The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the "Hygiene Hypothesis," have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too "clean" lack the requisite exposure to "immune-tolerizing" microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS. Our central hypothesis is that the microbiome in MS represents a "defective environment" that fails to provide normal levels of "TLR2-tolerizing" bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.

中文翻译：

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多发性硬化症，微生物组，TLR2和卫生学假设。

自身免疫性疾病（例如多发性硬化症（MS））的病理生理学涉及遗传和环境因素之间的复杂相互作用。单卵双胞胎的研究表明环境因素在MS易感性中起着重要作用。在“卫生假说”的推动下，许多研究集中于环境因素在变应性和自身免疫性疾病中的作用。卫生假说假设生活在过于“干净”的环境中的个人缺乏必要的“免疫耐受”微生物产品，导致免疫系统调节不良和免疫介导的疾病增加。有趣的是，很少有研究将MS与卫生假说联系起来。同样，尽管许多研究已经检查了微生物组在自身免疫性疾病中的作用，尚无关于MS微生物组中疾病特异性改变的一致文献。在这篇综述中，我们提供证据表明，将卫生假说与微生物组结合起来可以确定MS中新的病理生理机制。我们的中心假设是，MS中的微生物组代表“缺陷环境”，无法为全身免疫系统提供正常水平的“ TLR2耐受”细菌产品。与卫生学假设一致，我们认为这种缺陷的微生物组功能会导致异常调节的全身性先天免疫TLR2反应，该反应在MS的炎症性和髓鞘再生不良中均起着至关重要的作用。我们已经完成了支持炎症，髓鞘再生，和这种范例的人体免疫反应成分。我们的研究表明，诱导TLR2耐受性可能代表了一种新的治疗MS的方法，既可以抑制自身免疫炎症，又可以促进髓鞘再生。