Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes
Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes
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DOI：
10.1084/jem.192.8.1151
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发表时间：
2000-10-16
影响因子：
15.3
通讯作者：
Chiorazzi, N
中科院分区：
文献类型：
--
作者：
Itoh, K;Meffre, E;Chiorazzi, N
成熟B细胞可以通过多种机制改变其抗体库，包括免疫球蛋白重链可变区（V-H）替代。该过程通过用新的V-H片段的相应部分取代原V-H/多样性/重链连接区（V-H- dj (H)）重排的一部分来改变抗原结合位点。这种交换可能涉及嵌入在V-H基因编码区域的隐七聚体样序列。在研究类风湿关节炎（RA）患者滑膜组织中扩张的B淋巴细胞时，发现明显由V-H替代产生的V(H)DJ(H)变异克隆的频率惊人（接近8%）。多个独立的V-H替换事件发生在不同的后代克隆的例子也被确定。这些次级V-H重排在cDNA和基因组DNA水平上都有记录，涉及V-H内四个不同位置的几个七聚体样序列（三个位点在框架区3，一个在互补决定区2）。嵌入七聚体的钝端双链DNA断裂的鉴定和重组酶激活基因（RAG）的表达表明，这些重排可能发生在滑膜组织中，可能发生在伪生发中心，并且可能由RAG以识别信号序列特异性的方式介导。在经过替换的克隆中存在V-H突变，表明这些B细胞具有免疫能力，可以接收和响应多样化信号。应考虑这些继发性V-H基因重排与RA自身免疫特性之间的关系。
Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (V-H) replacement. This process changes the antigen combining site by replacing a portion of the original V-H/diversity/heavy chain joining region (V-H-DJ(H)) rearrangement with a corresponding portion of a new V-H segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of V-H genes.While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with V(H)DJ(H) variants that were apparently generated by V-H replacement were identified with surprising frequency (similar to8%). Examples of multiple independent V-H replacement events occurring in distinct progeny clones were also identified. These secondary V-H rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V-H (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence-specific manner. The presence of V-H mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary V-H gene rearrangements and the autoimmunity characteristic of RA should be considered.