Rheumatoid factors (RF, anti-IgG) are important in the pathophysiology of human autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The specificities and idiotypes of these rheumatoid factors may be relevant to their pathogenic potential in autoimmune diseases, since human RFs in nonrheumatoid conditions appear to have different specificities. Theoretically, rheumatoid factors could develop as a response to a specific autoimmunogenic stimulus, polyclonal activation, or to altered homologous IgG or immune complexes. These stimuli might trigger different immunoregulatory mechanisms. Unfortunately, experimental systems where such isolated, defined stimuli can be applied are uncommon. For example, though RF titers correlate with arthritis in the MRL-1pr/1pr mouse strain, analysis is confounded by the fact that the congenic MRL line is also autoimmune. In the proposed experiments, anti-IgG spontaneously produced in B6-1pr/1pr and normal non-autoimmune B6-+/+ mice will be characterized. Anti-IgG will also be induced by mitogenic and chronic antigenic stimulation and by immunization with altered IgGs. RF activity will be characterized by quantity, specificity, and idiotype. Preliminary studies strongly suggest that the anti-IgG specificities occurring spontaneously in the B6-1pr/1pr female are distinct from those of the B6-1pr/1pr male and anti-IgGs inducible or occurring spontaneously in normal B6 mice. Significant RF clonotypes will be identified by specificity and isoelectric focusing, and hybridomas initially isolated by specificity. Anti-idiotypic reagents will then be utilized to investigate the RF idiotypic representation in sera of other 1pr and their respective parent congenic strains. These reagents will also be used in the study of the in vitro production of RF, in which the cellular requirements and sources for the production of various RF idiotypes and specificities will be defined. These results should provide clues to the mechanism of rheumatoid factor production in human autoimmune disease.
