When we talk about immune responses and their effects on our health, we sometimes neglect the roles that sex (the biology) and gender (the social and cultural constructs) play in regulating our immune responses. A better understanding of how sex and gender affect immune responses can be advantageous to advancements in personalized medicine for both men and women. Unfortunately, we still do not fully understand how the biology of sex is able to affect immune responses. In this article we will describe our current understanding of how the biology of sex drives immune responses in the context of infection and autoimmunity, highlighting the importance for the consideration of these differences when conducting scientific research.

The beginning
It has long been known that adult females have stronger immune responses and are better at clearing viral and bacterial infections than males. However, the robust strength of the female immune response presents disadvantages when it comes to autoimmunity – many autoimmune diseases have higher incidence in females than males such as multiple sclerosis (MS) and lupus. Early observational studies demonstrated that women have higher numbers of circulating CD4+ T lymphocytes and higher antibody titers as compared to men at baseline. Studies of the immune response to influenza vaccination showed that healthy women between the ages of 18 and 64 years develop a more robust antibody response after vaccination – as little as a half dose of the vaccine generated an effective response in women. In addition to sex differences in adaptive immunity, males and females also have different innate immune responses. Antigen presenting cells are more abundant in females and are better at presenting peptides than those from males. Furthermore, females have increased expression of genes associated with toll-like receptor pathways as well as type I interferon (IFN) responses under anti-viral responses.

Sex differences in immunity precede puberty, albeit less commonly. Males between 12 months of age and the onset of puberty show increased rates of bacterial meningitis. During this stage of life, there are no differences in sex hormones between males and females, and as such the effects of differences in sex chromosomes are thought to drive the differing immune responses in males and females.

Sex chromosomes
One of the major differences between male and female immune responses is the X chromosome. Examining the X chromosome, we find that it encodes more than 1100 genes – 10 times more genes than the Y chromosome. Many genes encoded on the X chromosome play either direct or indirect roles in immunity, and as such, the state of being ‘XX’ or ‘XY’ has a very profound effect on immune responses. As female cells carry two copies of the X chromosome, female cells undergo X chromosome inactivation to prevent double dosage of the genes encoded, leading to a phenomenon known as cellular mosaicism. Female cells therefore express roughly half of their X-encoded genes from the maternal X chromosome, and half from the paternal X chromosome. As a result, females are more protected from primary immunodeficiencies that arise from deleterious mutations on the X chromosome. Depending on the genes involved, primary immunodeficiencies affect the innate or adaptive immune response. In some cases they may be so severe that they lead to death of affected male fetuses during pregnancy, or they may result in chronic infection and eventually, premature death. Mutations in genes required for efficient phagocytosis such as NOX2 lead to an impaired ability for innate immune cells to kill microorganisms, resulting in X-linked chronic granulomatous disease (X-CGD). Mutations in genes required for normal lymphocyte development and differentiation such as FOXP3 or IL2RG lead to immunodysregulation, resulting in X-linked syndrome (IPEX) and X-linked severe combined immunodeficiency (X-SCID), respectively. Treatments for these conditions involve either gene therapy or bone marrow transplantation. Interestingly, regions of the Y chromosome have recently been implicated in chromatin dynamics, suggesting that the Y chromosome may also have roles in regulation of gene expression and male immune responses. Furthermore, sex chromosomes have been found to modulate autosomal gene expression and lead to specific downstream phenotypes. An example of this is a deletion in the Y chromosome which causes infertility in only a subset of those with this specific mutation, suggesting the influence of the autosomal genes.

Sex hormones
Epidemiological studies have demonstrated that sex hormones regulate autoimmune responses. For instance, a sex bias is not evident in young children with pediatric MS, though the female preponderance emerges as these children approach puberty. Female sex hormones that contribute to differences in immune responses are progesterone, estradiol, and estriol. Though both progesterone and estradiol exist at various concentrations during menstruation, estriol can only be detected during pregnancy at increasing levels along with gestation. The male sex hormones, testosterone and its derivative dihydrotestosterone (DHT), may also contribute to sex differences in immune responses.

While progesterone is considered immuno-suppressive through inhibition of the T helper (Th)-1 pathway, the effects of estradiols are somewhat controversial as they have biphasic effects on the immune system. Low levels of estradiols can be associated with a pro-inflammatory Th1 response and increased incidence of T cell-mediated autoimmune diseases such as MS, while high levels of estradiols drives an anti-inflammatory Th2 response and leads to antibody-mediated autoimmune diseases such as lupus. For instance, ex vivo estradiol treatment of antigen-specific T cell clones from people with MS promotes the secretion of pro-inflammatory cytokines at lower concentrations while favouring the secretion of more anti-inflammatory cytokines at higher concentrations. The effects of pregnancy-related estriols are less ambiguous – they tend to drive the immune response away from a Th1 and more towards a Th2-type response and antibody production. As a result, MS patients experience alleviated symptoms while symptoms in lupus patients become exacerbated during pregnancy. The protective effects of estriols in Th1-driven autoimmune diseases have been demonstrated in a trial with MS patients: 12 non-pregnant female MS patients were treated with estriols for 6 months and exhibited decreased MRI activity as well as a more anti-inflammatory cytokine expression profiles in peripheral blood mononuclear cells (PBMC). Unfortunately, the protective effects do not seem to be long lasting after treatment, similar to the natural worsening of MS observed post-partum.

Testosterone and its derivative dihydrotestosterone (DHT) are generally agreed upon to be immune-suppressive of the Th1 pathway, hence playing a protective role in autoimmunity driven by Th1 responses. A small pilot clinical trial involving 10 male patients with relapsing remitting form of MS showed that the testosterone treatment is effective in generating an anti-inflammatory environment and improving cognitive function in these patients. In female lupus patients, testosterone was not found to have beneficial effects, but this might be due to the fact that androgens have a Th1-suppresive nature.

Sex, immunity and microbes
Several recent studies have been focusing on further understanding how sex hormones and specifically androgens affect immunity in both humans and mice. In 2012, an article in PNAS demonstrated that anti-CD3 and anti-CD28-stimulated naïve CD4+ T cells from healthy women produce higher levels of IFNγ while lower levels of IL-17 as compared to those from healthy men. This observation is unique in the sense that though women have been shown to produce higher levels of Th1-type cytokines such as IFNγ, men were generally said to produce more Th2-type cytokines such as IL-5 and IL-13 in PBMC with antigen specific stimulation in the context of autoimmunity. This skewing away from the pathogenic Th1 to more protective Th2-type immune responses in men is thought to be linked to men being less likely to develop MS. This article instead reported that even at baseline, men may actually have more of a Th17 immune profile, which has been shown to induce a somewhat different kind of pathogenicity in an animal model of MS.

[pullquote]Despite the enormous role of sex in the regulation of immune responses, sex differences are still very much under-studied and poorly understood in scientific research.[/pullquote]

This novel observation hinted to the interesting possibility that men may not simply be more protected than women – instead, men may potentially be more predisposed to develop a different kind of disease. It has been shown that when men do acquire MS later in life when their testosterone levels start declining, they tend to progress faster, have worse outcomes, and no longer exhibit a lower incidence than women. Indeed, this article found that stimulated naïve CD4+ T cells from these healthy men already express higher levels of a Th1 suppressor molecule called peroxisome proliferator-activated receptor alpha (PPARα) that can be positively regulated by androgens – as such, men with lower androgens have lower expression of PPARα.

Though we still do not fully understand why such striking sex difference already exists in a healthy population, a seminal article in Science in the following may have shed some light on that. The authors demonstrated that at least in mice, females and males have distinct microbiomes that may contribute to higher disease incidence of type 1 diabetes in the female sex. When female mice were given an oral gavage of male microbiota over a period of time, female mice became more protected from type 1 diabetes. This protective effect was in fact androgen-dependent where the inhibition of androgens led to a complete loss of protection after females were given male microbiota, highlighting a novel connection between sex hormones, immunity, and microbiota.

New Initiatives
Despite the enormous role of sex in the regulation of immune responses, sex differences are still very much under-studied and poorly understood in scientific research. This is also reflected in the fact that women have a long history of being under-represented in clinical trials for diseases where females show a higher prevalence. Even in the case where both sexes were present in a particular trial in the hope of establishing a proper assessment of treatment efficacy, the identification of sex-specific biomarkers may still not be considered a priority. Fortunately, major funding agencies have shown a growing awareness in incorporating sex and gender in health research. Last year, the Gender and Health Institute of the Canadian Institute of Health Research started a new five-year strategic plan to foster a scientific environment where both sex and gender would be incorporated in the design and interpretation of experiments, in part through supporting scientists and trainees who study sex or gender in health research. In the US, The Office of Research on Women’s Health at the National Institutes of Health has expressed similar sentiments through supporting research with a focus on sex and gender as crucial components in the immune response.

-Leesa Pennell and Angela Zhang

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Angela Zhang and Leesa Pennell

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