Female Immune Response Research Articles

Sexual dimorphism in fish innate immunity: A functional and transcriptional study in yellowtail kingfish

Sexual dimorphism in immunity has been extensively documented across vertebrates, with marked contrasts observed in immune responses between males and females. These variations are mainly attributed to oestrogens conferring enhanced immune responses in females, while males exhibit greater susceptibility to pathogens. However, in the light of the data, consensus is lacking, as different physiological and environmental factors such, as epigenetics, may impact sex-biased immunity. In fish, the regulation of immune responses through sex hormones is primarily determined by the leucocyte function, which contains sex steroid receptors. However, comparative sex-based research in fish immunity is still very limited. This study aimed to evaluate, for the first time, the disparities between males and females yellowtail kingfish (Seriola lalandi) juveniles in several parameters of local humoral innate immunity related to mucosae (skin mucus and foregut homogenates) and reproductive tissue (ovary and testis homogenates), as well as in serum. We investigated the sexual dimorphism in the expression patterns of genes coding for antimicrobial peptides, antiviral markers, and cytokines. Our findings revealed that the yellowtail kingfish males exhibit significantly higher levels of innate immune parameters, both functionally and transcriptionally, compared to females. These results suggest that females may have a higher susceptibility to pathogen infections, potentially leading to latent infections, which deservers further investigations. Understanding these sex-based differences in immunity could guide breeding strategies improvements and disease management in aquaculture facilities.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

Developmental instability, body mass, and reproduction predict immunological response in short-tailed bats

Abstract Developmental instability (DI) is a phenomenon whereby organisms are unable to buffer developmental disturbances, resulting in asymmetric variation of paired traits. Previous research has demonstrated a negative relationship between DI, measured as forearm asymmetry, and survival in the bat Carollia perspicillata. This study aims to test the hypothesis that individuals with higher DI exhibit a lower immune response. We measured a delayed-type hypersensitivity to the antigen phytohemagglutinin (PHA) on 74 males and 65 females of C. perspicillata before and after the breeding season. Linear models were used to predict the immunological response based on body mass, forearm asymmetry, sex, breeding season, and testicle length. The best-fitting model accounted for 29% of the variation in immune response and included asymmetry, body mass, sex, and breeding season as predictors. The immune response was negatively associated with asymmetry and testicle length in males, but positively related to asymmetry in females. Both sexes showed a reduced immune response in the late breeding season. Additionally, the association between immune response and body mass changed direction seasonally, with heavier individuals showing weaker responses early in the breeding season and stronger responses later. Individual variation in male immunity was predicted by individual attributes, whereas variation in immune response in females was mostly seasonal. Our results support the link between DI, survival, and immune response in short-tailed bats, and suggest that the immunological component measured by the PHA response may be under finer selection in males due to its stronger correlation with individual traits.

CSIG-10. SEX-DIFFERENCES IN NF-ΚB SIGNALING DRIVE SEX-BIASED RESPONSES TOWARDS SENESCENCE AND INFLAMMATION IN GLIOBLASTOMA

Abstract Male glioblastoma (GBM) patients have a higher incidence rate and worse median survival in comparison to females. The molecular mechanisms that drive these sex differences in incidence and survival are not well understood. Using a murine in vitro GBM model, we identified that male and female cells tend to segregate into two unique groups based on differential gene expression. Male-enriched processes included myc, E2F and G2-M checkpoint signaling. Female-enriched processes included epithelial-mesenchymal transition, interferon responses and TNF-α signaling by NF-κB. Reports from human GBM patients corroborate an increased enrichment for inflammatory and innate immune responses in females. Since the NF-κB pathway regulates senescence and its associated inflammatory response, the senescence-associated secretory phenotype, we examined if there are sex differences in NF-κB signaling as we have reported that female GBM cells undergo senescence more readily. We found that low levels of NF-κB activity were correlated with higher levels of senescence, and that cells from the female-enriched group correspondingly had lower levels of NF-κB activity. Interestingly, p-p65 S536 expression (a marker of increased NF-κB transcriptional activity) was negatively correlated with NF-κB activity in cells within the female-enriched group. Furthermore, female cells with low NF-κB activity responded more readily to TNF-α treatment. These results suggest that female cells can more readily modulate the NF-κB pathway in response to stimuli, thereby poising them towards a pro-inflammatory state. Since inflammation and senescence regulate therapeutic responses in GBM, and we have previously reported that female GBM cells undergo senescence more readily following radiation, these results suggest that further studies to understand the sex differences in NF-κB signaling may improve patient response to radiation and chemotherapy treatment.

Coxsackievirus B3 elicits a sex-specific CD8+ T cell response which protects female mice.

Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8+ T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+ T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. This response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+ T cell epitope, we found that the expansion of CD8+ T cells in females is viral-specific and not due to bystander activation. Finally, the depletion of CD8+ T cells, prior to infection, led to enhanced mortality, indicating that CD8+ T cells are protective against CVB3 in female mice. These data demonstrate that CVB3 induces a CD8+ T cell response in female mice and highlight the importance of sex-specific immune responses to viral pathogens.

Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption

Circadian rhythms and sex differences are involved in the pathophysiology of asthma. Yet, there are no reports that simultaneously address the role of the circadian clock and sex-based differences in chronic house dust mite (HDM)-induced asthma. Here, we sought to determine if chronic HDM exposure during the resting phase (zeitgeber time: ZT0/6:00 a.m.) versus the active phase (ZT12/6:00 p.m.) differentially affects the circadian clock and alters asthma pathobiology in female and male mice. HDM exposure at ZT12 exaggerated infiltration of eosinophil subtypes and associated chemokines in females compared to males. Furthermore, HDM exposure augmented eosinophil chemokines, Th2 gene expression and cytokine release, and humoral immune response in females compared to males at ZT12. Concurrently, histopathological evaluation confirmed increased airway inflammation at ZT12 in both females and males. Overall, we showed a time-of-day response and sex-based differences in HDM-induced exaggerated asthmatic phenotypes (inflammation/remodeling) and circadian clock disruption in females compared to males.

Coxsackievirus B3 elicits a protective, sex-specific CD8 +T cell response in female mice

Abstract Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8 +T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8 +T cells in female Ifnar −/−mice but not in male Ifnar −/−mice. Using a recombinant CVB3 virus expressing a model CD8 +T cell epitope, we found that the expansion of CD8 +T cells is viral-specific and not due to bystander activation. CVB3 also increased the proportion and number of CD11a hiCD62L loCD8 +T cells in female mice, indicative of T cell activation. However, CD8 +T cell activation is dampened by the primary male sex hormone, testosterone, in male mice. Finally, using antibodies to deplete CD8 +T cells, we found that CD8 +T cells are required to limit CVB3-induced disease in female mice. These data demonstrate that CVB3 induces a sex-dependent CD8 +T cell response that is important for viral clearance in female mice and highlights the importance of sex differences in the immune response to viral pathogens. This work was funded by a K01 DK110216, R03 DK124749, and a Biomedical Research Grant from the Indiana Clinical and Translational Sciences Institute to CMR.

The impact of sex and physical activity on the local immune response to muscle pain

Induction of muscle pain triggers a local immune response to produce pain and this mechanism may be sex and activity level dependent. The purpose of this study was to measure the immune system response in the muscle following induction of pain in sedentary and physically active mice. Muscle pain was produced via an activity-induced pain model using acidic saline combined with fatiguing muscle contractions. Prior to induction of muscle pain, mice (C57/BL6) were sedentary or physically active (24hr access to running wheel) for 8 weeks. The ipsilateral gastrocnemius was harvested 24hr after induction of muscle pain for RNA sequencing or flow cytometry. RNA sequencing revealed activation of several immune pathways in both sexes after induction of muscle pain, and these pathways were attenuated in physically active females. Uniquely in females, the antigen processing and presentation pathway with MHC II signaling was activated after induction of muscle pain; activation of this pathway was blocked by physical activity. Blockade of MHC II attenuated development of muscle hyperalgesia exclusively in females. Induction of muscle pain increased the number of macrophages and T-cells in the muscle in both sexes, measured by flow cytometry. In both sexes, the phenotype of macrophages shifted toward a pro-inflammatory state after induction of muscle pain in sedentary mice (M1 + M1/2) but toward an anti-inflammatory state in physically active mice (M2 + M0). Thus, induction of muscle pain activates the immune system with sex-specific differences in the transcriptome while physical activity attenuates immune response in females and alters macrophage phenotype in both sexes.

SEX-DIMORPHIC REGULATION OF INNATE IMMUNITY DURING AGING

Abstract Aging is accompanied by striking changes in chromatin and gene expression across cell types and species. Yet, how chromatin landscapes change with age and regulate transcription, and how epigenomic changes in turn influence aging in response to external or internal cues, is largely unknown. In addition, accumulating evidence indicates that sex hormones play a key role in driving aspects of cellular and molecular sex-dimorphism. In parallel to sex hormones, karyotypic sex (i.e. XX vs. XY) is also likely to have important impact outside of gonadal sex determination. A key compartment whose activity can be actively modulated by sex-dimorphic mechanisms throughout life is the immune system, whose function declines sharply with aging and may be actively modulated by sex. Indeed, aspects of the immune responses differ between sexes, with a more robust immune response in females and an increased susceptibility to infection in males. Thus, our main cell models of study are key components of the innate immune system and the inflammatory response: macrophages, which accomplish key tasks such as phagocytosis, antigen presentation and cytokine production, and neutrophils, the most abundant leukocyte type serving as a “first line of defense” against infection. Excitingly, we and others have observed strong sex-related differences in the transcriptional and functional phenotypes of these cells and have observed sex-dimorphic “omic” trajectories for these cells with aging. Based on our data and published literature, it is likely that mechanisms involving both gonadal hormones and sex chromosomes may fine-tune different aspects of immunity and, thus, overall health and lifespan.

Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study

BackgroundIt has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced in females. The existence of these effects, and any implications for the development of vaccines and the design of vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the RCT and a nested case–control study to test this hypothesis.MethodsRandomised controlled trial with a nested case–control study.DiscussionWe expect that, among the placebo group, males will have higher mortality caused by higher pathogen loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs of non-live vaccines in high-mortality populations.

Sex‐dimorphism in aging: are we missing half of the picture?

Aging is accompanied by striking changes in chromatin and gene expression across cell types and species. Yet, how chromatin landscapes change with age and regulate transcription, and how epigenomic changes in turn influence aging in response to external or internal cues, is largely unknown. In addition, accumulating evidence indicates that sex hormones play a key role in driving aspects of cellular and molecular sex‐dimorphism. In parallel to sex hormones, karyotypic sex (i.e. XX vs. XY) is also likely to have important impact outside of gonadal sex determination. A key compartment whose activity can be actively modulated by sex‐dimorphic mechanisms throughout life is the immune system, whose function declines sharply with aging and may be actively modulated by sex. Indeed, aspects of the immune responses differ between sexes, with a more robust immune response in females and an increased susceptibility to infection in males. Thus, our main cell models of study are key components of the innate immune system and the inflammatory response: macrophages, which accomplish key tasks such as phagocytosis, antigen presentation and cytokine production, and neutrophils, the most abundant leukocyte type serving as a “first line of defense” against infection. Excitingly, we and others have observed strong sex‐related differences in the transcriptional and functional phenotypes of these cells and have observed sex‐dimorphic “omic” trajectories for these cells with aging. Based on our data and published literature, it is likely that mechanisms involving both gonadal hormones and sex chromosomes may fine‐tune different aspects of immunity and, thus, overall health and lifespan.

Androgens protect ILC2s from interferon-mediated functional suppression during influenza virus infection

Abstract Biological sex differences in morbidity upon influenza A virus (IAV) infection are linked to stronger interferon-centered immune responses in females, yet the regulatory role of sex hormone receptors in immune cell subsets is incompletely understood. Lung-resident group 2 innate lymphoid cells (ILC2s) express notably high levels of androgen receptors (AR). In IAV infection, ILC2s produce type 2 cytokines and facilitate tissue repair, but they also may be functionally suppressed by type 1 inflammation. Here we report sex differences in the magnitude of lung ILC2 functional suppression at the peak of sublethal IAV infection. Relative to males, ILC2s in female lungs showed attenuated proliferation, decreased propensity for IL-5 and amphiregulin production and reduced expression of GATA3 and IL-33R. Single cell RNA sequencing revealed sex-divergent transcriptomes, with female cells preferentially present in clusters of stressed, functionally suppressed ILC2s and male cells dominating in clusters of canonically activated ILC2s. Equivalent inflammatory cytokine levels and viral load suggested sex differences in ILC2-intrinsic factors. Indeed, naïve female ILC2s showed elevated IFNGR expression and higher phospho-STAT1 levels following IFNG stimulation, and lymphocyte-restricted STAT1 deficiency reversed IAV-induced suppression of female ILC2s. Lymphocyte-restricted AR deficiency or loss of androgens via orchiectomy led to increased IFNGR expression and suppression of male ILC2s. Collectively, these data show that ILC2-intrinsic AR activity regulates IFNGR-STAT1 signaling pathways to preserve canonical ILC2 function in males during IAV infection. Supported by grants from NIH (HL 119501) and the Presbyterian Health Foundation

High-fat Diet Alters Male Seminal Plasma Composition to Impair Female Immune Adaptation for Pregnancy in Mice.

Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high-fat diet (HFD) or control diet (CD) for 14 weeks. Although HFD consumption caused only minor changes to parameters of sperm quality, the volume of seminal vesicle fluid secretions was increased by 65%, and the concentrations and total content of immune-regulatory TGF-β isoforms were decreased by 75% to 80% and 43% to 55%, respectively. Mating with BALB/c females revealed differences in the strength and properties of the postmating immune response elicited. Transcriptional analysis showed >300 inflammatory genes were similarly regulated in the uterine endometrium by mating independently of paternal diet, and 13 were dysregulated by HFD-fed compared with CD-fed males. Seminal vesicle fluid factors reduced in HFD-fed males, including TGF-β1, IL-10, and TNF, were among the predicted upstream regulators of differentially regulated genes. Additionally, the T-cell response induced by mating with CD-fed males was blunted after mating with HFD-fed males, with 27% fewer CD4+ T cells, 26% fewer FOXP3+CD4+ regulatory T cells (Treg) cells, and 19% fewer CTLA4+ Treg cells, particularly within the NRP1+ thymic Treg cell population. These findings demonstrate that an obesogenic HFD alters the composition of seminal vesicle fluid and impairs seminal plasma capacity to elicit a favorable pro-tolerogenic immune response in females at conception.

Gender Differences in COVID-19; A Narrative Review

As the COVID-19 pandemic continues to affect millions of people worldwide, its predilection for the male gender has continued to baffle scientists and there is a need for understanding factors which underlie this association. An overwhelming body of evidence from both developed and developing countries has shown that not only is there male preponderance for infection with SARS-Cov-2 but there is a greater severity of illness as well as mortality difference between sexes. These differences could be attributed to enhanced T-cell mediated immune responses in females and low androgen levels; the evidence for which has been extrapolated by studies evaluating differential responses to viral infections between sexes. There is also an increased risk of thromboembolic complications of COVID-19 infection in males which is a major cause of morbidity and mortality. Moreover behavioural differences between genders has also been postulated to play a role in acquisition and predisposition to SARS-Cov-2 infection.

Sex-dependent association between inflammation, neural stress responses, and impaired myocardial function.

Evidence to date has failed to reveal unique female determinants of cardiovascular disease. However, a strong association was recently observed between increased metabolic activity in the amygdala, a neural centre involved in the processing of emotions, and impaired myocardial function in women, but not in men. Given the stronger immune responses in females, we sought to retrospectively investigate the interaction between inflammation, perceived stress, and myocardial injury. Overall, 294 patients (mean age 66.9 ± 10.0years, 28.6% women) underwent both, 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography for the assessment of cardiac function, bone marrow metabolism (surrogate marker of inflammation), and resting amygdalar activity. A positive association was found between amygdalar metabolism and 18F-FDG bone marrow uptake in women (r = 0.238, p = 0.029), but not in men (r = 0.060, p = 0.385). Linear regression models selected both, abnormal left ventricular ejection fraction (LVEF) and abnormal myocardial perfusion, as significant indicators of an increased amygdalar activity in women (B-coefficient LVEF, - 0.096; p = 0.021; abnormal myocardial perfusion, 3.227; p = 0.043), but not in men (bone marrow p = 0.076; abnormal myocardial perfusion p = 0.420). Accordingly, an interaction term consisting of sex and LVEF/abnormal myocardial perfusion was significant (p = 0.043 and p = 0.015, respectively). Upregulated amygdalar metabolism is associated with an enhanced inflammatory state in female patients with impaired cardiac function. Given that enhanced activity of the limbic system is associated with worse cardiovascular outcomes, our study suggests that a focus on inflammatory markers and indicators of distress might help to tailor cardiovascular risk assessment and therapy towards the female cardiovascular phenotype.

Alterations in Blood Monocyte Functions in Parkinson's Disease.

PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied. The purpose of this study was to investigate the PD-related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression. Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α-synuclein by measuring the expression of CD14, CD163, and HLA-DR and by analysis of soluble immune-related molecules in the supernatant. Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients' cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti-inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males. Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society.

The Pathogenesis and Immune-Response in Dengue Haemorrhagic Fever

Introduction: Dengue fever has spread to be endemic in addition of 100 countries to a total estimate incidence of 50 – 100 million cases annually globally. About 0.7% of these cases become the complication that is dengue hemorrhagic fever which is severe and leads to about 22,000 deaths annually.
 The pathogenesis of benign dengue fever becoming dengue hemorrhagic fever, and aspects of the immune-response behind it, have remained relatively unknown.
 Methods: Existing literature on the Topic was retrieved through Google Scholar and PubMed searches, and the literature reviewed.
 Results: Dengue hemorrhagic fever appears commoner in females and those with co-morbids such as diabetes-mellitus and obesity. Also, the case-fatality rate in severe dengue appears much bigger in females. The reasons for this are largely unknown but the additionally robust immune response in females, resulting in females to be additionally prone to develop bigger inflammatory response or enhanced susceptibility to capillary permeability could be the reason.
 It has been shown that viremic-load, including the initial viremic-load at the bite of the Aedes-mosquito may be a factor leading to dengue hemorrhagic fever.
 Yet different factors felt to be causative in the pathogenesis of dengue hemorrhagic fever include the role of the viral-protein, and then that which is termed the original antigenic-sin, the antibody-directed enhancement, autoimmunity, inhibition of interferon-alpha and cytokine-storm within the memory-cells.
 Regionally, certain different strains of the DENV also seem to be associated with dengue hemorrhagic fever.
 Newer-vaccines, based on the immunology of the disease, offer much hope in the near future.
 Conclusion: Much knowledge has been forthcoming in realizing the pathogenesis of dengue hemorrhagic fever. But, additional studies need to be done.

Toll-like receptor 3 dynamics in female C57BL/6J mice: Regulation of alcohol intake

Although there are sex differences in the effects of alcohol on immune responses, it is unclear if sex differences in immune response can influence drinking behavior. Activation of toll-like receptor 3 (TLR3) by polyinosinic:polycytidylic acid (poly(I:C)) produced a rapid proinflammatory response in males that increased alcohol intake over time (Warden et al., 2019). Poly(I:C) produced a delayed and prolonged innate immune response in females. We hypothesized that the timecourse of innate immune activation could regulate drinking behavior in females. Therefore, we chose to test the effect of two time points in the innate immune activation timecourse on every-other-day two-bottle-choice drinking: (1) peak activation; (2) descending limb of activation. Poly(I:C) reduced ethanol consumption when alcohol access occurred during peak activation. Poly(I:C) did not change ethanol consumption when alcohol access occurred on the descending limb of activation. Decreased levels of MyD88-dependent pathway correlated with decreased alcohol intake and increased levels of TRIF-dependent pathway correlated with increased alcohol intake in females. To validate the effects of poly(I:C) were mediated through MyD88, we tested female mice lacking Myd88. Poly(I:C) did not change alcohol intake in Myd88 knockouts, indicating that poly(I:C)-induced changes in alcohol intake are dependent on MyD88 in females. We next determined if the innate immune timecourse also regulated drinking behavior in males. Poly(I:C) reduced ethanol consumption in males when alcohol was presented at peak activation. Therefore, the timecourse of innate immune activation regulates drinking behavior and sex-specific dynamics of innate immune response must be considered when designing therapeutics to treat excessive drinking.

Sex differences in autoimmune disorders of the central nervous system.

Stronger adaptive immune responses in females can be observed in different mammals, resulting in better control of infections compared to males. However, this presumably evolutionary difference likely also drives higher incidence of autoimmune diseases observed in humans. Here, we summarize sex differences in the most common autoimmune diseases of the central nervous system (CNS) and discuss recent advances in the understanding of possible underlying immunological and CNS intrinsic mechanisms. In multiple sclerosis (MS), the most common inflammatory disease of the CNS, but also in rarer conditions, such as neuromyelitis optica spectrum disorders (NMOSD) or neuronal autoantibody-mediated autoimmune encephalitis (AE), sex is one of the top risk factors, with women being more often affected than men. Immunological mechanisms driving the sex bias in autoimmune CNS diseases are complex and include hormonal as well as genetic and epigenetic effects, which could also be exerted indirectly via modulation of the microbiome. Furthermore, CNS intrinsic differences could underlie the sex bias in autoimmunity by differential responses to injury. The strong effects of sex on incidence and possibly also activity and progression of autoimmune CNS disorders suggest that treatments need to be tailored to each sex to optimize efficacy. To date, however, due to a lack of systematic studies on treatment responses in males versus females, evidence in this area is still sparse. We argue that studies taking sex differences into account could pave the way for sex-specific and therefore personalized treatment.

Male Syrian hamsters are more susceptible to intravenous infection with species C human adenoviruses than are females

Recently, increasing attention has been focused on the influence of sex on the course of infectious diseases. Thus far, the best-documented examples point toward an immune-mediated mechanism: the generally stronger immune response in females can result in a faster clearance of the pathogen or, conversely, a more severe immune-mediated pathology. Here, we report that human species C adenoviruses replicate more and cause more pathology in male Syrian hamsters than in females. We also show that this sex disparity is not caused by a stronger immune response to the infection by the female hamsters. Rather, the liver of male hamsters is more susceptible to adenovirus infection: after intravenous injection, more hepatocytes become infected in male animals than in females. We hypothesize that Kupffer cells (hepatic tissue macrophages) of female animals are more active in sequestering circulating virions, and thus protect hepatocytes more efficiently than those of males.