Molecular basis for the cross-reactive idiotypes on human anti-IgG autoantibodies (rheumatoid factors)

Abstract

High titres of anti-IgG autoantibodies (rheumatoid factors, RF) are characteristic of patients with rheumatoid arthritis, Sjögren's syndrome, and mixed cryoglobulinaemia, and may contribute to immune complex formation and tissue damage. The monoclonal RFs from cryoglobulinaemia patients frequently display cross-reactive idiotypes. The genetic basis for the cross-reactive idiotypes on RF autoantibodies has not been determined. To clarify structural and genetic relationships among RFs from unrelated subjects, a series of anti-peptide antibodies have been generated that define primary sequence-dependent idiotypes on RF heavy and light chains. Multiple monoclonal and polyclonal RFs from unrelated individuals have been probed by Western blotting with the anti-idiotypic reagents. The results show that sequences in the kappa light chain variable region represent a common structural element among RF autoantibodies. This hypothesis is confirmed by the cloning and sequencing of the conserved germline variable region gene which encodes human RF kappa chains.