The Molecular Basis Of The Sex-linked Functional Differences In B Cells

在不同的文化和社会结构中，死于新冠肺炎的风险在男性中是女性的两倍，特别是在中年类别中。然而，这种差异背后的生物学原因尚不清楚。最近的研究强调了两性在免疫系统反应方面的显著差异。与这一观察相平行的是，在B细胞和T细胞中发现了组织特异性的不活跃X染色体常染色质化，同时发现了免疫相关基因，这些基因特异性地逃避B细胞中的新激活。其中一名逃亡者TLR7是单链RNA病毒(如SARSCoV-2)的受体。由女性双等位基因表达引起的剂量增加，已被证明有利于刺激TLR7的B细胞反应。此外，最近的研究表明，TLR7亚型等位基因会导致年轻男性严重的新冠肺炎。我们推测，在逃避X失活后，参与B细胞激活的一个或多个X编码基因的加倍剂量可能是新冠肺炎与性别相关的死亡率差异的基础。为了确定在女性中存在较高剂量的X编码的B细胞特异性蛋白，我们提出了一种无偏见的方法，使用来自健康的中年男性和女性的B细胞的定量质谱仪。因此，我们的目标是寻找相关蛋白，为改善SARS-CoV-2的预后提供潜在的药物靶点。

The risk of mortality from Covid-19 is up to two-fold higher in men versus women, especially in themiddle-age category, across different cultures and social structures. However, the biologicalreasons behind this difference is unknown. Recent research has highlighted significant divergencesin the immune system response between the two sexes. This observation has been paralleled bythe discovery of tissue-specific euchromatinisation of the inactive X chromosome in both B and Tcells, accompanied by the identification of immune-related genes that specifically escape Xinactivation in B cells. One of these escapees, TLR7, is a receptor for ssRNA viruses such as SARSCoV-2. Its increased dosage caused by bi-allelic expression in women, has been shown to beadvantageous for B cells response upon stimulation of TLR7. Moreover, recent studies have shownhypomorphic alleles of TLR7 lead to severe Covid-19 in young men. We hypothesised that,following escape from X inactivation, double-dosage of one or more X-encoded genes involved in Bcell activation could be at the basis of the sex-linked differential mortality from Covid-19. Toidentify the X-encoded B-cell specific proteins that are present in higher dosage in women, wepropose an unbiased approach, employing quantitative mass spectrometry from B cells fromhealthy, middle-aged men and women. We thus aim at identifying relevant proteins which couldrepresent potential pharmaceutical targets to improve the prognosis of SARS-CoV-2.