Rethinking mechanisms of autoimmune pathogenesis.
Rethinking mechanisms of autoimmune pathogenesis.
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DOI：
10.1016/j.jaut.2013.05.003
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发表时间：
2013-09
影响因子：
12.8
通讯作者：
Pillai S
中科院分区：
文献类型：
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作者：
Pillai S
究竟为什么有些人会患上自身免疫性疾病，目前尚不清楚。被广泛接受的范例是，遗传易感性导致免疫耐受性的一些破坏，可能增加自身抗原的可获得性，并可能增强炎症反应。在这种易感性背景下发生的一些环境侮辱可能会导致自身免疫。在这篇综述中，我们讨论了与抑制信号和罕见的遗传变异有关的一些方面，以及可能有助于自身免疫的其他因素，包括克隆性体细胞突变的可能作用，表观遗传事件的作用和肠道微生物组的贡献。遗传易感等位基因通常导致免疫耐受性丧失、自身抗原可获得性增加或炎症增加。除了常见的遗传变异外，罕见的功能丧失遗传变异也可能与自身免疫的发病机制有关。对B细胞中抑制信号通路的研究有助于确定一种名为唾液酸乙酰酯酶的负调控酶。对这种酶的罕见遗传变异的研究提供了一个说明性的例子，表明对变异等位基因进行详细的功能分析的重要性，以及从分析中排除功能正常、常见或罕见的遗传变异的必要性。同样清楚的是，受到常见或罕见缺陷变体功能影响的通路也可能更明显地受到表观遗传改变导致的基因表达变化的影响。另一个已被讨论的重要且不断发展的领域与肠道微生物群在影响辅助T细胞极化和自身免疫发展中的作用有关。
Why exactly some individuals develop autoimmune disorders remains unclear. The broadly accepted paradigm is that genetic susceptibility results in some break in immunological tolerance, may enhance the availability of autoantigens, and may enhance inflammatory responses. Some environmental insults that occur on this background of susceptibility may then contribute to autoimmunity. In this review we discuss some aspects related to inhibitory signaling and rare genetic variants, as well as additional factors that might contribute to autoimmunity including the possible role of clonal somatic mutations, the role of epigenetic events and the contribution of the intestinal microbiome. Genetic susceptibility alleles generally contribute to the loss of immunological tolerance, the increased availability of asutoantigens, or an increase in inflammation. Apart from common genetic variants, rare loss-of-function genetic variants may also contribute to the pathogenesis of autoimmunity. Studies of an inhibitory signaling pathway in B cells helped identify a negative regulatory enzyme called sialic acid acetyl esterase. The study of rare genetic variants of this enzyme provides an illustrative example showing the importance of detailed functional analyses of variant alleles and the need to exclude functionally normal common or rare genetic variants from analysis. It has also become clear that pathways that are functionally impacted by either common or rare defective variants can also be more significantly compromised by gene expression changes that may result from epigenetic alterations. Another important and evolving area that has been discussed relates to the role of the intestinal microbiome in influencing helper T cell polarization and the development of autoimmunity.