Sex differences in immune function and disease risk are not easily explained by an evolutionary mismatch

Chapter 1 - Sex Differences in Immunity and Inflammation: Implications for Brain and Behavior

Understanding sex differences in immunological responses in the context of obesity is important to improve health outcomes. This systematic review aimed to investigate sex differences in systemic inflammation, immune cell phenotype, and function in diet-induced obesity (DIO) animal models. A systematic search in Medline, Embase, and CINAHL from inception to April 2023 was conducted, using a combination of the following concepts: sex, obesity, cytokines, and immune cell phenotypes/function. Forty-one publications reporting on systemic inflammation (61%), cell phenotype (44%), and/or function (7%) were included. Females had lower systemic inflammation compared with males in response to DIO intervention and a higher proportion of macrophage (M)2-like cells compared with males that had a higher proportion of M1-like in adipose tissue. Although there were no clear sex differences in immune function, high-fat DIO intervention remains an important factor in the development of immune dysfunction in both males and females, including disturbances in cytokine production, proliferation, and migration of immune cells. Yet, the mechanistic links between diet and obesity on such immune dysfunction remain unclear. Future studies should investigate the role of diet and obesity in the functionality of immune cells and employ adequate methods for a high-quality investigation of sex differences in this context.

Sex differences in parasitism are common and may depend on sex differences in intensity of sexual competition, immunosuppression, or exposure to parasites. We used a large data set on the mass of two immune defense organs in birds (the bursa of Fabricius and the spleen) to test for consistent sex differences in immune defense. Males had a relative spleen mass that was consistently smaller, but more variable, than that of females across species of birds. A sex difference in the size of the spleen was not present among juveniles but was large and statistically significant among adults. The suppression of spleen mass in adult males increased with a measure of intensity of sexual selection: the frequency of extra‐pair paternity. These findings suggest that sexdifferences in parasitism may arise as a consequence of sex differences in immune function, as mediated by sexual selection.

Males and females have the same immunological cells, proteins, and pathways in place to protect against the development of disease. The kinetics, magnitude, and skewing of the responses mounted against pathogens, allergens, toxins, or self-antigens, however, can differ dramatically between the sexes. Generally, females mount higher innate and adaptive immune responses than males, which can result in faster clearance of pathogens but also contributes to increased susceptibility to inflammatory and autoimmune diseases in females compared with males. Hormonal and genetic factors contribute significantly to sex differences in immune function and disease pathogenesis. In particular, the expression of X-linked genes and microRNA as well as sex steroid hormones signaling through hormone receptors in immune cells can affect responses to immunological stimuli differently in males and females. Despite data illustrating profound differences between the sexes in immune function, sex differences in the pathogenesis of disease are often overlooked in biomedical research. Establishing journal policies that require authors to report the sex of their cells, animals, and subjects will improve our understanding of the pathogenesis of diseases, with the long-term goal of personalizing treatments for immune-mediated diseases differently for males and females in an effort to protect us equally.

Despite the availability of effective antiretroviral therapies, cognitive impairment (CI) remains prevalent in HIV-infected (HIV+) individuals. Evidence from primarily cross-sectional studies, in predominantly male samples, implicates monocyte- and macrophage-driven inflammatory processes linked to HIV-associated CI. Thus, peripheral systemic inflammatory markers may be clinically useful biomarkers in tracking HIV-associated CI. Given sex differences in immune function, we focused here on whether mean and intra-individual variability in inflammatory marker-predicted CI in HIV+ and HIV- women. Seventy-two HIV+ (36 with CI) and 58 HIV- (29 with CI) propensity-matched women participating in the Women's Interagency HIV Study completed a neuropsychological battery once between 2009 and 2011, and performance was used to determine CI status. Analysis of 13 peripheral immune markers was conducted on stored biospecimens at three time points (7 and 3.5years before neuropsychological data collection and concurrent with data collection). HIV+ women showed alterations in 8 immune markers compared to HIV- women. The strongest predictors of CI across HIV+ and HIV- women were lower mean soluble tumor necrosis factor receptor I (sTNFRI) levels, higher mean interleukin (IL)-6 levels, and greater variability in C-reactive protein (CRP) and matrix metalloproteinase (MMP)-9 (p values <0.05). Stratified by HIV, the only significant predictor of CI was greater variability in CRP for both HIV+ and HIV- women (p values <0.05). This variability predicted lower executive function, attention/working memory, and psychomotor speed in HIV+ but only learning in HIV- women (p values <0.05). Intra-individual variability in CRP levels over time may be a good predictor of CI in predominately minority low-socioeconomic status midlife women.

It is evident that human male and female children differ in their outcomes following infectious challenge and vaccination. This chapter explores some of the evidence for this in children <5 years of age, which is the age group that suffers the greatest morbidity and mortality from infections, and the target age group for many vaccinations. The sex-differential effects commence both preimplantation and in utero and continue throughout childhood. The mechanisms include genetic influences, epigenetic differences, the influences of sexually dimorphic hormones, sex differences in innate immunity, differences in thymic development, and sex differences in the effect of diet and breastfeeding. There may also be behavioral factors at play such as differential treatment of males and females. Studies in this age group are limited, and yet understanding the factors that determine key sex differences in immunity could lead to therapeutic strategies to improve childhood survival.

Males generally exhibit reduced immune responses and greater susceptibility to disease than females. The suppressive effect of testosterone on immune function is hypothesized to be one reason why males have lower immune responses than females. Presumably, this effect of testosterone should be more pronounced among polygynous than monogamous species because circulating testosterone is higher among polygynous than monogamous males. The present study examined the extent to which sex differences in specific humoral immunity are related to the endocrine status and mating system of two arvicoline rodents. Humoral immunity was evaluated among polygynous meadow voles (Microtus pennsylvanicus) and monogamous prairie voles (Microtus ochrogaster) by challenging them with the novel antigen keyhole limpet hemocyanin (KLH) and assessing specific immune responses 5, 10, and 15 d following immunization. Overall, meadow voles mounted higher anti-KLH IgM and IgG responses than prairie voles did. Sex differences were also apparent for anti-KLH IgM responses; male meadow voles mounted higher antibody responses than conspecific females, whereas female prairie voles mounted greater responses to KLH than did conspecific males. Male meadow voles had significantly higher testosterone concentrations and reproductive organ mass than male prairie voles did but had elevated immune responses, suggesting that testosterone may not be the primary factor involved in the observed sex and species differences in immune responses. Species and sex differences in corticosterone concentrations were also evident and may contribute to the observed differences in immune function. The influence of extrinsic factors on immune function is also discussed. Taken together, these data provide evidence that the mating system may influence endocrine-immune interactions.

Autoimmunity represents a potentially diverse and complex category among the range of adverse outcomes for detection with immunotoxicity testing. For this reason, the risk of autoimmune disease is discussed in this overview chapter with additional mention among the later specific protocol chapters. Improvements in clinical diagnostic capabilities and disease recognition have led to a more accurate picture of the extent of autoimmune diseases across different human populations. While the risk of any single autoimmune disease remains modest when compared with that of lung or heart disease, the cumulative prevalence of autoimmune diseases is both significant and increasing. Autoimmune diseases are usually viewed in the context of the damaged tissue or organ (e.g., as a thyroid, gastrointestinal, cardiovascular or neurological disease). But improved recognition that underlying immune dysfunction can connect the risks for these as well as other diseases is critical for optimizing risk assessment. Since autoimmune diseases are chronic in nature with many first appearing in children or in young adults, these diseases exert a serious impact on both health care costs and quality of life. This chapter provides a discussion of the issues that should be considered with immunotoxicity testing for risk of autoimmunity.

The ongoing COVID-19 pandemic has increased awareness about sex-specific differences in immunity and outcomes following SARS-CoV-2 infection. Strong evidence of a male bias in COVID-19 disease severity is hypothesized to be mediated by sex differential immune responses against SARS-CoV-2. This hypothesis is based on data from other viral infections, including influenza viruses, HIV, hepatitis viruses, and others that have demonstrated sex-specific immunity to viral infections. Although males are more susceptible to most viral infections, females possess immunological features that render them more vulnerable to distinct immune-related disease outcomes. Both sex chromosome complement and related genes as well as sex steroids play important roles in mediating the development of sex differences in immunity to viral infections.

The Prevalence of Second Malignancies and Autoimmune Diseases in Patients with Lymphoproliferative Disorders.

Previous studies have suggested that vitamin D has a protective effect on allergic diseases, while an individual's sex may have a moderating effect on the relationship between vitamin D and allergic-related immunity. This study aimed to determine the role of vitamin D in children with coexisting allergic diseases in the context of sex differences and to explore the behavioral profiles of these patients. We recruited a total of 103 children with atopic diseases and divided them into four groups: males with one allergic disease (MA1, n = 20), males with two or more allergic diseases (MA2, n = 26), females with one allergic disease (FA1, n = 30), and females with two or more allergic diseases (FA2, n = 27). We measured serum calcium levels using the colorimetric method and serum 25-OH vitamin D total levels using electrochemiluminescence immunoassay. We found that MA2 had significantly lower vitamin D levels than MA1 and FA2. The levels of IgE were negatively correlated with vitamin D in females, whereas the levels of IgE were not significantly correlated with vitamin D in males. Furthermore, serum IgE was significantly correlated with children's adaptive skills, and different sexes were associated with different aspects of adaptive skills. Our findings suggest a protective role of vitamin D in the development of one allergic disease against the coexistence of allergic diseases in males, as well as extend the evidence for sex differences in immunity by demonstrating a sex-different correlation between IgE and vitamin D and the relationship between IgE and children's adaptive skills.

1 The pathogenesis of graves' disease

BackgroundColour polymorphisms are widespread and one of the prime examples is the colour polymorphism in female coenagrionid damselflies: one female morph resembles the male colour (andromorph) while one, or more, female morphs are described as typically female (gynomorph). However, the selective pressures leading to the evolution and maintenance of this polymorphism are not clear. Here, based on the hypothesis that coloration and especially black patterning can be related to resistance against pathogens, we investigated the differences in immune function and parasite resistance between the different female morphs and males.ResultsOur studies of immune function revealed no differences in immune function between the female morphs but between the sexes in adult damselflies. In an experimental infection females infected shortly after emergence showed a higher resistance against a fungal pathogen than males, however female morphs did not differ in resistance. In a field sample of adult damselflies we did not find differences in infection rates with watermites and gregarines.ConclusionWith respect to resistance and immune function 'andromorph' blue females of Coenagrion puella do not resemble the males. Therefore the colour polymorphism in coenagrionid damselflies is unlikely to be maintained by differences in immunity.

Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female-biased genes, whereas male-biased genetic factors remain understudied. Here, we show that the Y-linked noncoding RNA, RP11-424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF-κB pathway as the top biological pathway affected by RP11-424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11-424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X-linked long noncoding RNA XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11-424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11-424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11-424G14.1-IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11-424G14.1 being a human-specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes.

Type 1 diabetes mellitus (T1D) results from autoimmune destruction of pancreatic β cells. T1D individuals face increased risk of autoimmune thyroid disease (AITD) and celiac disease (CD). While most patients present with β-cell autoantibodies, 5-10 % do not and are classified as antibody-negative T1D (AB- T1D). Whether autoimmune disease risk differs between AB- and antibody-positive T1D (AB+ T1D) remains uncertain. Children aged 6months to 18years diagnosed with T1D between January 2010 and June 2023 were reviewed and categorized as AB+ or AB- based on islet cell antigen, insulin, and GAD-65 autoantibodies at diagnosis. Each AB- patient was matched with two age- and sex-matched AB+ controls within the diagnosis date. Chi-square testing compared CD and AITD prevalence between groups, with significance set p<0.05. The study included 149 AB- and 298 AB+ subjects. CD prevalence was 5.0 % in the AB+ group and 3.4 % in the AB- group. AITD prevalence was 4.4 % in the AB+ group and 2.7 % in the AB- group. No significant differences were identified. A combined diagnosis of CD and AITD occurred only in the AB+ group (2.2 %, p=0.024). At diagnosis, AB+ patients had higher glucose and beta-hydroxybutyrate levels and lower C-peptide, while venous pHwas similar. AITD and CD prevalence did not differ significantly between AB- and AB+ children with T1D, though coexistence of both conditions occurred only in AB+ patients. These findings suggest that AB- T1D may still involve autoimmunity and support similar surveillance strategies for autoimmune diseases in both groups.