A first update on mapping the human genetic architecture of COVID-19

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Estrogen receptor-dependent modulation of dendritic cell biology of mice and women

Autoimmune and infectious diseases differentially affect women from men. Women tend to develop stronger immune responses and thus in general men are more susceptible to infectious diseases whereas women are more likely to develop autoimmune diseases. These differences could be in part attributable to the pro-inflammatory role of the female sex hormone estrogen on immunity and particularly on dendritic cells (DCs), a key subset of innate immune cells. For several years now, we have undertaken studies to understand how estrogens influence the biology of murine and human DCs. We and others have demonstrated that estradiol (E2) was required for the optimal in vitro differentiation of murine DCs and acquisition of their effector functions. These effects on DC biology were dependent on the activation of the estrogen receptor a (ERa). More recently, we focused our interest on plasmacytoid dendritic cells (pDCs). Indeed, this subset that produces large amounts of IFN-a/b in response to viral or endogenous nucleic acids through activation of their TLR-7 and TLR-9 show gender differences with enhanced IFN-a production by pDCs from women, compared to men. We could establish, in Human and in mice, that in vivo treatment with E2 enhanced the TLR-dependent production of IFNa by pDCs. In mice, we demonstrated that the amplifying effect of endogenous and exogenous estrogens is dependent on the intrinsic activation of ERα by hormone in the pDCs. To further characterize the mechanisms underlying this sex-based difference in pDC innate functions, we investigated the respective contribution of X chromosome dosage versus sex hormones using a humanized mouse model in which male or female NOD-SCID-ß2m-/- mice were transplanted with human progenitor cells (HPCs) purified from either male (XY) or female (XX) donors. We could show that cell-intrinsic ER-signaling and X chromosome complement both independently contribute to the enhanced TLR-7-mediated response of pDCs in women, which may account for the sex-based differences in autoimmune and infectious diseases. Altogether, our work demonstrates that estrogen-mediated activation of ER signaling is a key regulator of DC biology both in Human and in mouse

Prédominance féminine des maladies auto-immunes : les lymphocytes ont-ils un sexe ?

International audienceWomen represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system involved in autoimmunity, recent data demonstrate that female sex hormones are not the only cause of the female predisposition. In addition to the action of sex steroid hormones, there is growing evidence for a role of genetic factors linked to the X chromosome. In female mammals, following the mechanisms of X chromosome inactivation (ICX), one of the two X chromosomes is randomly inactivated, resulting in a cellular mosaicism, where about one-half of the cells in a tissue express the maternal X chromosome and the other half the paternal one. However, 15–23% of inactive X (Xi) genes escape XCI, contributing to the emergence of a female specific heterogeneous population of cells expressing the same gene from both X chromosomes. Among these genes, some immune-related genes have recently been identified. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity remains to be fully established, the cellular mosaicism resulting from XCI and escape from XCI is likely to create a unique functional plasticity within female immune cells.Les femmes représentent 80 % des personnes affectées par les maladies auto-immunes. Le rôle des hormones sexuelles sur la réponse immune est bien documenté, résultant en particulier de la fixation des œstrogènes sur leurs récepteurs nucléaires exprimés par nombre de cellules immunitaires. En plus de l’action des hormones stéroïdes sexuelles, des preuves s’accumulent en faveur d’un rôle des facteurs génétiques liés au chromosome X. Chez la femme, suite aux mécanismes d’inactivation de l’X (ICX), un des deux chromosomes X est inactivé de manière aléatoire, générant ainsi une mosaïque de cellules exprimant des gènes de l’X hérités, soit de la mère, soit du père portés par l’X actif. Cependant, 15 à 23 % de gènes de l’X inactif (Xi) échappent à l’ICX, contribuant à l’émergence d’une autre population hétérogène de cellules exprimant le même gène à partir des deux chromosomes X. Parmi ces gènes, certains gènes de l’immunité ont été récemment identifiés. Si la contribution directe de ce mécanisme de dosage génétique dans la susceptibilité à l’auto-immunité reste encore à être explorée en profondeur, le mosaïsme cellulaire résultant de l’ICX et de l’échappement à l’ICX induit une plasticité fonctionnelle unique au sein des cellules immunitaires de femmes

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells

Biais de sexe dans l’asthme allergique

L’asthme allergique est une maladie inflammatoire chronique caractérisée par une hyperréactivité bronchique. Il touche plus de 10 % de la population et débute souvent dans l’enfance. Il existe des disparités sexuelles dans la prévalence et la sévérité de l’asthme. La maladie est en effet plus fréquente chez les jeunes garçons, mais cette tendance s’inverse à la puberté suggérant un rôle régulateur des hormones sexuelles. Dans cette synthèse, nous résumons les connaissances actuelles sur le rôle des hormones sexuelles dans l’inflammation allergique, en soulignant l’impact des androgènes sur le développement et la fonction des cellules lymphoïdes innées du groupe 2 (ILC2), acteurs critiques des réponses allergiques

Sex hormone regulation of innate lymphoid cells

International audienceInnate lymphoid cell (ILC) subsets at barrier surfaces contribute to maintain tissue homeostasis and appropriate responses to infection. ILCs respond to environmental factors produced by non-hematopoietic cells within tissues, but also circulating cytokines or dietary compounds which allow them to adapt to organ milieu. Among these extrinsic signals, evidence is emerging that sex steroid hormones may act in a cell-intrinsic manner to regulate the development, maintenance in tissues and effector functions of specific subsets of ILCs. Understanding the nature and molecular mechanisms of sex steroid hormone actions on ILCs is important to unravel the cause of sexual disparity in human diseases and could lead to new drug development for the treatment of chronic inflammatory diseases or cancers. This review discusses the recent development in our understanding of the cell-intrinsic actions of sex steroid hormones on ILCs and their consequences on tissue-specific immunity with a particular focus on group 2 innate lymphoid cells and NK cells

Biais de sexe dans l’asthme allergique

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Sex Differences in Asthma: A Key Role of Androgen-Signaling in Group 2 Innate Lymphoid Cells

Infectious diseases, autoimmune diseases, and also allergy differentially affect women and men. In general, women develop strongest immune responses and thus the proportion of infected individuals and the severity of many viral, bacterial, or parasitic infections are increased in men. However, heightened immunity in women makes them more susceptible than men to autoimmunity and allergy. While sex differences in immunity are well documented, little is known about the cellular and molecular mechanisms underlying these immunological differences, particularly in allergic asthma. Asthma is a chronic inflammation of the airways mediated by exacerbated type 2 immune responses. Sex differences have been reported in the incidence, prevalence, and severity of asthma. While during childhood, males are more susceptible to asthma than females, there is a switch at the onset of puberty as for many other allergic diseases. This decrease of asthma incidence around puberty in males suggests that hormonal mediators could play a protective role in the susceptibility to allergic responses in male. Group 2 innate lymphoid cells (ILC2s) have recently emerged as critical players in the initiation of allergic responses, but also in the resolution of parasitic infection, through their capacity to rapidly and potently produce type 2 cytokines. This review will cover the current understanding of the impact of sex-linked factors in allergic inflammation, with a particular focus on the role of sex hormones on the development and function of tissue-resident ILC2s