THE IMMUNOGLOBULIN-KAPPA LIGHT CHAIN REPERTOIRE EXPRESSED IN THE SYNOVIUM OF A PATIENT WITH RHEUMATOID-ARTHRITIS
THE IMMUNOGLOBULIN-KAPPA LIGHT CHAIN REPERTOIRE EXPRESSED IN THE SYNOVIUM OF A PATIENT WITH RHEUMATOID-ARTHRITIS
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DOI：
10.1002/art.1780350809
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发表时间：
1992-08-01
影响因子：
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通讯作者：
SCHROEDER, HW
中科院分区：
文献类型：
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作者：
LEE, SK;BRIDGES, SL;SCHROEDER, HW
客观的。分析类风湿性关节炎 (RA) 患者滑膜组织中 B 细胞反应的性质。具体来说，我们试图确定免疫球蛋白表达模式是否与 B 细胞的多克隆刺激或抗原驱动的反应一致。方法。我们从一位有 18 年 RA 病史的类风湿因子 (RF) 阳性患者的患病滑膜中生成了一个非限制性互补 DNA (cDNA) 文库。鉴定了 kappa 轻链重组体的随机样本，并进行了序列分析。将可变结构域与种系和 cDNA kappa 序列的广泛数据库进行比较。结果。我们发现了富含 kappa 转录本的轻链库，其中包含 2 个 V-kappa 基因片段（Humkv325 和 Humkv328），这些片段通常与表达 RF 活性的副蛋白相关。来自滑膜的 Kappa 可变结构域含有大量体细胞突变，导致编码经典抗原结合位点的氨基酸频繁替换。出乎意料的是，许多这些 kappa 转录本在 V-kappa-J-kappa 连接位点包含非种系编码的核苷酸（N 区）。 N区添加和V-kappa-J-kappa剪接位点变异的组合产生了异常长的互补决定区3区域和V-kappa-J-kappa剪接位点附近的带电氨基酸。结论。在该患者样本中发现的体细胞突变模式支持这样的假设：这些滑膜来源的浆细胞是免疫球蛋白受体依赖性（即抗原驱动）选择的产物。 N 区添加的程度提出了额外的可能性，即这些抗体源自一组不寻常的、逃脱了正常调节的 B 淋巴细胞。
Objective. To analyze the nature of the B cell response in the synovial tissue of a patient with rheumatoid arthritis (RA). Specifically, we sought to determine if the pattern of immunoglobulin expression was consistent with polyclonal stimulation of B cells or an antigen-driven response.Methods. We generated an unrestricted complementary DNA (cDNA) library from the diseased synovium of a rheumatoid factor (RF)-positive patient with an 18-year history of RA. A random sample of kappa-light chain recombinants was identified, and sequence analysis was performed. The variable domains were compared with an extensive database of germline and cDNA kappa-sequences.Results. We found a light chain repertoire enriched for kappa-transcripts containing 2 V-kappa gene segments (Humkv325 and Humkv328) that are frequently associated with paraproteins expressing RF activity. Kappa variable domains from synovium contained numerous somatic mutations which resulted in frequent replacement of amino acids that encode the classic antigen-binding site. Unexpectedly, many of these kappa-transcripts contained non-germline-encoded nucleotides (N regions) at the site of V-kappa-J-kappa joining. The combination of N-region addition and variation in the sites of V-kappa-J-kappa splicing generated unusually long complementarity-determining region 3 regions and charged amino acids near the V-kappa-J-kappa splice site.Conclusion. The pattern of somatic mutations found in this patient sample supports the hypothesis that these synovium-derived plasma cells are the product of immunoglobulin receptor-dependent (i.e., antigen-driven) selection. The extent of N-region addition raised the additional possibility that these antibodies derive from an unusual set of B lymphocytes that have escaped normal regulation.