Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, UPS, 31300 Toulouse, France.
Arthritis R&D, 92200 Neuilly-Sur-Seine, France.
Int J Mol Sci. 2021 Jan 23;22(3):1114. doi: 10.3390/ijms22031114.
Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.
女性占自身免疫性疾病患者的 80%。尽管许多研究表明性激素受体信号，特别是雌激素，在直接调节免疫系统的先天和适应性成分方面具有重要作用，但最近的数据表明，女性性激素并不是女性易患自身免疫性疾病的唯一原因。除了性甾体激素外，越来越多的证据表明 X 连锁遗传因素的作用。在雌性哺乳动物中，两条 X 染色体中的一条在胚胎发育过程中随机失活，导致细胞嵌合体，即给定组织中的大约一半细胞表达母性 X 染色体或父性 X 染色体。然而，X 染色体失活（XCI）并不完全，15%至 23%的失活 X 染色体（Xi）上的基因逃避 XCI，从而导致一些 X 连锁基因的双等位基因表达的女性特有的异质性细胞群体的出现。尽管这种遗传机制对女性自身免疫易感性的直接贡献仍有待确定，但 XCI 逃逸产生的细胞嵌合体可能会在女性免疫细胞中产生独特的功能可塑性。在这里，我们回顾了最近的发现，这些发现确定了逃避 XCI 的关键免疫相关基因，以及基因剂量失衡与女性细胞功能反应性之间的关系。
