Mechanisms of Autoantibody Diversification to SLE-Related Autoantigens
Systemic lupus erythematosus is a prototype of systemic autoimmunity with autoantibodies (autoAbs) to ribonucleoproteins such as Ro/La, snRNP, dsDNA, and other cellular constituents. A/J mice were used to explore the mechanism of autoAb diversification with recombinant proteins and synthetic peptides. Previous studies showed that Ro60316335 induced Abs to Ro60, La, and snRNP proteins. Specific Abs to determinants outside Ro60316-335 were detected. Absorption experiments showed that Abs to La and snRNP proteins were due to the induction of anti-Ro60 Abs cross-reactive with these peptides. With snRNP proteins, SmD, SmB, and A-RNP as immunogens, specific patterns of intermolecular spreading were obtained in addition to Abs to the immunogens. With SmD-immunized mice, specific Abs to A-RNP and SmB were detected. With SmB as the immunogen, specific Abs to A-RNP were detected in the majority of the mice. Only in a rare incident, specific Abs to SmD were induced. In A-RNP-immunized mice, only Abs to the 70-kD U1-RNP were seen. In all cases, Abs capable of precipitating snRNP particles were detected. Thus, the intermolecular epitope spreading is immunogen-dependent. Evidence for the presence of cross-reactive T cells to more than one autoAg was obtained. The Ag-dependent unique patterns of Ab diversification will facilitate analyses of patients' sera. These results have implications regarding the nature of the Ag-driven autoimmune process.
autoantibodies systemic lupus erythematosus snrnp cross-reactivity epitope spreading t cell b cell