A systematic approach to defining the germline gene counterparts of a mutated autoantibody from a patient with rheumatoid arthritis

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Abstract
Objective. To define the germline counterparts of potentially highly mutated autoantibodies in disease states. Methods. We developed a systematic approach by first characterizing a rearranged Ig gene and its upstream flank, and then designing suitable primers to amplify specifically the putative germline counterpart. Results. We identified and characterized the germline counterpart of a rheumatoid factor heavy chain variable region. Conclusion. We showed unequivocally that the heavy chain of a rheumatoid factor, derived from synovial tissue, has 4 replacement mutations from the corresponding germline gene. The technique allows quick assessment of the degree of somatic mutation in many autoantibodies, and thus can help to elucidate the underlying mechanisms for the induction and sustained production of such antibodies in patients.