Our Environment Shapes Us: The Importance of Environment and Sex Differences in Regulation of Autoantibody Production

Abstract

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., sex hormones, sex chromosomes, etc.) and extrinsic (microbiome composition, external triggers, and immune modulators) 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.

Keywords: DNA methylation; endocrine disrupting chemicals; epigenetics; lupus; microbiota; sex hormones.

Figure 1

Interactions of multiple factors are required for the development of autoimmunity. Genetic susceptibility, sex chromosomes, sex hormones, infections and microbial stimuli, and environmental factors are all thought to contribute to autoimmune pathogenesis and lead to autoantibody production. There is little evidence that any one particular factor is able to initiate autoimmunity without input from another factor. The specific relationships and interplay among each of the various factors, such as the relative importance of one factor compared with the others, age at, or duration of, exposure, is not yet understood.

Figure 2

Autoimmune disease prevalence in relation to life stage. Autoimmune diseases can develop during childhood, but most autoimmune diseases develop following the onset of puberty and in later life.

Figure 3

Possible mechanism for estrogens to influence immunity and autoimmune disease development. The exact mechanism for estrogenic influence on autoimmune disease development is likely disease- and context-dependent, and research is ongoing to identify distinct pathways in which estrogen is able to exert its effects. The figure illustrates potential molecular mechanisms of estrogen regulation. AIRE, autoimmune regulator.

Figure 4

Possible mechanism for sex differences in environmental EDC exposure on immune function. The exact mechanism for immune system alterations due to EDC exposure in each sex is not yet well understood. Here, we propose possible mechanisms in which EDCs may exert sex-specific influence on immune cell functions.

Figure 5

Possible mechanism for androgens to influence immunity and autoimmune disease development. The exact mechanism for androgenic influence on autoimmune disease development is likely disease and context dependent. Potential mechanisms of androgen regulation are depicted. Research is ongoing to identify distinct pathways in which androgens are able to exert effects on immune system regulation.

Figure 6

Overview of the responses by male and female B cells to external stimuli and subsequent production of autoantibodies. Before conception, the maternal systems are augmented in various ways, including exposure to endocrine disrupting chemicals (EDCs). Following conception, the fetus is subjected to EDC exposure through continued maternal exposure. Fetal and maternal hormones contribute to immune system development. Following parturition, an infant becomes exposed to microbial organisms and the establishment of commensal microbial population begins, being influenced by both endogenous and exogenous factors before stabilization. The microbiota composition will influence the developing immune system and promote recognition of pathogens and support the development of tolerance mechanisms. Juveniles continue to be exposed to EDCs and pathogenic microbes will be encountered, further stimulating the immune system. At puberty, cells become exposed to higher levels of female or male sex hormones, altering immune cell function and signaling pathways. During adulthood, immune cells continue to be exposed to EDCs and microbial stimuli, both commensal and pathogenic. Sex differential levels of cytokines, chemokines, hormones, and other soluble factors make up the microenvironment that the immune cells are exposed to, further promoting or inhibiting immune cell activation and response. The female cells, which may be primed due to sex differences and environmental contributing factors, generally respond more robustly to the same immunological stimulus compared with male cells. This more robust response likely contributes to the female biased dominance in many autoimmune diseases.