Women have up to a fourfold increase in risk for autoimmune disease compared to men. Many explanations have been proposed, including sex hormones, the X chromosome, microchimerism, environmental factors, and the microbiome. However, the mechanism for this autoimmune sex bias remains obscure. In this manuscript, we evaluate the hypothesis that qualitative or quantitative differences in circulating antibodies may explain, at least in part, the pathogenesis of autoimmune disease and its sex bias—especially when considering an evolutionary perspective. Indeed, women have higher absolute levels of antibodies than men, and (auto)antibodies are also associated with most autoimmune diseases. Several facts suggest differences in antibodies may cause increased prevalence of autoimmune disease in women. First, the association between increased quantities of serum antibodies and increased prevalence of autoimmunity is found not only in women, but also in men with Klinefelter syndrome. Second, both serum antibody levels and autoimmunity spike in the postpartum period. Third, a dose–response effect exists between parity and both serum antibodies and prevalence of autoimmune disease. Fourth, many biologically plausible mechanisms explain the association, such as T cell‐dependent activation of B cells and/or VGLL3. The evolutionary underpinning of increased antibodies in women is likely to be protection of offspring from infections. Overall, this evolutionary paradigm can help explain why the phenomenon of autoimmunity occurs preferentially in women and raises the possibility of new treatment options.

中文翻译：

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为什么女性比男性更容易患自身免疫性疾病：进化视角


与男性相比，女性患自身免疫性疾病的风险增加四倍。人们提出了许多解释，包括性激素、X 染色体、微嵌合、环境因素和微生物组。然而，这种自身免疫性性别偏见的机制仍然不清楚。在这篇手稿中，我们评估了这样一个假设，即循环抗体的定性或定量差异可以至少部分解释自身免疫性疾病的发病机制及其性别偏见，尤其是在考虑进化角度时。事实上，女性的抗体绝对水平高于男性，并且（自身）抗体也与大多数自身免疫性疾病有关。一些事实表明，抗体的差异可能导致女性自身免疫性疾病的患病率增加。首先，血清抗体数量增加与自身免疫患病率增加之间的关联不仅存在于女性中，而且也存在于患有克兰费尔特综合征的男性中。其次，血清抗体水平和自身免疫在产后期都会激增。第三，胎次和血清抗体与自身免疫性疾病患病率之间存在剂量反应效应。第四，许多生物学上合理的机制可以解释这种关联，例如 B 细胞和/或 VGLL3 的 T 细胞依赖性激活。女性抗体增加的进化基础可能是保护后代免受感染。总体而言，这种进化范式可以帮助解释为什么自身免疫现象优先发生在女性身上，并提高了新治疗选择的可能性。