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 Ro60(316-335) induced Abs to Ro60, La, and snRNP proteins. Specific Abs to determinants outside Ro60(316-335) 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.
Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Umesh S
US
Deshmukh
Felicia
F
Gaskin
Janet E
JE
Lewis
Carol C
CC
Kannapell
Shu Man
SM
Fu
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D017411:Ribonucleoproteins, Small Nuclear