Williams D G, Moyes S P, Mageed R A
MRC Collaborative Centre, Mill Hill, London, UK.
Immunology. 1999 Sep;98(1):123-36. doi: 10.1046/j.1365-2567.1999.00841.x.
The presence of clonally-related B-lymphocyte aggregates within synovial lining tisue of rheumatoid arthritis (RA) patients suggests a germinal centre-like reaction, which may hold implications for disease pathogenesis and the causes of chronic inflammation. We studied 250 rheumatoid factor (RF) heavy-chain sequences cloned from the synovium of three patients with RA, to determine whether they undergo both somatic mutation and isotype switching consistent with this hypothesis. Size analysis of immunoglobulin heavy-chain cDNAs from synovial RF+ B cells revealed oligoclonal RF+ populations and identically-sized VH-D-JH transcripts of different immunoglobulin isotypes. Sequencing of individual inserts selected from cloned immunoglobulin heavy-chain cDNAs demonstrated a clonal relationship between immunoglobulin M (IgM) RF and IgA RF, suggesting that this isotype switch occurred in synovium. Furthermore, most somatic mutations were found to have occurred after this isotype switch. This finding suggests that the RA synovial microenvironment sustains somatic mutation and isotype switching in RF-specific B lymphocytes akin to secondary lymphoid organs.
类风湿关节炎（RA）患者滑膜衬里组织中存在克隆相关的B淋巴细胞聚集物，提示存在生发中心样反应，这可能对疾病发病机制和慢性炎症的病因具有重要意义。我们研究了从三名RA患者滑膜中克隆的250个类风湿因子（RF）重链序列，以确定它们是否经历了与该假设一致的体细胞突变和同种型转换。对滑膜RF+B细胞免疫球蛋白重链cDNA的大小分析显示了寡克隆RF+群体以及不同免疫球蛋白同种型的大小相同的VH-D-JH转录本。对从克隆的免疫球蛋白重链cDNA中选择的单个插入片段进行测序，证明免疫球蛋白M（IgM）RF和IgA RF之间存在克隆关系，表明这种同种型转换发生在滑膜中。此外，发现大多数体细胞突变发生在这种同种型转换之后。这一发现表明，RA滑膜微环境在RF特异性B淋巴细胞中维持体细胞突变和同种型转换，类似于二级淋巴器官。
