Deftos M, Olee T, Carson D A, Chen P P
Department of Medicine, University of California, San Diego, La Jolla 92093-0663.
J Clin Invest. 1994 Jun;93(6):2545-53. doi: 10.1172/JCI117265.
A major diagnostic marker in most rheumatoid arthritis (RA) patients is the rheumatoid factor (RF), an autoantibody that binds to the Fc region of IgG. To delineate the Ig genes and the underlying mechanism for RF production in RA patients, we applied a systematic approach to define the genetic origins of three IgG RFs derived from the synovial fluid of two RA patients. The results show that two of three IgG RF have substantial numbers of somatic mutations in their variable (V) regions, ranging from 13 to 23 mutations over a stretch of 291-313 nucleotides, resulting in a frequency of 4.4-7.8%. However, one IgG RF has only one mutation in each V region. This result indicates that an IgG RF may arise from a germline gene by very few mutations. The mutations occur mainly in the complementarity-determining regions (CDRs), and the mutations in the CDRs often lead to amino acid substitutions. Five of the six corresponding germline V genes have been found to encode either natural autoantibodies or autoantibodies in other autoimmune disorders; and three of the six V genes have been found in fetal liver. Taken together with other results, the data show that (a) several potentially pathogenic RFs in RA patients arise from natural autoantibodies, and (b) only a few mutations are required to convert the natural autoantibodies to IgG RFs.
大多数类风湿关节炎（RA）患者的一个主要诊断标志物是类风湿因子（RF），它是一种与IgG的Fc区域结合的自身抗体。为了描绘RA患者中RF产生的Ig基因及潜在机制，我们采用了一种系统方法来确定源自两名RA患者滑液的三种IgG RF的基因起源。结果显示，三种IgG RF中的两种在其可变（V）区域有大量体细胞突变，在291 - 313个核苷酸的片段上有13至23个突变，频率为4.4% - 7.8%。然而，一种IgG RF在每个V区域只有一个突变。这一结果表明，一种IgG RF可能仅通过极少的突变就从种系基因产生。这些突变主要发生在互补决定区（CDR），且CDR中的突变常常导致氨基酸替换。已发现六个相应种系V基因中的五个编码天然自身抗体或其他自身免疫性疾病中的自身抗体；六个V基因中的三个在胎儿肝脏中被发现。结合其他结果，数据表明：（a）RA患者中几种潜在致病性RF源自天然自身抗体；（b）只需少数突变就能将天然自身抗体转化为IgG RF。
