Idiotypic and Subgroup Analysis of Human Monoclonal Rheumatoid Factors Implications for Structural and Genetic Basis of Autoantibodies in Humans

Rheumatoid factors (RFs) in humans have been studied inten-sively because of their association with autoimmune and lym-phoproliferative diseases. Many human IgM-RFs express cross-reactive idiotypes (CRIs) and have homologous light chains, some of which are encoded by a single V, gene, termed V.325. However, although antibody activity generally requires the interaction between heavy and light chain variable regions, much less is known about structural relationships among RF heavy chains. To delineate further the structural and genetic basis of RF autoantibody synthesis, we generated "sequence-dependent " reagents specific for the human heavy and kappa light chain subgroups, and used them to analyze a panel of 27 monoclonal RFs. In addition, these proteins were tested for the expression of a heavy chain-associated CRI (G6), and a light chain-associated CRI (17.109). The results showed that most 17.109-reactive RFs contain heavy chains of the VHI subgroup, which bear the G6 idiotypic marker. However, among the 14 17.109-reactive RFs, two have heavy chains of the VH sub-group, and another two contain heavy chains of the VHn1 sub-group. Previously, we have shown that 17.109 is a phenotypic marker of the human V,325 gene. Accordingly, these results demonstrate that the same human V, gene can combine with several VH genes from different V " gene subgroups to generate RF activity