Reciprocal T-B determinant spreading develops spontaneously in murine lupus: implications for pathogenesis.
Recent work from several laboratories has shown that, in contrast to the widely held notion that one autoimmune disease is caused by one or a few related autoantigenic determinants, autoimmunity is fundamentally a continuously evolving process. The autoimmune responses shift, drift and diversify with time not only to other determinants in the original antigen but also to other antigens. We have described a form of determinant spreading--reciprocal T-B determinant spreading--where the induction of first T cells by peptides from an autoantibody molecule could lead to help provided to a variety of B cells displaying a cross-reactive version of the original determinant. The response spreads in this way by reciprocal T-B stimulation until large cohorts of T and B cells have expanded. Such spontaneous expansion must be important in clinical disease, since tolerance induction to a limited set of T-cell determinant peptides derived from an anti-DNA antibody VH region delayed the appearance of IgG anti-dsDNA antibodies and onset of lupus nephritis in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Understanding the diversification patterns in autoimmune responses has enormous implications in developing peptide-targeted therapies.
Singh
R R
RR
Department of Medicine, University of California, Los Angeles 90095-1670, USA. rasingh@med1.medsch.ucla.edu
Hahn
B H
BH
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D000939:Epitopes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes