Sexual Dimorphism in Immune Defense

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.

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

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.

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.

In most animals, females are larger than males. Paradoxically, sexual size dimorphism is biased towards males in most mammalian species. An accepted explanation is that sexual dimorphism in mammals evolved by intramale sexual selection. I tested this hypothesis in primates, by relating sexual size dimorphism to seven proxies of sexual selection intensity: operational sex ratio, mating system, intermale competition, group sex ratio, group size, maximum mating percentage (percentage of observed copulations involving the most successful male), and total paternity (a genetic estimate of the percentage of young sired by the most successful male). I fitted phylogenetic generalised least squares models using sexual size dimorphism as the dependent variable and each of the seven measures of intensity of sexual selection as independent variables. I conducted this comparative analysis with data from 50 extant species of primates, including Homo sapiens, Pan troglodytes, and Gorilla spp. Sexual dimorphism was positively related to the four measures of female monopolisation (operational sex ratio, mating system, intermale competition, and group sex ratio) and in some cases to group size, but was not associated with maximum mating percentage or total paternity. Additional regression analyses indicated that maximum mating percentage and total paternity were negatively associated with group size. These results are predicted by reproductive skew theory: in large groups, males can lose control of the sexual behaviour of the other members of the group or can concede reproductive opportunities to others. The results are also consistent with the evolution of sexual size dimorphism before polygyny, due to the effects of natural, rather than sexual, selection. In birds, the study of molecular paternity showed that variance in male reproductive success is much higher than expected by behaviour. In mammals, recent studies have begun to show the opposite trend, i.e. that intensity of sexual selection is lower than expected by polygyny. Results of this comparative analysis of sexual size dimorphism and sexual selection intensity in primates suggest that the use of intramale sexual selection theory to explain the evolution of polygyny and sexual dimorphism in mammals should be reviewed, and that natural selection should be considered alongside sexual selection as an evolutionary driver of sexual size dimorphism and polygyny in mammals.

A recent report described sex differences in the effects of nicotine use and withdrawal on prepulse inhibition of acoustic startle (PPI), but no sex differences in PPI in non-smokers. To determine whether previously reported male>female acoustic PPI reflect sex differences in smoking effects on PPI, rather than simple sex differences in the regulation of PPI. A retrospective analyses of >600 carefully screened normals tested over the past 12 years was completed. Male>female acoustic PPI was detected in analyses that included: 1) all subjects; or 2) self-declared non-smokers. Sex differences in PPI cannot be accounted for by smoking history, because they are present across a large sample of non-smoking normal controls.

Assessing the long-term macroevolutionary consequences of sexual selection has been hampered by the difficulty of studying this process in the fossil record. Cytheroid ostracodes offer an excellent system to explore sexual selection in the fossil record because their readily fossilized carapaces are sexually dimorphic. Specifically, males are relatively more elongate than females in this superfamily. This sexual shape difference is thought to arise so that males carapaces can accommodate their very large copulatory apparatus, which can account for up to one-third of body volume. Here we test this widely held explanation for sexual dimorphism in cytheroid ostracodes by correlating investment in male genitalia, a trait in which sexual selection is seen as the main evolutionary driver, with sexual dimorphism of carapace in the genus Cyprideis. We analyzed specimens collected in the field (C. salebrosa, USA; C. torosa, UK) and from collections of the National Museum of Natural History, Washington, DC (C. mexicana). We digitized valve outlines in lateral view to obtain measures of size (valve area) and shape (elongation, measured as length to height ratio), and obtained several dimensions from two components of the hemipenis: the muscular basal capsule, which functions as a sperm pump, and the section that includes the intromittent organ (terminal extension). In addition to the assessment of this primary sexual trait, we also quantified two dimensions of the male secondary sexual trait—where the transformed right walking leg functions as a clasping organ during mating. We also measured linear dimensions from four limbs as indicators of overall (soft-part) body size, and assessed allometry of the soft anatomy. We observed significant correlations in males between valve size, but not elongation, and distinct structural parts of the hemipenis, even after accounting for their shared correlation with overall body size. We also found weak but significant positive correlation between valve elongation and the degree of sexual dimorphism of the walking leg, but only in C. torosa. The correlation between the hemipenis parts, especially basal capsule size and male valve size dimorphism suggests that sexual selection on sperm size, quantity, and/or efficiency of transfer may drive sexual size dimorphism in these species, although we cannot exclude other aspects of sexual and natural selection.

Through secondary data analyses, we investigated sex differences in the effects of IQOS, a heated tobacco product, on combustible cigarette smoking. Adults who smoke cigarettes (N = 118; 21-65 years old) completed a baseline ad-lib smoking period (days 1-5), two laboratory visits (days 6-7), and a 14-day period where they were instructed to switch from smoking cigarettes to using IQOS 3.0 (days 8-21). Models estimated the changes in cigarettes smoked per day (CPD) and the percentage of baseline CPD substituted by HeatSticks during the switch period. Bivariate statistics assessed sex differences in covariates and IQOS-associated effects (i.e., subjective reward, relative reinforcing value, craving relief, and withdrawal relief) for model inclusion. Males and females significantly reduced their CPD to 29.8 % and 21.8 % of their baseline CPD by the end of the switch period, respectively. CPD slopes were significant for males (β =-0.46/day [CI95 % -0.97 to -0.04] p = 0.002) and females (β =-0.83/day [CI95 % -1.34 to -0.31] p < 0.001), although slopes did not significantly differ (p = 0.3). Males and females substituted HeatSticks at 83.2 % and 67.4 % of their baseline CPD across the switch period. The IQOS slopes were significant for males (β =1.136/day [CI95 % 0.59-2.14] p = 0.001) but not females (β =0.64/day [CI95 % -0.67-1.94] p = 0.34), although the slopes did not significantly differ (p = 0.36). There were no significant sex differences in IQOS-associated effects (all p values > 0.05). Males and females do not appear to differ in IQOS-associated effects or the initial substitutability of IQOS for combustible cigarettes.

Similar anxiety-like responses in male and female rats exposed to repeated withdrawals from ethanol

Sex differences in the effects of neuropeptide FF and IgG from neuropeptide FF on morphine- and stress-induced analgesia

Sexual dimorphism in immunocompetence, with males having lower immune function, is a prevalent pattern in nature. The main evolutionary explanation for this pattern is that males preferentially allocate resources away from immune function and towards reproductive effort to increase their competitiveness for limited females. However, the role of differential predation risk between the sexes has not been considered, despite predation risk being a major driver of life history strategies and male sexual traits often having associated predation costs. It is unclear whether increased predation risk should increase or decrease investment in immune function, as males have been shown to utilize both behavioural (e.g. decrease foraging activity) and/or life-history (e.g. decrease investment in sexual trait) defense strategies to manage predation risk. Here, we modelled optimal resource acquisition and allocation towards immune function under differential predation risk with multiple defense strategies. If males have limited defense strategies, increasing predation risk caused males to trade-off immune function for reproductive effort, leading to reduced immunocompetence. In contrast, if males can only decrease predation risk through reduction of reproductive effort (e.g. decrease colouration or calling rates), then increasing predation risk causes immune function to increase. If males can utilize multiple defense strategies and sexual selection is low, then males maintain a constant immune function as predation risk increases. Sexual selection robustly resulted in decreased immunocompetence. Overall, our results suggest that predation plays an important role in the evolution of sexual dimorphism in immunocompetence, but predicting its effect requires understanding the integrated defense strategies available.

Climatic conditions may impact on the body condition of animals and thereby affect their survival prospects. However, climate may also impact directly on the survival prospects of animals by affecting the size of immune defence organs that are used for defence against parasites. We used a large long-term database on body condition and size of the spleen in birds to test for immediate and delayed relationships between climatic conditions as indexed by the North Atlantic Oscillation (NAO) and body condition and spleen mass, respectively. Across 14 species of birds, spleen mass was significantly positively correlated with the NAO index, while the delayed effect of NAO on spleen mass was not significant. Spleen mass was positively related to body condition, but body condition did not depend significantly on NAO or delayed NAO effects. Bird species with a strong positive effect of NAO on spleen mass tended to have small spleens for their body size, while species with a strong negative effect of NAO on spleen mass tended to have relatively large spleens. Since bird species with relatively large spleen have been shown to suffer more from the negative effects of parasites, we can infer that the effects of climate as indexed by NAO on the size of the spleen depends on the importance of parasite-mediated natural selection.

-Sexual wing dimorphism in relation to tail ornaments and body size was studied in the strikingly sexually dimorphic widowbirds and bishops (Euplectes) of the African tropics. Seven widowbirds grow long tails, varying from 7 cm in Fan-tailed Widowbird (E. axillaris) to 0.5 m in the Long-tailed Widowbird (E. progne). Aerodynamic drag increases with tail length, and adaptations to compensate for this cost might be expected (e.g. increasing wing length), a prediction that was supported among the widowbirds. After controlling for overall size dimorphism (estimated by tarsus length), 70% of the variation in residual wing dimorphism among the widowbirds was explained by tail dimorphism. Bishops were more dimorphic in wing length than expected, which may be related to their slow display flight. The results suggest caution in using wing length alone for interspecific comparisons of sexual size dimorphism. Based on tarsus length, the lekking E. jacksoni is more size dimorphic than the average of its congeners, in contrast to what has been concluded in previous studies based on wing length. Received 13 May 1993, accepted 2 July 1993. SEXUALLY SELECTED characters, such as the elongated tails or the exaggerated displays of some birds, are expected to evolve until their mating advantages are balanced by costs (Fisher 1930), like predation or physiological constraints (Harvey and Bradbury 1991, Andersson 1994). At this dynamic equilibrium, morphological or behavioral adaptations that reduce the costs (hence, improve survival and allow further exaggeration of the trait) can be expected to evolve. Two such indirect effects of sexual selection on avian morphology have recently been reported. Hedenstrom and M6ller (1992) used aerodynamic theory to predict morphological adaptations to the demands of song flight. Consistent with their predictions, they found greater sexual dimorphism in wing span and wing area in eight passerines with song flight than in related species without this (supposedly sexually selected) behavior. Evans and Thomas (1992) estimated the aerodynamic costs of elongated tails in three species of sunbirds (Nectarinia spp). An increased tail area was shown to affect the aerodynamics in several ways, but most importantly increase the drag on the bird, which is a major component of flight cost (Norberg 1990). This cost should be particularly strong for birds with graduated tail ornaments (i.e. in I Present address: Department of Biology 0116, University of California at San Diego, La Jolla, California 92093, USA. which all rectrices are elongated) compared to pin tails and fork tails (Balmford et al. 1993). As predicted based on higher energy costs of flight, sunbirds with experimentally elongated tails spent less time flying than controls (Evans and Hatchwell 1992). Based on a correlation between wing length and tail length in one of the species (Nectarinia johnstoni), Evans and Hatchwell (1992) suggested that the sunbirds compensate for the energetic costs of a long tail by increasing wing span. Likewise, intraspecific relationships between ornamental tail length and wing length have been found in the Long-tailed Widowbird (Euplectes progne; Craig 1989) and Jackson's Widowbird (E. jacksoni; Andersson 1992a), suggesting similar compensations for the cost of carrying long tails. In particular, the exceptionally long wings of the Long-tailed Widowbird have made it an outlier in comparative studies of sexual size dimorphism based on wing length (Payne

Hypertension is a key modifiable risk factor for cardiovascular disease. Several observational studies have found a stronger association of blood pressure and cardiovascular disease risk in women compared to men. Since observational studies can be affected by sex-specific residual confounding and reverse causation, it remains unclear whether these differences reflect actual differential effects. Other study designs are needed to uncover the causality of sex differences in the strength of risk factor and treatment effects. Mendelian randomisation (MR) uses genetic variants as instrumental variables to provide evidence about putative causal relations between risk factors and outcomes. By exploiting the random allocation of genes at gamete forming, MR is unaffected by confounding and results in more reliable causal effect estimates. In this review, we discuss why and how sex-specific MR and cis-MR could be used to study sex differences in risk factor and drug target effects. Sex-specific MR can be helpful to strengthen causal inferences in the field of sex differences, where it is often challenging to distinguish nature from nurture. The challenge of sex-specific (drug target) MR lays in leveraging robust genetic instruments from sex-specific GWAS studies which are not commonly available. Knowledge on sex-specific causal effects of hypertension, or other risk factors, could improve clinical practice and health policies by tailoring interventions based on personalised risk. Drug target MR can help to determine the anticipated on-target effects of a drug compound and to identify targets to pursue in drug development.