A genetic study of the anti-DNA associated idiotype 8.12: Analysis of 8.12(+) antibodies and autoantibodies, and characterization of the VlambdaII gene family

Abstract

Individuals with systemic lupus erythematosus (SLE) characteristically display high serum titers of autoantibodies directed against a variety of nuclear antigens. While SLE autoantigens typically include both proteins and nucleic acids, antibodies against double stranded DNA are the hallmark of this disease and have been implicated in its pathogenesis. 8.12 is an anti-DNA associated idiotype present in elevated titers in the serum of over 50% of patients with SLE and can constitute up to one third of a patient's anti-DNA antibodies. Generation and analysis of a panel of 8.12{dollar}\sp+{dollar} antibodies, both DNA binding and non-DNA binding, was undertaken to identify the genes which encode anti-DNA antibodies and the structures that impart anti-DNA specificity. In conjunction with RFLP studies of 8.12- encoding genes, such an analysis may elucidate the origins and the (dys)regulation of SLE anti-DNA autoantibodies. This thesis comprises three sections: (1) correlation of the 8.12 idiotypic family with the V{dollar}\lambda{dollar}II gene family and genetic mapping of the idiotope to a region near CDR1, (2) characterization of the V{dollar}\lambda{dollar}II gene family and determination of V{dollar}\lambda{dollar}II and C{dollar}\lambda{dollar} polymorphisms in SLE, and (3) a structural and mechanistic analysis of two 8.12{dollar}\sp+{dollar} anti-dsDNA antibodies, exploring their origins and evaluating their relationship to idiotypically and/or genetically homologous DNA and non-DNA binding antibodies. ftn*All degree requirements completed in 1992, but degree will be granted in 1993.