Evidence of Antigen Receptor-influenced Oligoclonal B Lymphocyte Expansion in the Synovium of a Patient with Longstanding Rheumatoid Arthritis

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Abstract

Plasma cell infiltration of synovium is common in longstanding rheumatoid arthritis (RA).The mechanism(s) underlying synovial B cell proliferation remains unclear. One theory invokes nonspecific polyclonal stimuli; another implicates antigen as the driving force. Antigen-driven repertoires are characteristically enriched for related sets of V gene segments containing similar sequence in the antigen binding site (complementarity-determining regions; CDRs). To study the forces shaping B cell proliferation, we analyzed Vkappa transcripts expressed in the synovium of an RA patient. We found Humkv325, a developmentally regulated VkappaIII gene segment associated with autoantibody reactivity, in > 10% of randomly-chosen synovial Ckappa cDNAs. Two sets of sequences contained identical charged amino acid residues at the Vkappa-Jkappa join, apparently due to N region addition. We generated "signature" oligonucleotides from these CDR3s and probed PCR amplified Vkappa products from the synovium and PBLs of the same patient, and from PBLs and spleen of individuals without rheumatic disease. Significant expression of transcripts containing these unique CDR3 sequences occurred only in the patient's synovium. Thus, in this synovium there is expansion of a limited set of B cell clones expressing antigen receptors that bear evidence of antigen selection. (J. Clin. Invest. 1994. 93:361-370.) Key words: rheumatoid arthritis. immunoglobulins-kappa chain. genes-immunoglobulin. antibody diversity. B lymphocytes

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