UPMC Sorbonne Universities, Paris, France.
INSERM U974, Paris, France.
Ann N Y Acad Sci. 2018 Jan;1412(1):21-32. doi: 10.1111/nyas.13529. Epub 2017 Dec 31.
Women are more susceptible to autoimmune diseases than men. Autoimmunity results from tolerance breakdown toward self-components. Recently, three transcription modulators were identified in medullary thymic epithelial cells that orchestrate immune central tolerance processes: the autoimmune regulator (AIRE), FEZ family zinc finger 2 (FEZF2 or FEZ1), and PR domain zinc finger protein 1 (PRDM1). Interestingly, these three transcription modulators regulate nonredundant tissue-specific antigen subsets and thus cover broad antigen diversity. Recent data from different groups demonstrated that sex hormones (estrogen and testosterone) are involved in the regulation of thymic AIRE expression in humans and mice through direct transcriptional modulation and epigenetic changes. As a consequence, AIRE displays gender-biased thymic expression, with females showing a lower expression compared with males, a finding that could explain the female susceptibility to autoimmune diseases. So far, FEZF2 has not been related to an increased gender bias in autoimmune disease. PRDM1 expression has not been shown to display gender-differential thymic expression, but its expression level and its gene polymorphisms are associated with female-dependent autoimmune disease risk. Altogether, various studies have demonstrated that increased female susceptibility to autoimmune diseases is in part a consequence of hormone-driven reduced thymic AIRE expression.
女性比男性更容易患自身免疫性疾病。自身免疫是由于对自身成分的耐受性丧失而导致的。最近，在髓质胸腺上皮细胞中鉴定出三种转录调节剂，它们协调免疫中枢耐受过程：自身免疫调节因子（AIRE）、FEZ 家族锌指 2（FEZF2 或 FEZ1）和 PR 结构域锌指蛋白 1（PRDM1）。有趣的是，这三种转录调节剂调节非冗余的组织特异性抗原亚群，从而覆盖广泛的抗原多样性。来自不同研究小组的最新数据表明，性激素（雌激素和睾酮）通过直接转录调节和表观遗传变化参与人类和小鼠胸腺 AIRE 表达的调节。因此，AIRE 表现出性别偏向的胸腺表达，女性的表达水平低于男性，这一发现可以解释女性易患自身免疫性疾病的原因。到目前为止，FEZF2 与自身免疫性疾病的性别偏见增加无关。PRDM1 的表达尚未显示出性别差异的胸腺表达，但它的表达水平及其基因多态性与女性依赖性自身免疫性疾病风险相关。总之，各种研究表明，女性自身免疫性疾病易感性增加部分是由于激素驱动的胸腺 AIRE 表达减少所致。
