Rheumatoid arthritis is an extravascular immune complex disease that affects several million Americans. The exact cause of the illness is unknown. However, IgM and IgG autoantibodies against IgG (rheumatoid factors, RF), in the absence of exogenous antigens, form the largest fraction of the complement-fixing immunoglobulin aggregates that are abundant in rheumatoid synovial fluids. Experiments from this laboratory have demonstrated the inheritance of RF-associated private idiotypes in families of patients with rheumatoid arthritis, and the sharing of idiotypes by the kappa light chains of RF's from unrelated individuals. Additionally, the investigations have shown that IgM-RF precursors circulate in normal subjects at birth and are frequent among the immature B lymphocytes of normal adults. These results have prompted us to suggest that the sustained production of RF in rheumatoid patients, in the absence of any apparent exogenous stimulus, may signify an underlying, abnormal regulation of B lymphocytes at early stages of differentiation. We now propose (1) to use newly developed and unique anti-idiotypic reagents to elucidate how immunoglobulin structural genes influence RF synthesis and fine specificity in normal and rheumatoid subjects, (2) to determine the role of accessory T cells in the switch from IgM-RF to IgG-RF, (3) to disclose the part played by autologous anti-idiotypic antibody in the regulation of RF synthesis, and in the formation of immune complexes, (4) to modify RF production with drugs that alter immature B cell function, with anti-receptor antibodies, and by active immunization with synthetic-hypervariable region peptides. The experiments will help ascertain why IgM-RF and IgG-RF regularly develop in rheumatoid patients, and will show how these normally protective autoantibodies contribute to a self-perpetuating synovitis. They may lead to new modalities for the treatment of rheumatoid disease.
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