Sex-Specific Regulation of Peripheral and Central Immune Responses
Summary and Keywords
Sex is a biological variable that affects immune responses to both self and foreign antigens (e.g., microbial infections) in the central nervous system (CNS) as well as in peripheral organs. The sex of an individual is defined by the differential determination of the sex chromosomes, the organization of the reproductive organs, and the subsequent sex steroid hormone levels in males and females. Sex is distinct from gender, which includes self-identification as being a male or female as well as behaviors and activities that are determined by society or culture in humans. Male and female differences in immunological responses may be influenced by both sex and gender, with sex contributing to the physiological and anatomical differences that influence exposure, recognition, clearance, and even transmission of microbes in males and females. By contrast, gender may reflect behaviors that influence exposure to microbes, access to health care, or health-seeking behaviors that indirectly affect the course of infection in males and females. Though both sex and gender influence the immune response, the focus of this article is the biological factors that influence immunological differences between the sexes in both the CNS and peripheral tissues to alter the course of diseases across the life span.
Sex Differences in the Pathogenesis of Diseases Associated With Immune Function
The immune system contributes to differences between the sexes in the diagnosis of, prognosis for, and pathogenesis of many diseases in the central nervous system (CNS) and peripheral organs (Figure 1). For example, cardiovascular disease is the leading cause of morbidity and mortality in both males and females in the United States; there are, however, distinct differences between males and females in the onset, severity, and symptoms of the disease. Among individuals younger than 50 years of age, the prevalence of cardiovascular disease is greater in males, but the prevalence is reversed among individuals over 50 years of age (Pucci et al., 2017). Similarly, the onset of hypertension is earlier in males than in females, with sex differences in immune system modulation of blood pressure and vascular function contributing significantly to the sex differences in the onset, severity, and symptoms of vascular diseases (Sandberg, Ji, & Hay, 2015).
Sex differences are also reported in the severity and outcomes of many pulmonary diseases. For example, after puberty and into adulthood, human females are at greater risk of developing allergy-induced asthma, chronic bronchitis, and chronic obstructive pulmonary disease (even among nonsmokers), and females have more severe cystic fibrosis than their male counterparts (Raghavan & Jain, 2016). Adult females of reproductive ages are also at greater risk for hospitalization with severe influenza during pandemics (Peretz, Hall, & Klein, 2015). The complexities of sex differences in pulmonary inflammation have been characterized in the context of influenza pathogenesis using small animal models and primary cell cultures derived from humans and mice (Hall et al., 2016; Peretz, Pekosz, Lane, & Klein, 2016; Robinson, Hall, Nilles, Bream, & Klein, 2014; Robinson, Huber, et al., 2011; Robinson, Lorenzo, Jian, & Klein, 2011; Vom Steeg et al., 2016). Using murine models, investigators have shown that females develop higher pulmonary inflammatory responses and experience a more severe outcome from influenza A virus (IAV) infection than males, despite comparable virus titers in both sexes (Hoffmann et al., 2015; Larcombe et al., 2011; Lorenzo et al., 2011; Robinson, Huber, et al., 2011; Robinson, Lorenzo, et al., 2011).
Liver diseases, including hepatitis and cancer, occur more frequently and with more severe outcomes in males than in females. Hepatitis B and C viruses (HBV and HCV) cause chronic infections and are a major risk factor for the development of liver cancer and hepatocellular carcinoma. The presence of serum HBV surface antigen (HBsAg) is consistently higher in men than in women (Koulentaki et al., 1999; Robinson, Bullen, Humphries, Hornell, & Moyes, 2005; Tsay et al., 2009). Male sex is also an independent factor associated with elevated HBV DNA titers (Chen et al., 2006). Development of hepatocellular carcinoma occurs at a 2:1 to 4:1 ratio of males to females (El-Serag & Rudolph, 2007). In fact, most cancers arising in tissues outside of the reproductive tract have a twofold higher incidence in males than in females (Clocchiatti, Cora, Zhang, & Dotto, 2016).
Autoimmune diseases that affect the CNS and peripheral organs are more prevalent in females than in males. For example, multiple sclerosis (CNS), systemic lupus erythematosus (multiple organs), Graves’ disease (thyroid), Hashimoto’s thyroiditis (thyroid), and Sjögren’s syndrome (mucus-producing glands) occur 7 to 10 times more frequently in females than in males (Rubtsova, Marrack, & Rubtsov, 2015). Even bone diseases, such as osteoarthritis and the autoimmune disease rheumatoid arthritis, occur more frequently in females than in males, with earlier onset of symptoms in females (Srikanth et al., 2005; Tedeschi, Bermas, & Costenbader, 2013).
There are sex differences in the diagnosis and symptoms of a number of mental health disorders (Bao & Swaab, 2010; Schwarz & Bilbo, 2012), many of which have been linked to inflammation or dysregulation of the immune system. For example, schizophrenia is diagnosed more often in men than in women around the time of puberty and adolescence, and also has suspected links to early-life immune activation or dysregulation (Abazyan et al., 2010; Volk, 2017). Boys are also more likely to be diagnosed with autism and other pervasive developmental disorders, which have links to early-life immune activation or dysregulation (Ashwood et al., 2010, 2011; Careaga, Van de Water, & Ashwood, 2010; Garay & McAllister, 2010). Human females are more than twice as likely to be diagnosed with depression, mood disorders, anxiety-related disorders, and even posttraumatic stress disorder after the onset of puberty (Bekhbat & Neigh, 2017; Hodes, Walker, Labonte, Nestler, & Russo, 2017). Many of these disorders have been associated with inflammation or immune dysregulation (Dantzer, 2006; Miller & Raison, 2016; Pace & Heim, 2011). In addition, exaggerated neuroimmune activation has been implicated in the cognitive decline associated with Alzheimer’s disease, which is more often diagnosed in women (Capuron & Miller, 2011; Caserta et al., 2009; Gate, Rezai-Zadeh, Jodry, Rentsendorj, & Town, 2010; Lee & Landreth, 2010; Lynch, 2010).
In each of these cases, health-related behaviors, occupational exposures, and other gender-associated factors influence the outcomes of diseases in peripheral organs differently for males and females. There is also a growing appreciation that immunological differences between the sexes, which involve complex interactions between the immune system and sex hormones, sex chromosome complement, and the microbiome, can also differentially impact the development of diseases in a sex-dependent manner (Klein & Flanagan, 2016). The diverse mechanisms by which hormones, sex chromosomes, and the microbiome influence immune responses in sex-specific ways are the focus of this article.
Sex Differences in the Peripheral Immune Response
Among mammals, males and females differ in their innate immune responses, which suggests that some sex differences in immune function may be germline encoded. For example, innate detection of nucleic acids by pattern recognition receptors (PRRs) differs between the sexes. The Toll-like receptor 7 (TLR7) gene, encoded on the X chromosome, may escape X inactivation, resulting in higher expression of TLR7 in immune cells from females than in cells from males (Pisitkun et al., 2006). Exposure of peripheral blood mononuclear cells (PBMCs) to TLR7 ligands in vitro causes higher production of interferon alfa (IFN-α) in cells from women than in cells from men (Berghofer et al., 2006), and plasmacytoid dendritic cells (pDCs) from female humans and mice have higher basal levels of IFN regulatory factor 5 (IRF5) and IFN-α production following TLR7 ligand stimulation (Griesbeck et al., 2015). Transcriptional regulation of IRF5 in female mice is also under the control of signaling through estrogen receptor alpha (ERα; Griesbeck et al., 2015). Stimulation of DCs with CpG, a TLR9 ligand, results in no sex difference in IFN-α production (Berghofer et al., 2006); however, transcriptional analyses, have revealed sex differences in the expression of genes along various TLR pathways and the induction of type I IFN responses (Hannah, Bajic, & Klein, 2008; Klein, Jedlicka, & Pekosz, 2010). Moreover, putative androgen and estrogen response elements (AREs and EREs) are present in the promoters of several innate immunity genes, suggesting that sex steroids may directly cause dimorphic innate immune responses (Hannah et al., 2008).
The production of cytokines and chemokines by innate immune cells also differs between the sexes. Activation of TLR9 with viral or synthetic ligands in PBMCs from human males results in greater interleukin-10 (IL-10) production than in PBMCs from females, which is positively correlated with androgen concentrations in males (Torcia et al., 2012). PBMCs from human males produce more TNFα than PBMCs from females following stimulation with the endotoxin and TLR4 agonist lipopolysaccharide (LPS; Asai et al., 2001; Moxley et al., 2002). Neutrophils from human males express higher levels of TLR4 and produce more TNF than neutrophils from females both constitutively and following activation with LPS (Aomatsu, Kato, Kasahara, & Kitagawa, 2013). Peritoneal macrophages from male mice express higher levels of TLR4 and produce more CXC-chemokine ligand 10 (CXCL10) following LPS stimulation than do macrophages from females (Marriott, Bost, & Huet-Hudson, 2006). Peritoneal macrophages isolated from female rodents produce higher levels of anti-inflammatory prostanoids than male-derived cells following LPS treatment (Marriott et al., 2006). Because TLR4 expression is greater on peripheral immune cells from males than cells from females, stimulation with LPS results in greater proinflammatory cytokine production by immune cells from males, which can be reversed by removal of androgens in male rodents (Rettew, Huet-Hudson, & Marriott, 2008). In contrast, higher expression of TLR7 in immune cells from females than in cells from males appears to cause greater cytokine production by immune cells from females and is regulated by sex chromosome expression. The sex-differential expression of PRRs is critical for interpreting sex-specific activity of innate immune cells following stimulation.
Sex influences multiple aspects of adaptive immunity. Females have higher CD4+ T-cell counts and higher CD4:CD8 ratios than age-matched males (Abdullah et al., 2012; Lee et al., 1996; Lisse et al., 1997; Uppal, Verma, & Dhot, 2003), whereas males have higher CD8+ T cell frequencies (Lee et al., 1996; Lisse et al., 1997; Uppal et al., 2003). Following in vitro stimulation of PBMCs, women have higher numbers of activated CD4+ T cells and CD8+ T cells and proliferating T cells in peripheral blood than men have (Abdullah et al., 2012; Sankaran-Walters et al., 2013).
The activity and distribution of CD4+ T-cell subsets differ between the sexes. Adult female mice produce higher levels of T helper 1 (Th1)-type cytokines (for example, IFN-γ) than males, at least following parasitic infections, such as Leishmania major and Plasmodium chabaudi, in which females are better protected (Roberts, Walker, & Alexander, 2001). Polyclonal activation of human PBMCs with the mitogen phytohemagglutinin (PHA) results in higher production of Th2-type cytokines, including IL-4 and IL-10, in female PBMCs than in male PBMCs (Giron-Gonzalez et al., 2000). Naïve CD4+ T cells from human females preferentially produce IFN-γ upon stimulation, whereas naïve T cells from males produce more IL-17 (Zhang et al., 2012). Expression of IL-17A is higher in males (Hewagama, Patel, Yarlagadda, Strickland, & Richardson, 2009) or females (Sankaran-Walters et al., 2013), depending on the stimulation and purity of the T-cell population. Human studies also found higher numbers of regulatory T cells (Tregs) in healthy adult males than in females (Afshan, Afzal, & Qureshi, 2012).
Regardless of age, females tend to show greater antibody responses than males, higher basal immunoglobulin (Ig) levels, and higher B-cell numbers (Abdullah et al., 2012; Furman et al., 2014; Teixeira et al., 2011). Global analysis of B-cell gene expression signatures reveals that the majority of genes differentially expressed between the sexes are significantly upregulated in B cells from females compared with cells from males (Fan et al., 2014).
Sex Differences in Immune Responses in the CNS
Brain and Peripheral Immune Cell Communication
There are numerous pathways through which peripherally derived immune factors can influence the brain, and various reciprocal pathways through which the brain can affect peripheral immune responses. As a result, sex differences in peripheral immune responses can affect the central immune response in a sex-dependent manner. The pathways of brain−immune communication involve the autonomic nervous system, activation of the hypothalamic-pituitary-adrenal (HPA) axis, passage of peripheral cytokines across the blood−brain barrier via active and passive transport, and entry of peripherally derived immune cells into the brain.
Cytokines are also produced by cells in the brain in response to perturbation of CNS homeostasis caused by trauma, stroke, ischemia, neurodegeneration, or infection. Cytokines are also produced within the brain in response to peripheral cytokine production, LPS administration, or peripheral infection, indicating that peripheral cytokine signals can be transmitted from the periphery into the brain. The cytokine response in the brain can differ between males and females after peripheral immune activation, as has been demonstrated in several rodent models. There is a sex difference in the febrile response produced by peripheral endotoxin administration, with adult males having a greater febrile response than females, an effect that is caused by a sex difference in cytokine expression in the brain (Ashdown, Poole, Boksa, & Luheshi, 2007; Murakami & Ono, 1987). Specifically, females express elevated levels of IL-1 receptor antagonist (IL-1ra), an endogenous anti-inflammatory cytokine, within the hypothalamus following LPS administration. IL-1ra attenuates the production of other proinflammatory cytokines, including IL-1β, in the brain, thereby attenuating the febrile response in adult female rats (Ashdown et al., 2007). Adult male mice also have greater fluctuations in body temperature and greater sickness behavior after peripheral LPS administration than female mice, a sex difference that becomes apparent only after puberty (Cai et al., 2016). As discussed in the previous section, adult males typically have a more robust peripheral innate immune response to an LPS immune challenge, thus these data highlight that cytokine production in the brain can mimic that seen in the periphery; therefore, males have a more robust sickness and febrile response to peripheral TLR4 activation. The data also highlight that changes in immune responses that occur during puberty, which are the result of age-related changes in immune function and the combined effect of increasing levels of sex steroid hormones, may ultimately increase the vulnerability of males to the neural and behavioral consequences of peripheral immune activation during puberty or adolescence (Kane & Ismail, 2017), which may be particularly important for understanding the etiology of mental health disorders, such as schizophrenia.
There are challenges with measuring cytokine concentrations directly in the brains of humans. Limited research in humans, however, indicates that females may be more vulnerable to the CNS effects of peripheral immune activation and peripheral cytokine production. For example, both human males and females have an increase in circulating proinflammatory cytokines following LPS stimulation; however, females are more likely to exhibit depressed mood and decreased feelings of social connectedness following exposure to LPS (Moieni et al., 2015). Similarly, increased concentrations of circulating IL-6 in human females are associated with greater neural activity in the dorsal anterior cingulate cortex and anterior insula, two brain regions associated with depressed mood and social pain, an effect that is not observed among males (Eisenberger, Inagaki, Rameson, Mashal, & Irwin, 2009). Similar findings have been reported in rodents, in which intranasal LPS administration produces greater depressive-like behavior in female rats, with associated increases in TNFα in the hippocampus, a brain region implicated in the etiology of depression (Tonelli, Holmes, & Postolache, 2008). The data highlight that, even in the absence of overt sex differences in peripheral cytokine levels, the impact of peripheral cytokines on neural function can be sex-specific, with females being more vulnerable to the neural and possibly mood-related effects of inflammation than males.
In addition to the propagation of peripheral cytokine signals to the brain, the vagus nerve also communicates signals from peripheral immune responses to the brain (Berthoud & Neuhuber, 2000; Tracey, 2002). The vagus nerve projects through the brainstem to the hypothalamus, where it can initiate a stress response (Ter Horst, de Boer, Luiten, & van Willigen, 1989). Surgical removal of the vagus nerve blocks the induction of a fever produced by peripheral administration of IL-1β or LPS, a finding that emphasizes the important role that the vagus nerve has in modulating brain−immune communication (Hansen, O’Connor, Goehler, Watkins, & Maier, 2001; Konsman, Luheshi, Bluthe, & Dantzer, 2000; Luheshi et al., 2000). To date, there are no studies that have directly examined sex differences in vagus nerve function as a mechanism of cytokine production in the CNS. Sex differences in neural activity that are the result of peripheral immune activation (Eisenberger et al., 2009; Moieni et al., 2015) may be the result of sex differences in the function of a direct neural pathways from the periphery to the brain, such as the vagus nerve, or the active transport of cytokines across the blood−brain barrier, both of which require further consideration.
The brain can also influence the peripheral immune system via the autonomic nervous system, which is an extensive network of nerves that organizes interactions between the nervous system, endocrine system, and immune system (Rabin, Ganguli, Lysle, & Cunnick, 1990); these interactions may have sex-specific patterns of activation and influences on disease processes. The well-known sex difference in the prevalence of anxiety and mood disorders may be the result of sex-specific changes in neural activity caused by dysregulated peripheral immune function that are precipitated or further exacerbated by sex differences in the physiological response to stress, including production of epinephrine (autonomic nervous system), norepinephrine (autonomic nervous system), and glucocorticoids (HPA axis).
Several studies in humans and nonhuman animals have reported sex differences in the hormonal, behavioral, and neural response to stress, and often these sex differences are the direct result of sex hormone effects on the production and secretion of stress hormones (e.g., glucocorticoids and epinephrine; Donadio et al., 2007; Viau & Meaney, 1991). In general, females have higher circulating baseline levels of adrenocorticotropic hormone (ACTH) and glucocorticoids and more robust increases in glucocorticoids after exposure to a stressor (Handa, Burgess, Kerr, & O’Keefe, 1994; Handa et al., 1994; Stephens, Mahon, McCaul, & Wand, 2016). There are also well-documented sex differences in the expression of glucocorticoid receptors (GR) throughout the brain, in which GR expression is higher in females than in males, with sex steroid hormones directly mediating GR expression and function in the brain (Bourke, Harrell, & Neigh, 2012; Bourke et al., 2013; Malviya et al., 2013).
In response to peripheral IL-1β stimulation, circulating ACTH and corticosterone concentrations are higher in females than in males, in both rats (Rivier, 1994) and mice (Girard-Joyal et al., 2015). Among humans, females had greater peripheral cytokine responses and greater levels of activation in the amygdala—a brain region that controls emotion and stress—than males during a Trier Social Stress Test (Muscatell et al., 2015). Human females also had greater levels of a circulating soluble TNFα following a stress test and were more likely to have overactivity of the anterior cingulate cortex and insular cortex—regions of the brain that modulate mood and depression—than males (Slavich, Way, Eisenberger, & Taylor, 2010).
The effects of stress on immune function can be dependent upon the duration of the stressor (Dhabhar, 2000), and often males and females respond differently to chronic versus short-term stressors (Farrell, Gruene, & Shansky, 2015; Shansky & Lipps, 2013). For example, females are more vulnerable to the cognitive deficits associated with acute stress (Shansky, Rubinow, Brennan, Arnsten, 2006), while males show significant learning and memory deficits after exposure to chronic stressors (Bowman, 2005). In contrast, females are more likely to exhibit depressive-like behaviors following chronic stress, an effect that is not seen in males (Bourke & Neigh, 2011). It is likely that interactions among the sex of the individual, the age of the individual, the peripheral immune response, the neuroendocrine stress response, and the reciprocal effect that stress and its duration can have on immune function in the periphery and the brain are sex-specific, and they require greater consideration. The sex-specific interactions of these factors may be important for understanding sex differences in mental health disorders that have known or suspected immune etiologies and links to stress or trauma, such as depression, anxiety, and schizophrenia.
Immune Responses by Resident Immune Cells in the Brain
Immune responses in the brain are not identical to those generated in the periphery. For example, the immune response produced by resident immune cells in the brain is often attenuated to protect delicate neural tissues. The brain has resident immune cells, namely microglia, that produce cytokines and present antigens in response to disturbances in homeostasis within the brain in a manner similar to peripheral immune cells. Other cell types within the brain, including astrocytes, endothelial cells, and neurons, can also produce cytokines and chemokines, and some of these cell types express receptors for these immune molecules, although to a much lesser extent than microglia in most cases. Microglia have a close relationship, both physically and via signaling molecules, with other surrounding cell types in the brain, including neurons, astrocytes, endothelial cells, and oligodendrocytes. Thus, activation of microglia can have profound effects on the function of other cell types within the brain, both during development and in adulthood. Neurons, in turn, exhibit a marked sensitivity to the inflammatory signals produced by microglia; if left unchecked, these stimuli can cause neuronal dysfunction, cognitive dysfunction, or even neuronal death (Northrop & Yamamoto, 2011). Microglia express cytokine and chemokine receptors and can respond to peripheral cytokines. Microglia also express receptors for steroid hormones, including adrenergic receptors and GR (Sierra, Gottfried-Blackmore, Milner, McEwen, & Bulloch, 2008). Thus, stress hormones are capable of modulating the immune response from microglial cells directly, in addition to the effects of glucocorticoids on the peripheral immune system (Bellavance & Rivest, 2014). In contrast, microglia do not appear to express androgen or estrogen receptors (AR and ER, respectively; Lenz, Nugent, Haliyur, & McCarthy, 2013; Turano, Lawrence, & Schwarz, 2017), although there are reports that the BV2 microglial cell line expresses the progesterone receptor (PR) and ERβ (Habib & Beyer, 2015; Lei et al., 2014; Saijo, Collier, Li, Katzenellenbogen, & Glass, 2011). Converging data suggest that microglia, in contrast to many peripheral immune cells, cannot directly respond to circulating sex steroid hormones. Instead, the function of microglia may be influenced in a sex-dependent manner by surrounding neural cells or via sex differences in gene expression that are independent of sex hormones.
Microglia originate early in fetal life and are long-lived, meaning that microglia can reside in the brain for most of the life of the individual. From embryonic development to early postnatal development, and from adolescence to adulthood, microglia continuously change their morphology rapidly and dramatically in a brain region−dependent manner that is indicative of their maturation. In rodents, there is a robust sex difference in the colonization and maturation of microglia in the brain. Early in brain development, around postnatal day (P) 4, male rats have significantly more microglia in many cortical brain regions than female rats have (Schwarz, Sholar, & Bilbo, 2012). During this time, microglia have a critical role in neurodevelopmental processes, including the sexual differentiation of the male brain, via the testosterone-induced production of prostaglandin E2 (Lenz et al., 2013). Female microglia also are more mature than male microglia at P4, but treatment of male microglia with LPS can accelerate microglial development (Hanamsagar et al., 2017), which may be important to consider in the context of neurodevelopmental disorders, such as autism or schizophrenia. These neurodevelopmental disorders are more often diagnosed in boys than in girls, and evidence suggests that the disorders are associated with early-life immune activation or immune dysregulation (Schwarz & Bilbo, 2012). Early-life immune activation can produce long-term changes in central and peripheral immune function, with significant consequences for neural and cognitive function (Bilbo & Schwarz, 2009). Thus, sex differences in microglial number or function during neural development may contribute to a sex difference in the vulnerability to early-life immune activation and thus the sex difference in neurodevelopmental disorders, although this direct link remains to be determined.
Prior to puberty, the sex difference in microglial number reverses, and females have significantly more microglia, with thicker, branched processes throughout the cortex, hippocampus, and amygdala, an effect that is maintained into adulthood, at least in rats (Schwarz et al., 2012). Notably, baseline microglial expression of inflammatory molecules does not change across the estrous cycle in female mice in the absence of an immune challenge (Hanamsagar et al., 2017); sex steroid hormones, however, can influence the cytokine response produced by microglia, particularly following an immune challenge. Estradiol (E2) significantly inhibits the production of proinflammatory molecules from microglia, and E2 treatment of primary microglial cultures reduces the synthesis of IL-1β after LPS stimulation (Baker, Brautigam, & Watters, 2004; Loram et al., 2012; Smith, Das, Butler, Ray, & Banik, 2011; Vegeto et al., 2001). Treatment of female mice with E2 also inhibits the synthesis of monocyte chemoattractant protein (MCP) 1, macrophage inflammatory protein (MIP) 2, and TNFα by microglia (Vegeto et al., 2006). The expression of inflammatory cytokines in the brain increases as a function of age (Sierra, Gottfried-Blackmore, McEwen, & Bulloch, 2007) in a sex-dependent manner (Crain & Watters, 2015). Because sex and sex steroid hormones affect proinflammatory cytokine expression after puberty, with additional changes occurring in adulthood, future studies should consider sex-specific, age-related changes in the activity of microglia in the context of anxiety and mood disorders (Bekhbat & Neigh, 2017), as well as stroke (Chauhan, Moser, & McCullough, 2017; Spychala, Honarpisheh, & McCullough, 2017) and neurodegenerative diseases like Alzheimer’s (Candore et al., 2010)—all of which are associated with inflammation in the brain and are more likely to be diagnosed, or to have worse outcomes, in females.
Glucocorticoids produce sex-specific changes in microglial function. In general, acute stress, which produces an increase in glucocorticoid secretion, can suppress microglial function; elevated levels of stress in chronic or even subchronic stress, however, may “prime” microglial activation, making these cells more sensitive and responsive to subsequent immune challenges (Bekhbat & Neigh, 2017; Bollinger, Bergeon Burns, & Wellman, 2016; Frank, Miguel, Watkins, & Maier, 2010; Kopp, Wick, & Herman, 2013), which can also be sex-specific. For example, brief restraint stress induces microglial activation to a greater extent in males than in females (Hinwood, Morandini, Day, & Walker, 2012) but has no significant effect on microglial cell morphology (Bollinger et al., 2016; Kopp et al., 2013). In females, either acute or chronic stress can reduce the number of “primed” microglia, which can be described as those cells with more branches and thicker processes (Bollinger et al., 2016), and the production of IL-1β in the brain (Arakawa, Arakawa, Hueston, & Deak, 2014). Taken together, these data illustrate that sex-specific responses to stress and activation of microglia are age-dependent and likely underlie sex differences in the development of mental illnesses associated with stress, including anxiety and depression—both of which are more prevalent in females than in males.
Sex Steroids Mediate Sex Differences in Immune Responses
Levels of estrogen (for example, E2) are variable during the menstrual cycle, high during pregnancy, and low after menopause in females. ERs are expressed in various lymphoid tissue cells, in lymphocytes, in macrophages, and in DCs. The two ER subtypes for classical estrogen signaling, ERα and ERβ, exhibit differential expression among immune cell subsets, with ERα highly expressed in T cells and ERβ upregulated in B cells (Phiel, Henderson, Adelman, & Elloso, 2005). Nonclassical ER signaling also occurs in immune cells, enabling protein−protein interactions between ERs and ERE-independent transcription factors, including NF-κB, specific protein 1 (Sp1), and activator protein 1 (AP-1; Kovats, 2015). Differential effects of estrogens on immune function reflect not only estrogen concentration but also the density, distribution, and type of ERs in immune cells.
E2 affects many aspects of innate immunity. Treatment of either humans or mice with E2 increases neutrophils in the blood and lungs, respectively (Jilma et al., 1994; Robinson et al., 2014). Exposure of natural killer (NK) cells to E2 in vitro enhances the production of IFN-γ and overall cytotoxicity (Nakaya, Tachibana, & Yamada, 2006). E2 has bipotential effects on monocytes and macrophages derived from humans, with low doses enhancing the production of proinflammatory cytokines (e.g., IL-1, IL-6, and TNF) and high concentrations reducing the production of these cytokines (Bouman, Heineman, & Faas, 2005). E2 also enhances the expression of PRRs, including TLR4, on the surface of peritoneal macrophages in rodents (Rettew, Huet, & Marriott, 2009). In vitro E2 exposure facilitates the differentiation of bone marrow precursor cells into functional CD11c+ DCs (Paharkova-Vatchkova, Maldonado, & Kovats, 2004) and increases the synthesis of CXCL8 and CCL2 by immature DCs in mice (Bengtsson, Ryan, Giordano, Magaletti, & Clark, 2004). Treatment of ovariectomized mice with physiological doses of E2 increases production of proinflammatory cytokines by CD11c+ DCs (Miller & Hunt, 1996; Siracusa, Overstreet, Housseau, Scott, & Klein, 2008). E2 acts primarily through ERα, not ERβ, to regulate DC differentiation in mice (Paharkova-Vatchkova et al., 2004). In response to GM-CSF in human monocytes, E2 promotes differentiation of monocytes into inflammatory DCs, with increased production of IFN-α and proinflammatory cytokines, TLR7 and TLR9 signaling, and presentation of antigen to naïve T cells (Seillet et al., 2012).
Estradiol enhances both cell-mediated and humoral immune responses. Generally, low E2 concentrations promote Th1-type responses and cell-mediated immunity, whereas high E2 concentrations augment Th2-type responses and humoral immunity in diverse species and cell culture systems (Straub, 2007). Binding of E2 to ERs increases Ifnγ transcription via EREs in the promoter region of the Ifnγ gene (Fox, Bond, & Parslow, 1991). In mice, low-dose E2 also upregulates mitogen-activated protein kinase (MAPK), T-bet, and select microRNAs to increase production of IFN-γ by T cells, an effect reversed by the ER antagonist ICI 182,780 (Dai et al., 2008; Karpuzoglu, Phillips, Gogal, & Ansar Ahmed, 2007; Suzuki et al., 2008). E2 regulates proinflammatory responses that are transcriptionally mediated by NF-κB through a negative feedback/transrepressive interaction with NF-κB (Straub, 2007).
Exogenous E2 enhances the expansion of Treg cell populations in mice and healthy women, and in vitro E2 increases the number of Treg cells generated from PBMCs (Dinesh, Hahn, & Singh, 2010; Polanczyk et al., 2004). Treatment of mice with high doses of E2 decreases IL-17 production by Th17 cells (Wang et al., 2009), whereas ovariectomy of female mice increases Th17 cell numbers and IL-17 production (Tyagi et al., 2012). E2 also induces somatic hypermutation and class switch recombination in B cells via the upregulation of activation-induced deaminase (Pauklin, Sernandez, Bachmann, Ramiro, & Petersen-Mahrt, 2009).
Progesterone (P4) is produced by the corpus luteum during the menstrual cycle and at high levels by the placenta during pregnancy in females. P4 signals through the PR, and to a lesser extent, through GR and mineralocorticoid receptors. Progesterone receptors are present on many different immune cell types, including NK cells, macrophages, DCs, and T cells (Teilmann, Clement, Thorup, Byskov, & Christensen, 2006).
Progesterone has broad anti-inflammatory effects. In comparison to non-hormone-treated cells, P4-exposed macrophages and DCs have a lower state of activation and produce lower amounts of IL-1β and TNF (Butts et al., 2007; Jones et al., 2010). P4 treatment of mouse bone marrow-derived macrophages induces the expression of FIZZ1 and YM1, both markers of alternatively activated macrophages, and reduces production of inducible nitric oxide synthase (iNOS) and nitric oxide (NO; Menzies, Henriquez, Alexander, & Roberts, 2011). TLR and the NF-κB pathways can also be antagonized by the action of P4 (Butts et al., 2007; Hardy, Janowski, Corey, & Mendelson, 2006). Treatment of human NK cells with P4 reduces activation and production of IFN-γ, via caspase-dependent apoptosis (Arruvito et al., 2008). Progesterone can promote skewing of CD4+ T-cell responses from Th1-type toward Th2-type responses, as characterized by increased IL-4, IL-5, and IL-10 production (Piccinni et al., 1995). When cord blood cells are treated with P4, the percentage of FOXP3+ Treg cells increases, while Th17 cell frequencies decline (Lee, Ulrich, Cho, Park, & Kim, 2011).
Androgens, including dihydrotestosterone (DHT) and testosterone, occur in higher concentrations in postpubertal males than in females and generally suppress immune cell activity (Roberts et al., 2001). Exposure to testosterone in vivo reduces murine NK cell activity (Hou & Zheng, 1988). Surface expression of TLR4 on macrophages is reduced by exposure to testosterone both in vitro and in vivo (Rettew et al., 2008). Testosterone reduces the synthesis of TNF, iNOS, and NO by macrophages (D’Agostino et al., 1999). Testosterone and DHT increase IL-10 and TGF-β synthesis, causing increased anti-inflammatory responses via AR signaling (D’Agostino et al., 1999; Liva & Voskuhl, 2001). Androgens also suppress proinflammatory responses by reducing extracellular signal-regulated kinases and leukotriene formation in neutrophils (Pergola et al., 2008).
Human males with androgen deficiencies have higher inflammatory cytokine (for example, IL-1β, IL-2, and TNF) concentrations, antibody titers, and CD4:CD8 T-cell ratios than men with normal testosterone levels (Bobjer, Katrinaki, Tsatsanis, Lundberg Giwercman, & Giwercman, 2013; Kalinchenko et al., 2010; Malkin et al., 2004; Musabak et al., 2003). Human males treated with a gonadotropin-releasing hormone (GnRH) antagonist, which significantly reduces testosterone levels, have lower peripheral blood Treg cell counts and higher NK cell counts than placebo-treated men or men treated with both the GnRH antagonist and exogenous testosterone (Page et al., 2006). Castrated male mice have higher numbers of CD4+ and CD8+ T cells (Roden et al., 2004) and higher numbers of macrophages and antigen-specific CD8+ T cells following viral infection than gonadally intact males (Lin, Wojciechowski, & Hildeman, 2010). Treatment of female mice with testosterone inhibits secretion of IFN-γ by NK cells (Lotter et al., 2013).
The immunosuppressive effects of androgens may reflect the inhibitory effects of AR signaling on transcriptional factors for proinflammatory and antiviral cytokines (McKay & Cidlowski, 1999). Androgens also enhance the expression of peroxisome proliferator-activated receptor-α (PPARα) in T cells by engaging AREs in the promoter of the PPARα gene, which repress the activity of NF-κB and JUN to control inflammation (Dunn et al., 2007). Taken together, these findings illustrate that sex steroids are potent regulators of immune responses.
Genetic Factors Associated With Sex Differences in Immune Responses
Many genes on the X chromosome regulate immune function and have an important role in modulating sex differences in the development of immune-related diseases (Libert, Dejager, & Pinheiro, 2010). The genes code for proteins ranging from PRRs (e.g., TLR7 and TLR8) to cytokine receptors (e.g., IL2RG and IL13RA2) and transcriptional factors (e.g., FOXP3). The Y chromosome also contains numerous regulatory response genes, and Y chromosome polymorphisms affect sex-dependent susceptibility to viral infection (Case et al., 2012; Krementsov et al., 2017).
The Sry gene on the Y chromosome causes testes formation and testosterone synthesis leading to male-typic phenotypic development, whereas the absence of Sry expression results in ovaries and female-typic development. The “four core genotypes” (FCG) mouse model was developed to investigate the impact of sex chromosomes (XX vs. XY) and gonadal type (testes vs. ovaries) on phenotypes. Deletion of Sry from the Y chromosome results in XY minus (XY-) FCG mice that are gonadal females (i.e., with ovaries). Insertion of the Sry transgene onto an autosome in XX or XY- FCG mice (XXSry and XY-Sry) results in gonadal males (i.e., with testes). Depletion of gonadal steroids by gonadectomy of FCG mice unmasks effects of sex chromosome complement on multiple functions, including susceptibility to autoimmune disease and viral infection (Robinson, Huber, et al., 2011; Smith-Bouvier et al., 2008). In experimental autoimmune encephalitis (EAE) and lupus, for example, the presence of the XX sex chromosome complement worsens disease progression relative to that in XY mice and results in decreased production of IL-4, IL-5, and IL-13, but increased IL-13Rα2 expression on DCs (Smith-Bouvier et al., 2008).
Klinefelter’s and Turner’s syndromes are two inherited disorders that further exemplify the effects of the X chromosome on immunity. Klinefelter’s syndrome occurs when males have an extra X chromosome, resulting in low testosterone, increased gonadotropins, and elevated estrogen concentrations. Immunologically, men with Klinefelter’s syndrome respond more like females, with higher immunoglobulin concentrations, CD4+ T-cell numbers, CD4:CD8 T-cell ratios, and B-cell numbers than XY male controls (Kocar et al., 2000). The immunological effects of Klinefelter’s syndrome are reversed by testosterone therapy (Kocar et al., 2000), illustrating that both sex chromosomes and sex steroids regulate immune responses. By contrast, Turner’s syndrome females have only one X chromosome (XO) or have major X chromosome deletions (Bianchi, Lleo, Gershwin, & Invernizzi, 2012). Turner’s syndrome females have lower IgG and IgM levels and lower T- and B-cell levels than XX females (Cacciari et al., 1981). Both patients with Klinefelter’s syndrome and patients with Turner’s syndrome show increased development of autoimmune disease, pointing to a major role for the X chromosome in influencing susceptibility to autoimmunity (Bianchi et al., 2012).
MicroRNAs and Long Noncoding RNA
Much of the mammalian genome encodes for transcripts that are not translated into proteins, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Despite the fact that male and female invertebrates and higher organisms differentially express miRNAs, few studies have addressed the role of miRNAs in sex differences in diseases (Sharma & Eghbali, 2014). The X chromosome contains 10% of the ~800 miRNAs in the human genome, whereas the Y chromosome only contains 2 miRNAs (Ghorai & Ghosh, 2014). MicroRNAs, including miRNA-18 and 19 that are encoded on the X chromosome, play a role in sex differences in immune responses (Pinheiro, Dejager, & Libert, 2011). MicroRNA expression can be under sex hormone control (Dai et al., 2013). The high density of miRNAs on the X chromosome means that females may express more, due to incomplete X inactivation, further contributing to sex differences in susceptibility to certain diseases. The lncRNAs play a vital role in the regulation of multiple immunological processes, including transcriptional regulation of innate and adaptive immunity (Zhang & Cao, 2016), and they act as a catalyst of X inactivation in a manner that has been shown to be different between the sexes (Gayen, Maclary, Hinten, & Kalantry, 2016).
Polymorphisms or variability in sex chromosome and autosomal genes encoding immunological proteins can have sex-differential effects on immunity. For example, sex-based differences in HLA alleles and genes that encode for IL-4, IL-10, and the IL-12 receptor have each been associated with differential antibody responses to vaccines against measles, mumps, hepatitis A, tetanus, and diphtheria in children and adults (Klein et al., 2010). Whether sex-based differences in the expression of gene variants are caused by differential selection pressures acting on each sex, hormone-dependent effects, or epigenetic mechanisms remains to be determined, but because the differences are apparent early in life and remain over the life course, genetic (as opposed to hormonal) mechanisms are likely involved (Baynam et al., 2008).
The Microbiome May Mediate Sex Differences in Immune Responses
A perturbed microbiome―referred to as dysbiosis―contributes to various disease processes related to inflammation, from diabetes to depression. Sex influences the host microbiome outside of the reproductive tract, which involves modulation of the microbiome by sex steroid hormones (Markle et al., 2013; Yurkovetskiy et al., 2013). Importantly, the microbiome is highly dynamic, and alterations in its composition occur throughout development (Borre et al., 2014). Early in life, there are no sex differences in the composition of gut microbiome, with deep sequencing of colonic contents in pre-pubescent mice showing no sex difference in bacterial community composition (Steegenga et al., 2014). After puberty, the gut microbiome begins to change. For example, the human female microbiome has less abundant Bacteroidetes than the microbiome in males (Dominianni et al., 2015), an effect that has also been seen in rodents (Markle et al., 2013; Yurkovetskiy et al., 2013). The same study in rodents (Yurkovetskiy et al., 2013) also found that the composition of the male microbiome begins to diverge quite dramatically during puberty and exhibits a distinctive phenotype from the female microbiome by adulthood (Yurkovetskiy et al., 2013). If the surge in testosterone during puberty is prevented via castration of males, the masculinization of the gut microbiome is eliminated in adulthood.
To illustrate that sex differences in the composition of the microbiome can influence disease processes, in a mouse model of spontaneous type 1 diabetes, adoptive transfer of male-enriched gut commensals into females resulted in systemic hormonal changes and protected against disease (Markle et al., 2013; Yurkovetskiy et al., 2013). Communication between the gut microbiome and the brain is now recognized as an integral factor in brain development and behavior. Following bacterial inoculation of the infant with the maternal vaginal microbiome at birth, communication between the flourishing gut microbes and the brain can function to integrate various signals from the body (e.g., autonomic, neuroendocrine, etc.) that in turn impact the brain. Transfer of the microbiome of an adult male to a pubertal female completely masculinizes the microbiota composition and metabolomic profile and produces an increase in testosterone levels that persist into adulthood, suggesting that the differentiation of the microbiome during development subsequently affects neural and hormonal function (Markle et al., 2013). If, however, the anti-androgen flutamide is administered with the microbiome transfer, all changes are prevented in females, demonstrating the important, mechanistic role of testosterone in producing the microbiome-induced masculinization.
The sex-dependent changes in microbiome composition throughout development may also have important implications for mental health disorders with suspected links to immune dysregulation. In a well-established mouse model of autism spectrum disorder (ASD; i.e., the BTBR inbred mice), both males and females have altered microbiome composition in comparison to wild-type mice; however, there were also sex differences in the alterations (Coretti et al., 2017). Specifically, Bacteroides, Parabacteroides, and Sutterella were significantly elevated in BTBR mice, but more so in females than in males. Dehalobacterium and Oscillospira were significantly decreased in BTBR mice compared to control mice, but more so in females than in males. BTBR mice also display sex differences in their inflammatory profile in colon tissue, with males showing significantly higher levels of IL-6 and proportions of CD11c compared to either BTBR females or wild-type mice. Thus, in this model of autism, both male and female mice experience dysbiosis but to varying degrees, and with varying results on proinflammatory cytokine expression in the periphery. In another model of ASD, male mice, but not female mice, that are treated with valproic acid on gestational day 11 show reduced social interactions and increased gut inflammation (de Theije, Wopereis, et al., 2014). Additionally, valproic acid significantly alters the composition of the gut microbiota, and the levels of social interaction correlate with metabolites of the microbiota (de Theije, Wu, et al., 2014). These data suggest that the gut microbiome affects the immune system and the brain differently between the sexes, which may be relevant for understanding the increased prevalence of ASD in males.
Conclusions and Future Directions
Taken together, the data highlight that sex can have a robust influence on the peripheral and central immune systems. Often, sex differences in immune function are the result of sex hormones that influence the innate and adaptive responses to peripheral immune activation. As a result, age is an important factor to consider when understanding sex differences in immune function and how they affect the risk and progression of illness and disease. Sex differences in immune function often emerge after puberty, when circulating sex hormones increase, but sex differences in immune function can also emerge as we age and sex hormone levels begin to decrease. Sex can also affect immune function and the expression of immune-related genes independently of sex hormones, via the sex differences in gene expression related to sex chromosome complement, X inactivation, or other epigenetic processes. Moreover, the stress response is an integral part of the immune response, and well-documented sex differences in the stress response can subsequently affect immune function and the associated risk of disease. As we continue to learn more about the various neural and peripheral systems that affect each other and influence the immune system, we can better understand how sex differences in these systems may contribute to one’s vulnerability to, or protection against, diseases, including infections, cancers, and even mental health disorders.
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