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.