context of these two models. From here we proceed to an evaluation of the mechanisms of onset of AD, discussing both extrinsic and intrinsic factors responsible for the breakdown in T-cell tolerance and reviewing the arguments in favor of suppressor T cells being actively involved in the prevention of autoimmunity. The last two sections are devoted to the effector mechanisms responsible for tissue injury in organ-specific AD and to T-cell-directed therapeutic interventions, respectively. We discuss the two main pathogenic hypotheses based on direct intervention of cytotoxic T cells or indirect involvement of inflammatory cytokines and macrophages, and evaluate the importance of ecotaxis in leading autoreactive T cells to the site of injury. We conclude on a brief and nonexhaustive list of strategies aimed at selectively neutralizing potentially harmful T cells.
Carnaud
C
C
INSERM U 25, Hôpital Necker, Paris, France.
Bach
J F
JF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude / Q000276:immunology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell