Prevention and control of reciprocal T-B cell diversification: implications for lupus-like autoimmunity.
Prevention and control of reciprocal T-B cell diversification: implications for lupus-like autoimmunity.
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T-B 细胞相互多样化的预防和控制：对狼疮样自身免疫的影响。
DOI：
10.1016/j.molimm.2003.11.029
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发表时间：
2004
影响因子：
3.6
通讯作者：
Singh,RamRaj
中科院分区：
文献类型：
--
作者：
Singh,RamRaj
自身免疫从根本上来说是一个不断发展的过程。自身免疫反应随着时间的推移而发生变化、漂移和多样化，不仅针对原始抗原中的其他表位，而且还针对其他相关抗原，有时针对不相关抗原。我们描述了一种免疫多样化形式——T-B表位相互扩散——其中来自自身抗体分子的表位激活第一个T细胞可能会为多种显示原始表位交叉反应版本的B细胞提供帮助。反应以这种方式传播，直到大量 T 细胞和 B 细胞在易患狼疮的小鼠中扩增。这种 T-B 细胞的相互反应也可以在正常动物中诱导，其程度受到抑制性 T 细胞的出现的限制。狼疮小鼠中这种抑制性 T 细胞的诱导通常受到损害。然而，通过质粒 DNA 载体传递 T 细胞表位可以克服狼疮小鼠的这种缺陷。由此诱导的抑制性 T 细胞可以通过消除或抑制自身反应性 B 细胞来抑制自身抗体的产生和狼疮疾病。因此，在正常动物中，狼疮小鼠自发产生的 T-B 多样化可能会被抑制性 T 细胞所抑制，每当病理性自身免疫“危险”即将来临时，抑制性 T 细胞就会出现。我们已经成功地利用正常免疫反应的这种调节潜力来抑制临床自身免疫。了解狼疮小鼠自身免疫多样化及其在正常动物中下调的机制可能为开发针对狼疮等自身抗体介导的疾病的新疗法铺平道路。
Autoimmunity is fundamentally a continuously evolving process. The autoimmune responses shift, drift and diversify with time not only to other epitopes in the original antigen but also to other related and sometimes to unrelated antigens. We have described a form of immune diversification—reciprocal T–B epitope spreading—where the activation of first T cells by epitopes from an autoantibody molecule could lead to help provided to a variety of B cells displaying a cross-reactive version of the original epitope. The response spreads in this way until large cohorts of T and B cells have expanded in lupus-prone mice. Such reciprocal T–B cell response can also be induced in normal animals, its extent is limited by the emergence of inhibitory T cells. The induction of such inhibitory T cells is generally impaired in lupus mice. The delivery of T cell epitopes via plasmid DNA vectors, however, can overcome this impairment in lupus mice. The inhibitory T cells thus induced can suppress autoantibody production and lupus disease by ablating or inhibiting autoreactive B cells. Thus, T–B diversification that develops spontaneously in lupus mice could be curtailed in normal animals by inhibitory T cells that emerge whenever there is an impending ‘danger’ of pathologic autoimmunity. We have successfully exploited this regulatory potential of the normal immune response to inhibit clinical autoimmunity. Understanding the mechanisms of autoimmune diversification in lupus mice and of its down-regulation in normal animals may pave the way for developing novel treatments for autoantibody-mediated diseases such as lupus.
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