Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.
Front Immunol. 2018 Mar 8;9:478. doi: 10.3389/fimmu.2018.00478. eCollection 2018.
Consequential differences exist between the male and female immune systems' ability to respond to pathogens, environmental insults or self-antigens, and subsequent effects on immunoregulation. In general, females when compared with their male counterparts, respond to pathogenic stimuli and vaccines more robustly, with heightened production of antibodies, pro-inflammatory cytokines, and chemokines. While the precise reasons for sex differences in immune response to different stimuli are not yet well understood, females are more resistant to infectious diseases and much more likely to develop autoimmune diseases. Intrinsic (i.e., .) and extrinsic () factors appear to impact the overall outcome of immune responses between sexes. Evidence suggests that interactions between environmental contaminants [e.g., endocrine disrupting chemicals (EDCs)] and host leukocytes affect the ability of the immune system to mount a response to exogenous and endogenous insults, and/or return to normal activity following clearance of the threat. Inherently, males and females have differential immune response to external triggers. In this review, we describe how environmental chemicals, including EDCs, may have sex differential influence on the outcome of immune responses through alterations in epigenetic status (such as modulation of microRNA expression, gene methylation, or histone modification status), direct and indirect activation of the estrogen receptors to drive hormonal effects, and differential modulation of microbial sensing and composition of host microbiota. Taken together, an intriguing question develops as to how an individual's environment directly and indirectly contributes to an altered immune response, dysregulation of autoantibody production, and influence autoimmune disease development. Few studies exist utilizing well-controlled cohorts of both sexes to explore the sex differences in response to EDC exposure and the effects on autoimmune disease development. Translational studies incorporating multiple environmental factors in animal models of autoimmune disease are necessary to determine the interrelationships that occur between potential etiopathological factors. The presence or absence of autoantibodies is not a reliable predictor of disease. Therefore, future studies should incorporate all the susceptibility/influencing factors, coupled with individual genomics, epigenomics, and proteomics, to develop a model that better predicts, diagnoses, and treats autoimmune diseases in a personalized-medicine fashion.
男性和女性的免疫系统在应对病原体、环境刺激物或自身抗原方面的能力存在必然差异，随后对免疫调节产生影响。一般来说，与男性相比，女性对致病刺激物和疫苗的反应更强烈，抗体、促炎细胞因子和趋化因子的产生水平更高。虽然导致不同性别对不同刺激物的免疫反应存在差异的确切原因尚不完全清楚，但女性对传染病的抵抗力更强，更有可能患上自身免疫性疾病。内在（即......）和外在（......）因素似乎会影响性别间免疫反应的总体结果。有证据表明，环境污染物[如内分泌干扰化学物质（EDCs）]与宿主白细胞之间的相互作用会影响免疫系统对外来和内源性刺激物产生反应的能力，以及/或在清除威胁后恢复正常活动的能力。本质上，男性和女性对外界触发因素的免疫反应存在差异。在这篇综述中，我们描述了环境化学物质，包括 EDCs，如何通过改变表观遗传状态（如调节 microRNA 表达、基因甲基化或组蛋白修饰状态）、直接和间接激活雌激素受体以驱动激素效应，以及微生物感应和宿主微生物群落组成的差异调节，对免疫反应的结果产生性别差异影响。总的来说，一个有趣的问题是，个体的环境如何直接和间接地导致免疫反应改变、自身抗体产生失调以及影响自身免疫性疾病的发展。利用包含两性的对照良好的队列进行的研究很少，这些研究旨在探索 EDC 暴露后的性别差异以及对自身免疫性疾病发展的影响。在自身免疫性疾病的动物模型中进行包含多种环境因素的转化研究，对于确定潜在的发病因素之间的相互关系是必要的。存在或不存在自身抗体并不是疾病的可靠预测指标。因此，未来的研究应将所有易感/影响因素与个体基因组学、表观基因组学和蛋白质组学结合起来，开发一种能够更好地预测、诊断和个体化治疗自身免疫性疾病的模型。
