Sex Hormones Determine Immune Response

Taneja, Veena

doi:10.3389/fimmu.2018.01931

Cited by 446 publications

(403 citation statements)

References 60 publications

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“…As ACE2 is located on the X chromosome, there may be alleles that confer resistance to COVID-19, explaining the lower fatality rate in females. Alternatively, the oestrogen and testosterone sex hormones have different immunoregulatory functions, which could influence immune protection or disease severity 34 .…”

Section: Host Cell Infection and Its Preventionmentioning

confidence: 99%

The trinity of COVID-19: immunity, inflammation and intervention

et al. 2020

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| Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract -severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally , we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

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Section: Host Cell Infection and Its Preventionmentioning

confidence: 99%

The trinity of COVID-19: immunity, inflammation and intervention

et al. 2020

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“…Due to the strong sex bias of males-to-females with a ratio of 3.5:1 in this study, we measured sex hormones known to play a key role not only in fertility but also in key innate and adaptive immune pathways 9,10 . Importantly, sex hormones were measured on the day of patient admission to exclude potential unspecific effects due to invasive procedures at the ICU.…”

Section: Low Testosterone Levels In the Majority Of Male Covid-19 Patmentioning

confidence: 99%

Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

Schroeder

Schaumburg

Mueller

et al. 2020

Preprint

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Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide and pose a major public health burden. There is increasing evidence that men are more likely to die from SARS-CoV-2 infection than women. However, underlying factors that mediate the observed sex bias in coronavirus disease 2019 (COVID-19) remain unknown. Methods. In this retrospective cohort, we included COVID-19 patients who were admitted to an Intensive Care Unit at the University Hospital Hamburg-Eppendorf, Germany. We obtained demographic data of all patients who were discharged or had died by 29th April 2020. We systematically analyzed sex hormones as well as cytokine and chemokine responses in male and female patients with laboratory-confirmed SARS-CoV-2 infections upon hospital admission. We used uni- and multivariable linear regression methods to identify potential risk factors for disease severity in males and females. Findings. All enrolled patients (n=45; n=35 males and n=10 females) presented comorbidities with hypertension being the most common (45.7% in males; 40% in females), followed by cancer (35% in males; 40% in females), obesity (34.3% in males and 30% in females), type II diabetes (25.7% in males and 20% in females) and chronic heart diseases (8.6% in males and 0% in females). We detected that the vast majority of male COVID-19 patients present low testosterone (68.6%) and low dihydrotestosterone (48.6%) levels. In contrast, most female COVID-19 patients have elevated testosterone levels (60%) without alterations in dihydrotestosterone levels. Both, female and male COVID-19 patients may present elevated estradiol levels (45.7% in males and 40% in females). Disease severity defined by SOFA score correlates with elevated cytokine responses (e.g. IL-6) in males and IL-2 in females. In male COVID-19 patients, testosterone levels negatively correlate with inflammatory IL-2 and IFN-γ, whereas estradiol levels positively correlate with the inflammatory cytokine IL-6. Vice versa, in female COVID-19 patients, testosterone levels positively correlate with inflammatory cytokines (e.g. IL-6). Interpretation. We here show that critically ill male COVID-19 patients suffer from severe testosterone and dihydrotestosterone deficiencies. Both androgens are required to mount antiviral immune responses to combat infection in males.

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“…Estrogen plays an important role in boosting the production of mature antibodies and autoantibodies (1,2). This provides an explanation for the greater antibody response to microbial vaccines and infections as well as the greater incidence of antibody-mediated autoimmunity, such as systemic lupus erythematosus, in females (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Like protective antibodies against pathogenic microorganisms, pathogenic autoantibodies in humans and mice with systemic autoimmunity are generally class-switched and hypermutated, strongly suggest a role for estrogen in modulation of immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM).…”

Section: Introductionmentioning

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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Sex Hormones Determine Immune Response

Cited by 446 publications

References 60 publications

The trinity of COVID-19: immunity, inflammation and intervention

The trinity of COVID-19: immunity, inflammation and intervention

Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

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

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