Molecular Mechanism of Immunoglobulin V-Region Diversification Regulated by Transcription and RNA Metabolism in Antigen-Driven B Cells
Molecular Mechanism of Immunoglobulin V-Region Diversification Regulated by Transcription and RNA Metabolism in Antigen-Driven B Cells
复制标题
抗原驱动B细胞转录和RNA代谢调节免疫球蛋白V区多样化的分子机制
DOI：
10.1111/j.1365-3083.2011.02557.x
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发表时间：
2011
影响因子：
3.7
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Sakaguchi N;et al
免疫系统产生针对外源性和内源性来源的任何抗原（Ag）的特异性抗体（Ab），具有多种V区特异性。免疫球蛋白（IG）V区、D和J片段在早期B细胞分化过程中插入N和P序列后发生重排，形成了V区的主要组成部分。最近的研究表明，外周淋巴器官中产生的IgV区域的次级多样化在产生有效的抗体以保护免受各种病原体的侵害中起着关键作用。与Ag反应的幼稚B细胞在滤泡区启动增殖和分化，并产生生殖中心（GC），在此活化诱导的胞苷脱氨酶（AID）依赖性IgV区体细胞超突变（SHM）和类别转换重组产生高亲和力和类别转换的成熟Ag特异性B细胞。我们的研究发现了一种210 kDa的核蛋白，称为GC相关核蛋白（GANP），在T细胞依赖性（TD）免疫应答期间在GC B细胞中上调。通过研究ganp基因突变形式的小鼠，我们证明GANP通过影响IgV区域的SHM，对于产生针对TD‐Ag的高亲和力B细胞至关重要。GANP与细胞质中的AID相关，GANP/AID复合物被募集到细胞核，特别是染色质，并选择性靶向B细胞中的IgV区域基因。GANP增强了AID对B细胞中IgV区域的进入。本文通过对B细胞IgV-区特异性产生SHM的分子机制的详细分析，综述GANP在获得性免疫中的作用。
The immune system produces specific antibodies (Ab) against any antigens (Ag) of exogenous and endogenous origins with a diverse repertoire of V‐region specificities. The primary V‐region repertoire is created by the rearrangement ofimmunoglobulin(Ig)V‐region,D‐andJ‐segmentswith the insertion ofN‐andP‐sequencesduring early B cell differentiation. Recent studies revealed that secondary diversification of the IgV‐region generated in the peripheral lymphoid organs plays a critical role in the generation of effective Ab production for protection from various pathogens. Naïve B cells that react with Ags initiate proliferation and differentiation in the follicular region and create the germinal centres (GCs), where activation‐induced cytidine deaminase (AID)‐dependentIgV‐regionsomatic hypermutation (SHM) and class‐switch recombination generate high‐affinity and class‐switched mature Ag‐specific B cells. Our studies have discovered a 210‐kDa nuclear protein, named GC‐associated nuclear protein (GANP) that is up‐regulated in GC B cells during the T cell–dependent (TD) immune responses. By studying mice with mutant forms of theganpgene, we demonstrated that GANP is essential for the generation of high‐affinity B cells against TD‐Ag by affecting SHM at the IgV‐regions. GANP is associated with AID in the cytoplasm and the GANP/AID complex is recruited to the nucleus, specifically, the chromatin, and targeted selectively to theIgV‐regiongene in B cells. GANP augments the access of AID towardsIgV‐regionsin B cells. Here, we review the role of GANP in acquired immunity through the detailed analysis of the molecular mechanism generating SHM specifically atIgV‐regionsin B cells.