The broad objective of this research is to elucidate mechanisms underlying the expression of rheumatoid factor (RF), an autoantibody implicated in the pathogenesis of tissue injury in rheumatoid arthritis (RA). While considerable progress has been made in defining the molecular basis of RF paraprotein diversity, the genetic basis of RF diversity in RA remains uncertain and the mechanisms underlying induction of RF production in RA unexplained. The goals of this project are: to delineate VH/VL genes which contribute to RF expression in RA; to investigate the role of clonal selection (and somatic mutation) in the RF response in RA; and to determine whether polymorphisms of relevant germline VH/VL genes contribute to RF production (and disease susceptibility). Clonal EBV-transformed B-cell lines (from RA and controls) which secrete RF characteristic of RA will be used to determine the nucleotide sequence of RF-associated VH/VL genes; the corresponding germline VH/VL genes will be identified; and the expressed sequences will be analyzed in comparison to the germline sequences for the presence of somatic mutations and the pattern of their distribution (i.e., CDR versus framework regions). Monoclonal antibodies (mAbs) directed against structurally defined VH and/or VL chain cross-reactive idiotopes (CRI) expressed by secreted RF will be generated and used to investigate the prevalence/distribution of these CRI among serum and synovial RF in RA patients from whom the clones were obtained. Moreover, the prevalence of these VH/VL CRI in serum and synovial RF will be investigated in cross- sectional and longitudinal studies in RA patients (and controls) and RA families. Using oligonucleotide probes complementary to framework and hypervariable region sequences of RF-associated V-region germline genes, polymorphisms of these genes will be examined in RA patients, RA families and controls. The relationship of VH/VL polymorphisms to RF expression and RA susceptibility will be analyzed. Taken together, these studies should shed new insights concerning the genetic origin of RF in RA mechanisms underlying its production.
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