In humans, increases in rheumatoid factor (RF) production are associated with rheumatoid arthritis (RA) and other autoimmune syndromes, chronic viral and bacterial infections, and secondary antigen challenge. It is hypothesized that RF contributes to the lymphocyte hyperactivity and inflammation characteristic of RA and the regulation of ongoing antibody responses in normal subjects. This hypothesis is based on the ability of RF to recognize autologous IgG; thus RF could contribute to the formation of biologically-active immune complexes (IC). Preliminary data generated thus far indicate that RF-containing IC isolated from the plasma of RF patients are able to induce, in normal mononuclear cell cultures, many of the immunological phenomena characteristic of the RA synovium, e.g., the stimulation of B cell differentiation to plasma cells and the stimulation of interleukin-1 and arachidonate metabolite release from monocytes. Studies will be initiated to characterize RF-IC from plasma and synovial fluid of autoimmune patients and to determine the parameters of lymphocyte and monocyte activation by these preparations. Other preliminary data indicate that Fc region fragments resulting from the enzymatic degradation of immunoglobulin also elicit the effects described above. Therefore, studies will be initiated to identify these active fragments in RA synovial fluid and plasma, to further localize active peptide sequences in Fc region fragments, and to determine whether monocytes are able to degrade RF-IC into immunostimulatory Fc region fragments. Finally, early studies have revealed that monoclonal human IgM RF, free of IC, is able to inhibit mitogen-induced B cell differentiation in normal human mononuclear cell cultures. Therefore, studies will be initiated to address the mechanism by which these preparations regulate B cell function.
