Many Achilles' heels of B and T cell tolerance.
Many Achilles' heels of B and T cell tolerance.
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DOI：
10.1111/imr.13076
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发表时间：
2022-05
影响因子：
8.7
通讯作者：
Zikherman J
中科院分区：
文献类型：
--
作者：
Pelanda R;Zikherman J
通过随机VDJ重组产生巨大的抗原受体库多样性是适应性免疫系统的基石，但其代价是产生大量具有致病潜力的自身反应性淋巴细胞。长期以来，人们认识到淋巴细胞采用一系列优雅的耐受机制来预防自身免疫性疾病。其中几种在T和B细胞中是广泛类似的，包括响应于发育早期递送的强抗原信号的缺失，除了抗原识别之外还需要共刺激以允许成熟淋巴细胞的免疫应答，以及成熟自身反应性淋巴细胞的功能性无应答性（“无反应性”）。此外，还有几种独特的机制可以区分T和B细胞耐受性，如中枢B细胞耐受性中的受体编辑和调节性T细胞的产生。这些机制在很大程度上是通过BCR和TCR转基因动物和其他遗传小鼠模型的开发和研究发现和分子解剖的。通过对小鼠和人类免疫学的研究，以及对不寻常患者表型的尖端分析，出现了新的见解。在这一期的《免疫学评论》中，投稿者描述了建立在这一经典文献基础上的工作，以进一步定义介导中枢和外周T和B细胞耐受性的生化、转录和表观遗传分子机制（Kurosaki，Pelanda，Zikherman，Tsubata，Getahun）。部分综述强调了淋巴细胞接收和传播的信号异常如何突破这些耐受性检查点，在小鼠和人类中产生自身免疫性疾病（韦斯、Kuchroo、Deenick、Acharya和杰克逊）。这些包括对家族性自身免疫综合征中鉴定的信号分子中罕见的生殖系获得性功能突变的讨论（韦斯，Deenick）。另外两篇综述描述了在小鼠模型和人类自身免疫中发现新的致病性T和B细胞群（Tph-Rao，ABCs-Pernis）。最后，里德描述了一个令人兴奋的新作用，体细胞突变的演变致病
Generation of enormous antigen receptor repertoire diversity through random VDJ recombination is the cornerstone of the adaptive immune system, but it comes at the cost of generating large numbers of self-reactive lymphocytes with potential for pathogenesis. It has long been appreciated that a series of elegant tolerance mechanisms are employed by lymphocytes to prevent autoimmune disease. Several of these are broadly analogous in T and B cells, including deletion in response to strong antigen signals delivered early during development, a requirement for co-stimulation in addition to antigen recognition to license immune responses by mature lymphocytes, and functional unresponsiveness of mature self-reactive lymphocytes (‘anergy’). In addition, there are several unique mechanisms that distinguish T and B cell tolerance, such as receptor editing in central B cell tolerance and the generation of regulatory T cells. These mechanisms were discovered and molecularly dissected in large part through the development and study of BCR and TCR transgenic animals and other genetic mouse models. Newer insights are emerging through study of both mouse and human immunology, and through cutting edge analyses of unusual patient phenotypes. In this issue of Immunological Reviews, contributors describe work that has built on this classic literature to further define the biochemical, transcriptional, and epigenetic molecular mechanisms that mediate central and peripheral T and B cell tolerance (Kurosaki, Pelanda, Zikherman, Tsubata, Getahun). Selected reviews highlight how abnormalities in signals received by and propagated in lymphocytes can breach these tolerance checkpoints to produce autoimmune disease in mice and humans (Weiss, Kuchroo, Deenick, and Acharya and Jackson). These include discussion of rare germline gain-offunction mutations in signaling molecules identified in familial autoimmune syndromes (Weiss, Deenick). Two other reviews describe the discovery of new pathogenic T and B cell populations in mouse models and human autoimmunity (Tph-Rao, ABCs-Pernis). Finally, Reed describes an exciting new role for somatic mutations in the evolution of pathogenic
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