B-CELLS PROCESS AND PRESENT LUPUS AUTOANTIGENS THAT INITIATE AUTOIMMUNE T-CELL RESPONSES

Antibodies against U small nuclear ribonucleoprotein (snRNP) particles are a common finding in the sera of humans with SLE and in certain st rains of mice with murine lupus. It is likely that Th cells are import ant in amplifying this autoantibody response. The focus of this work w as to investigate events that might initiate autoimmune B and T cell r esponses in non-autoimmune mice to native snRNP particles. Mice that w ere immunized and boosted with native mouse snRNPs failed to produce a ny detectable specific anti-snRNP antibody or T cell responses, sugges ting that these autoreactive cells were deleted from the repertoire or were anergic to stimulation with this self Ag. In contrast, immunizat ion with native foreign (human) snRNPs elicited both T cells and cross -reactive anti-snRNP antibodies; the latter predominantly were directe d toward the A protein of the U1 snRNP. When mice were immunized with human and mouse snRNPs together in adjuvant, T cells specific for mous e snRNPs could be elicited. The results of these experiments suggested that the mechanism of breaking T cell tolerance to self snRNPs was de pendent on the ability of cross-reactive B cells to process and presen t these autoantigens. To address this hypothesis, B cells purified fro m mice immunized with recombinant human A protein were transferred int o naive mice. Upon boosting with native mouse snRNPs, autoreactive CD4 + T cells specific for mouse Ags, and not cross-reactive with human sn RNPs, were observed. These studies support a model of molecular mimicr y whereby autoantigen-presenting B cells are generated by foreign cros s-reactive determinants that can, in turn, elicit an autoimmune T cell response.