Martin T, Blaison G, Levallois H, Pasquali J L
Laboratoire d'immunopathologie, Hôpital Civil, Strasbourg, France.
Eur J Immunol. 1992 Jul;22(7):1773-9. doi: 10.1002/eji.1830220716.
Much interest was stirred in recent years by the evidence that rheumatoid factors (RF) variable regions are encoded by a restricted set of V genes, with little or no somatic mutations, that are often overexpressed in the fetal repertoire. This is reminiscent of what has been observed for natural autoantibodies. However, these data come from studies of monoclonal RF (mRF) isolated from patients with lymphoproliferative disorders who usually do not present autoimmune symptoms. The molecular characterization of RF during autoimmune diseases such as rheumatoid arthritis (RA) has been hampered for some time because of their polyclonality; recently using the polymerase chain reaction method, we have demonstrated that RF kappa variable regions from a patient with RA were encoded by V kappa III genes known to code for mRF but that these genes had undergone somatic mutations with a pattern suggesting an antigen-driven maturation. Because an important role of the light chain third complementarity-determining region (CDR3) in anti-IgG reactivity and idiotype expression has already been suspected for RF, we now report the molecular characterization of the junction regions of these rearranged V kappa gens. Surprisingly, our data show that in 55% of the cases there is addition of a proline and/or glycine amino acid residue at the recombination site between V kappa and J kappa. The sequence analysis of our patients' germ-line Vg and J kappa 4 genes segments and their flanking regions demonstrates that the additional codons are not readily explicable by recombination between germ-line sequences and probably result from an N addition process. Since we could not find such an additional codon in 15 previously published mRF kappa chains we suggest that "pathogenic" RF during RA and mRF derive from different, although overlapping, B cell subsets. Moreover, since additional codons at the recombination site of V kappa and J kappa seem exceptional in expressed human kappa chains and because the resulting amino acid residue is a proline in most cases, we think that RF kappa chain CDR3 is under a very strong selective pressure during RA.
近年来，有证据表明类风湿因子（RF）可变区由一组有限的V基因编码，几乎没有体细胞突变，且这些基因在胎儿库中常过度表达，这引发了诸多关注。这让人想起在天然自身抗体中所观察到的情况。然而，这些数据来自对从通常无自身免疫症状的淋巴增生性疾病患者中分离出的单克隆RF（mRF）的研究。由于RF具有多克隆性，一段时间以来，类风湿关节炎（RA）等自身免疫性疾病中RF的分子特征一直难以确定；最近，我们使用聚合酶链反应方法证明，一名RA患者的RF κ可变区由已知编码mRF的V κ III基因编码，但这些基因发生了体细胞突变，其模式表明是抗原驱动的成熟过程。因为人们已经怀疑RF的轻链第三互补决定区（CDR3）在抗IgG反应性和独特型表达中起重要作用，所以我们现在报告这些重排的V κ基因连接区的分子特征。令人惊讶的是，我们的数据显示，在55%的病例中，V κ和J κ之间的重组位点处添加了脯氨酸和/或甘氨酸氨基酸残基。对我们患者的种系V κ和J κ 4基因片段及其侧翼区域的序列分析表明，这些额外的密码子不太可能通过种系序列之间的重组来解释，可能是由N添加过程导致的。由于我们在之前发表的15条mRF κ链中未发现此类额外密码子，我们认为RA期间的“致病性”RF和mRF源自不同但有重叠的B细胞亚群。此外，由于V κ和J κ重组位点处的额外密码子在表达的人κ链中似乎很罕见，并且在大多数情况下产生的氨基酸残基是脯氨酸，我们认为RA期间RF κ链CDR处于非常强的选择压力之下。
