Theory and treatment of the X-inactivation chimera in female-prevalent autoimmune disease.
The vast majority of patients with systemic autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus are female. The female prevalence of such autoimmune diseases is poorly understood. In theory, X-chromosome inactivation and resultant tissue chimerism may explain the female predisposition to systemic autoimmunity. For example, autoreactive T cells may fail to be tolerized by self antigens encoded by one of the two X chromosomes (the Kast conjecture). In the periphery, these autoreactive T cells may stimulate B cells expressing the target X-encoded antigen, so the Kast conjecture can be extended to explain how systemic autoimmunity may be induced. Another hypothesis proposes the X-encoded genes cause autoimmunity by affecting B or T cells directly; however, significant evidence has been raised discrediting this hypothesis. An attractive feature of X-inactivation hypotheses is that the discordance rate between monozygotic twins may readily be explained, because otherwise-identical twins may have different X-inactivation patterns. Reviewed here are the immunobiology of X-inactivation chimerism and its roles, both known and postulated, in autoimmune disease. Also discussed are methods appropriate for determining the cellular and molecular targets of autoreactive T cells in female-prevalent autoimmune diseases and methods by which these targets might be used as tolerogens to treat these diseases.
Stewart
J J
JJ
Department of Molecular Biology, Princeton Theoretical Immunology Group, Princeton University, NJ 08544, USA. jjs@alumni.princeton.edu
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D015551:Autoimmunity / Q000235:genetics; D002678:Chimera / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D004200:Diseases in Twins / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008957:Models, Genetic; D017634:Self Tolerance / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014430:Twins, Monozygotic