Sex Drives Dimorphic Immune Responses to Viral Infections

Ghosh, Soumitra; Klein, Robyn S.

doi:10.4049/jimmunol.1601166

Cited by 197 publications

(173 citation statements)

References 158 publications

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“…Given the greater vulnerability of women to memory disorders such as Alzheimer's disease (Snyder et al, 2016), we are particularly interested in the differential impact of subchronic immune challenge on males and females. Sex differences in peripheral responses are well described (Ghosh & Klein, 2017;Scotland, Stables, Madalli, Watson, & Gilroy, 2011) and there is growing evidence for sex differences in neuroimmune responses and function (Estefanía Acaz-Fonseca, Avila-Rodriguez, Garcia-Segura, & Barreto, 2016;Engler et al, 2016;Sorge et al, 2016;Speirs & Tronson, 2018). It is likely, therefore, that males and females are differentially susceptible to memory decline after subchronic immune challenge.…”

Section: Introductionmentioning

confidence: 99%

Memory deficits in males and females long after subchronic immune challenge

Tchessalova

Tronson

2018

Preprint

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Memory impairments and cognitive decline persist long after recovery from major illness or injury, and correlate with increased risk of later dementia. Here we developed a subchronic peripheral immune challenge model to examine delayed and persistent memory impairments in females and in males. We show that intermittent injections of either lipopolysaccharide or Poly I:C cause memory decline in both sexes that are evident eight weeks after the immune challenge. Importantly, we observed sex-specific patterns of deficits.Females showed impairments in object recognition one week after challenge that persisted for at least eight weeks. In contrast, males had intact memory one week after the immune challenge but exhibited broad impairments in memory tasks including object recognition, and both context and tone fear conditioning several months later. The differential patterns of memory deficits in males and in females were observed without sustained microglial activation or changes in blood-brain barrier permeability. Together, these data suggest that transient neuroimmune activity results in differential vulnerabilities of females and males to memory decline after immune challenge. This model will be an important tool for determining the mechanisms in both sexes that contribute to memory impairments that develop over the weeks and months after recovery from illness. Future studies using this model will provide new insights into the role of chronic inflammation in the pathogenesis of long-lasting memory decline and dementias.

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Section: Introductionmentioning

confidence: 99%

Memory deficits in males and females long after subchronic immune challenge

Tchessalova

Tronson

2018

Preprint

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“…Males and females display differential immunological responses to foreign-and self-antigens (7,12,60). Antibody responses to infections as well as bacterial and viral vaccines, such as influenza, hepatitis A, hepatitis B, rubella, measles, diphtheria, tetanus, Brucella, and rabies vaccines, are generally more vigorous in females than males (5,(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

Casali

Shen

et al. 2020

Front. Immunol.

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Estrogen contributes to females' strong antibody response to microbial vaccines and proneness to autoimmunity, particularly antibody-mediated systemic autoimmunity, in females. We have hypothesized that this is due to estrogen-mediated potentiation of class switch DNA recombination (CSR) and somatic hypermutation (SHM). As we have shown, estrogen boosts AID expression, which is critical for both CSR and SHM, through upregulation of HoxC4, which together with NF-κB critically mediates Aicda (AID gene) promoter activation. We contend here that additional regulation of Aicda expression by estrogen occurs through epigenetic mechanisms. As we have shown, histone deacetylase inhibitors (HDIs) short-chain fatty acid (SCFA) butyrate and propionate as well as the pharmacologic HDI valproic acid upregulate miRNAs that silence AID expression, thereby modulating specific antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone MRL/Fas lpr/lpr mice. Here, using constitutive knockout Esr1 −/− mice and B cells as well as conditional knockout Aicda cre/cre Esr1 flox/flox mice and B cells, we showed that the HDI-mediated downregulation of Aicda expression as well as the maturation of antibody and autoantibody responses is reversed by estrogen and enhanced by deletion of ERα or E2 inhibition. Estrogen's reversion of HDI-mediated inhibition of Aicda and CSR in antibody and autoantibody responses occurred through downregulation of B cell miR-26a, which, as we showed, targets Aicda mRNA 3 ′ UTR. miR-26a was significantly upregulated by HDIs. Accordingly, enforced expression of miR-26a reduced Aicda expression and CSR, while miR-26a-sponges (competitive inhibitors of miR-26a) increased Aicda expression and CSR. Thus, our findings show that estrogen reverses the HDI-mediated downregulation of AID expression and CSR through selective modulation of miR-26a. They also provide mechanistic insights into the immunomodulatory activity of this hormone and a proof-of-principle for using combined ER inhibitor-HDI as a potential therapeutic approach.

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“…Furthermore, these effects were reversible and are almost completely abrogated with the antioxidant glutathione 32 . The sexual dimorphism in immune response to viruses is well described (reviewed in 34,35 ). The reasons underlying this sexually dimorphic response is attributed to sex hormones, sex chromosomes linked genes involved in viral response or genes on autosomes that seem to be regulated by sex chromosome linked genes 34 .…”

Section: Discussionmentioning

confidence: 99%

“…The sexual dimorphism in immune response to viruses is well described (reviewed in 34,35 ). The reasons underlying this sexually dimorphic response is attributed to sex hormones, sex chromosomes linked genes involved in viral response or genes on autosomes that seem to be regulated by sex chromosome linked genes 34 . Certain sexually dimorphic immune responses are however present throughout life, and not necessarily between the years of puberty and reproductive senescence, suggesting that both genes and hormones are involved 36 .…”

Section: Discussionmentioning

confidence: 99%

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Yang

Shi

Ding

et al. 2019

Preprint

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Epidemiological studies have shown that female smokers are at higher risk of chronic obstructive pulmonary disease (COPD). Female patients have worse symptoms and health status and increased risk of exacerbations. We determined the differences in the transcriptome of the airway epithelium between males and females at baseline and in response to smoking. We processed public gene expression data of human airway epithelium into a discovery cohort of 211 subjects (never smokers n=68; current smokers n=143) and two replication cohorts of 104 subjects (21 never, 52 current, and 31 former smokers) and 238 subjects (99 current and 139 former smokers.We analyzed gene differential expression with smoking status, sex, and smoking-by-sex interaction and used network approaches for modules' level analyses. We identified and replicated two differentially expressed modules between the sexes in response to smoking with genes located throughout the autosomes and not restricted to sex chromosomes. The two modules were enriched in autophagy (up-regulated in female smokers) and response to virus and type 1 interferon signaling pathways which were down-regulated in female smokers compared to males. The results offer insights into the molecular mechanisms of the sexually dimorphic COPD risk and presentation potentially enabling a precision medicine approach to COPD.

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Sex Drives Dimorphic Immune Responses to Viral Infections

Cited by 197 publications

References 158 publications

Memory deficits in males and females long after subchronic immune challenge

Memory deficits in males and females long after subchronic immune challenge

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

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