Nossal G J
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Ciba Found Symp. 1997;204:220-30; discussion 230-1. doi: 10.1002/9780470515280.ch15.
Whereas lymphatic tissues were implicated as the chief sites for antibody production almost 100 years ago, three findings cemented the role of the plasma cell as the actual producer, namely the histological and tissue culture studies of Fagraeus, the beautiful immunofluorescent approach of Coons and his group, and the micromanipulation approach to the study of antibody formation by single cells introduced by Lederberg and myself. Proof that antibody-forming cells derived from B, rather than T, cells had to await the studies of Miller and Mitchell, with some minor technical contributions from myself. The physiology of the germinal centre also has a long history, and recently much interest has surrounded the relative roles of germinal centres as sites of somatic immunoglobulin V gene hypermutation and selection of high affinity B cells, versus the roles of extra-follicular proliferative foci as sources of the primary antibody response. Tolerance and self-antigens within the primary B lymphocyte repertoire is secured by clonal deletion within the bone marrow of those cells which are operationally the most threatening to the body, and a second level of functional impairment of B cell activity and life-span, capable of being induced centrally or peripherally, termed clonal anergy. As these concepts became progressively more refined through transgenic models of immunological tolerance, we turned our attention more towards tolerance within the secondary B lymphocyte repertoire. This is generated primarily inside germinal centres, where it appears that two quite separate mechanisms act as a bulwark against the possible creation of hypermutated anti-self cells. The first is that germinal centre activity and memory cell generation are dependent on antigen-specific, germinal centre-seeking CD4+ T cells, and if a putative anti-self mutant B cell gets no help because of T cell tolerance, it will not expand further. The second is a very specific mechanism confined to the germinal centre whereby antigen-specific B cells are especially sensitive to antigen-induced apoptosis if soluble, deaggregated antigen is presented to them before they reach the 'rescue' signal of follicular dendritic-cell-bound antigen. While some of the death in germinal centres is clearly apoptotic in nature, a further phenomenon observed electron microscopically relates to the formation of type B dark cells. It is not yet clear whether the DNA in this type of dying cell is cleaved. Transgenic expression of bcl-2 in germinal centre B lymphocytes confers incomplete protection from apoptosis caused by soluble antigen. The suggestion that at least some of this apoptosis is mediated via Fas-Fas ligand interactions is prompted by the observation that the apoptotic phenomenon is markedly reduced in lpr mice.
大约100年前，淋巴组织就被认为是抗体产生的主要部位，而有三项发现巩固了浆细胞作为实际产生者的作用，即法格雷斯的组织学和组织培养研究、库恩斯及其团队出色的免疫荧光方法，以及莱德伯格和我本人引入的用于研究单细胞抗体形成的显微操作方法。证明抗体形成细胞来源于B细胞而非T细胞，这要等待米勒和米切尔的研究，我本人也有一些小的技术贡献。生发中心的生理学也有很长的历史，最近人们对生发中心作为体细胞免疫球蛋白V基因超突变和高亲和力B细胞选择位点的相对作用，与滤泡外增殖灶作为初次抗体反应来源的作用非常感兴趣。初级B淋巴细胞库中的耐受性和自身抗原通过在骨髓中对那些对身体最具潜在威胁的细胞进行克隆清除来确保，以及B细胞活性和寿命的二级功能损害，这种损害能够在中枢或外周被诱导，称为克隆无能。随着这些概念通过免疫耐受的转基因模型逐渐变得更加精确，我们将注意力更多地转向次级B淋巴细胞库中的耐受性。这主要在生发中心内产生，在那里似乎有两种相当不同的机制作为防止可能产生超突变抗自身细胞的堡垒。第一种是生发中心活性和记忆细胞的产生依赖于抗原特异性、寻找生发中心的CD4 + T细胞，如果一个假定的抗自身突变B细胞由于T细胞耐受而得不到帮助，它就不会进一步扩增。第二种是一种局限于生发中心的非常特殊的机制，即如果可溶性、解聚的抗原在抗原特异性B细胞到达滤泡树突状细胞结合抗原的“救援”信号之前呈现给它们，那么这些抗原特异性B细胞对抗原诱导的凋亡特别敏感。虽然生发中心的一些死亡显然本质上是凋亡性的，但电子显微镜观察到的另一个现象与B型暗细胞的形成有关。这种类型的死亡细胞中的DNA是否被切割尚不清楚。生发中心B淋巴细胞中bcl - 2的转基因表达赋予了对可溶性抗原引起的凋亡的不完全保护。lpr小鼠中凋亡现象明显减少，这一观察结果提示至少部分这种凋亡是通过Fas - Fas配体相互作用介导的。
