RECIPROCAL T-B DETERMINANT SPREADING DEVELOPS SPONTANEOUSLY IN MURINELUPUS - IMPLICATIONS FOR PATHOGENESIS

Recent work from several laboratories has shown that, in contrast to t he widely held notion that one autoimmune disease is caused by one or a few related autoantigenic determinants, autoimmunity is fundamentall y a continuously evolving process. The autoimmune responses shift, dri ft and diversify with time not only to other determinants in the origi nal antigen but also to other antigens. We have described a form of de terminant 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 V-H region del ayed the appearance of IgG anti-dsDNA antibodies and onset of lupus ne phritis in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Understanding the diversification patterns in autoimmune responses ha s enormous implications in developing peptide-targeted therapies.