Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, INSERM, CNRS, Université Paul Sabatier, 31300, Toulouse, France.
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris-Descartes, 75014, Paris, France.
Semin Immunopathol. 2019 Mar;41(2):153-164. doi: 10.1007/s00281-018-0712-y. Epub 2018 Oct 1.
Women develop stronger immune responses than men, with positive effects on the resistance to viral or bacterial infections but magnifying also the susceptibility to autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, the dosage of the endosomal Toll-like receptor 7 (TLR7) is crucial. Murine models have shown that TLR7 overexpression suffices to induce spontaneous lupus-like disease. Conversely, suppressing TLR7 in lupus-prone mice abolishes SLE development. TLR7 is encoded by a gene on the X chromosome gene, denoted TLR7 in humans and Tlr7 in the mouse, and expressed in plasmacytoid dendritic cells (pDC), monocytes/macrophages, and B cells. The receptor recognizes single-stranded RNA, and its engagement promotes B cell maturation and the production of pro-inflammatory cytokines and antibodies. In female mammals, each cell randomly inactivates one of its two X chromosomes to equalize gene dosage with XY males. However, 15 to 23% of X-linked human genes escape X chromosome inactivation so that both alleles can be expressed simultaneously. It has been hypothesized that biallelic expression of X-linked genes could occur in female immune cells, hence fostering harmful autoreactive and inflammatory responses. We review here the current knowledge of the role of TLR7 in SLE, and recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in pDCs, monocytes, and B lymphocytes from women and Klinefelter syndrome men. Female B cells where TLR7 is thus biallelically expressed display higher TLR7-driven functional responses, connecting the presence of two X chromosomes with the enhanced immunity of women and their increased susceptibility to TLR7-dependent autoimmune syndromes.
女性比男性产生更强的免疫反应，这对抵抗病毒或细菌感染有积极影响，但也放大了自身免疫性疾病的易感性，如系统性红斑狼疮（SLE）。在 SLE 中，内体 Toll 样受体 7（TLR7）的剂量至关重要。小鼠模型表明，TLR7 过表达足以诱导自发性狼疮样疾病。相反，在狼疮易感小鼠中抑制 TLR7 会消除 SLE 的发展。TLR7 由 X 染色体上的基因编码，在人类中称为 TLR7，在小鼠中称为 Tlr7，并在浆细胞样树突状细胞（pDC）、单核细胞/巨噬细胞和 B 细胞中表达。该受体识别单链 RNA，其结合促进 B 细胞成熟和促炎细胞因子和抗体的产生。在雌性哺乳动物中，每个细胞随机失活其两条 X 染色体中的一条，以使基因剂量与 XY 雄性相等。然而，15%至 23%的 X 连锁人类基因逃避 X 染色体失活，从而使两个等位基因可以同时表达。有人假设 X 连锁基因的双等位基因表达可能发生在女性免疫细胞中，从而促进有害的自身反应性和炎症反应。我们在这里回顾了 TLR7 在 SLE 中的作用的现有知识，以及最近的证据表明，TLR7 在来自女性和克莱恩费尔特综合征男性的 pDC、单核细胞和 B 淋巴细胞中逃避 X 染色体失活。因此，TLR7 双等位基因表达的女性 B 细胞表现出更高的 TLR7 驱动的功能反应，将两条 X 染色体的存在与女性增强的免疫力及其对 TLR7 依赖性自身免疫综合征的易感性联系起来。
