Background and aims Autoantibodies targeting Ro52 occur in systemic lupus erythematosus, Sjogren’s syndrome and idiopathic inflammatory myopathies. Yet the most compelling evidence for their pathogenesis is the development of cardiac conduction abnormalities, a manifestation of neonatal lupus, in foetuses exposed to maternal anti-Ro52 autoantibodies. Recent studies investigating other pathogenic autoantibodies (anti-interferon, anti-desmoglein) report that they arise as a result of somatic mutation. The aim of this study was to determine how anti-Ro52 autoantibodies originate.
Methods We traced the evolution of two anti-Ro52 autoantibodies isolated from circulating IgG-switched memory B-cells from a mother of two children with cardiac neonatal lupus. Each antibody was expressed as its immune form or pre-immune ancestor by reverting somatic mutations to germline sequence. Antibody reactivity against autoantigens Ro52, Ro60, La and dsDNA were tested by ELISA.
Results Both anti-Ro52 autoantibodies utilised the same heavy and light chain genes (IGHV3-23 and IGLV1-44) but represented distinct clones based on differing complementarity determining region sequences. Anti-Ro52 autoantibodies exhibited a low frequency (3%–4%) of somatic mutations compared to the average rate of 8% in healthy switched memory B-cells. In contrast to other pathogenic autoantibodies, the pre-immune (germlined) anti-Ro52 autoantibodies showed specific binding to Ro52. However, Ro52 reactivity was higher for the mutated post-immune antibodies compared to their pre-immune counterparts demonstrating that autoreactivity was enhanced by affinity maturation.
Conclusions These data demonstrate that Ro52 reactivity is an intrinsic property of the germline antibody repertoire in a mother of children affected by neonatal lupus and indicate defects in central and peripheral tolerance pathways allow propagation of pathogenic autoantibodies.
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