Rheumatoid factors (RFs) are autoantibodies that are involved in the rheumatoid disease process. While they are found in the serums of patients with many diseases besides rheumatoid arthritis (RA), they are uniquely found in the rheumatoid synovium. Traditionally, RFs have been viewed as associated phenomena rather than directly related to the inciting agent in RA. Work from our laboratory has raised the possibility that RFs in RA may bear the internal image of Fc receptors of infectious agents and arise in RA as antiidiotypic antibodies (antiId) to antibodies to microbial Fc receptors. Staphylococcus aureus, groups A, C and G streptococci and the viruses of the herpes group, herpes virus type 1, herpes virus type 2, Epstein-Barr virus, cytomegalovirus and varicella-zoster virus all have or induce Fc receptors on cell surfaces. We seek to test this internal image hypothesis by developing a panel of monoclonal RFs from patients with RF-positive rheumatoid arthritis and RF-positive control diseases (systemic lupus erythematosus, subacute bacterial endocarditis, and otherwise normal individuals) using somatic cell hybridization with human mononuclear cells from peripheral blood, synovial tissue or spleen. The antigenic specificity for the RFs will be delineated and similarities to the sites that bind the microbial Fc receptors will be determined. Mouse monoclonal antibodies (MAb) to conformational (internal image) Id on the RF will be developed. These antiId will be tested for binding to the microbial Fc receptors. In addition, mouse MAb will be developed to each of the microbial Fc receptors and tested for binding to the monoclonal RFs. Those bacterial or viral Fc receptors that are most similar to the RFs in terms of their antigenic determinants and internal image match as probed with the MAb would be best candidates for further etiological considerations in RA. Differences in conformational Id determinants on RFs from patients with RA compared to those from control individuals may well provide the basis for diagnostic tests for RA. Auto-antiId will also be sought to determine their Id specificity and binding to microbial Fc receptors. Furthermore, since antiId can suppress the production of Id, the availability of a panel of antiId or auto-antiId that recognize the majority of RF Ids could potentially have therapeutic usefulness. The proposed systematic studies should therefore substantially enhance our knowledge of RFs with the potential for providing diagnostic and therapeutic reagents as well as to provide tools to probe the infectious etiology of RA.