Sex Hormones and Gender Differences in Immune Responses

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Background

Women mount stronger humoral and cellular immune responses than men. While this may favor pathogen clearance, stronger responses can contribute to immune-mediated pathologies such as autoimmune and inflammatory diseases. The major differences between female and male immune systems are sex hormones, the presence of two X chromosomes in females versus one X and one Y chromosome in males, and different responses to environmental factors, such as microbial exposure and diet. Sex hormones, such as estrogens, progesterone, androgens and prolactin, can influence different aspects of immune system functions and potentially contribute to the risk, activity and progression of autoimmune diseases. Generally, estrogens, in particular 17-β estradiol (E2) and prolactin, act as enhancers, at least of humoral immunity, and testosterone and progesterone as natural immunosuppressants.

The effects of sex hormones depend on their serum levels but also on the type of target cell and the receptor subtype expressed on a given cell type. Notably, E2 has opposite effects depending on its concentration. In fact, at periovulatory to pregnancy levels, it mainly has an anti-inflammatory effect inhibiting production and signaling of pro-inflammatory cytokines, inducing expression of anti-inflammatory cytokines, favoring a T helper 2 (Th2) phenotype, and inducing regulatory T cells (Treg). At lower concentrations, E2 stimulates a Th1 pro-inflammatory phenotype and NK cell activity, while it enhances antibody production by B cells both at high and low concentrations. Prolactin increases (i) antibody production, (ii) regulates the development of CD4+ T cells and (iii) triggers pro-inflammatory cytokine production. Progesterone stimulates a switch from a predominantly pro-inflammatory to an anti-inflammatory immune response, favors Treg differentiation, and exerts an inhibitory effect on NK cells. Several studies indicate that testosterone has suppressive effects on the immune system by inhibiting (i) pro-inflammatory cytokine production, (ii) Th1 differentiation, (iii) immunoglobulin production and (iv) NK cell cytotoxic activity, and by potentiating the expression of anti-inflammatory cytokines. A clear understanding of the mechanisms of action of sex hormones in the modulation of immune responses can be useful for the discovery of new biomarkers and targets for sex-specific therapeutic intervention and/or prevention of immune-mediated diseases.

A clear understanding of the mechanisms of action of sex hormones in the modulation of immune responses can be useful for the discovery of new biomarkers and targets for sex-specific therapeutic intervention and/or prevention of immune-mediated diseases. This Research Topic will give a comprehensive overview of current issues on sex differences in immunity and autoimmunity with a particular emphasis on the role played by sex hormones. The effects of estrogen, progesterone, prolactin and androgens on innate immune cells, such as monocytes/macrophages, NK cells and dendritic cells, and on adaptive immune cells i.e., T and B lymphocytes, will be discussed. We also aim to discuss the role of sex differences and sex hormones in autoimmune diseases including Systemic Lupus Erythematosus, Sjogren’s Syndrome, Rheumatoid Arthritis, Multiple Sclerosis and autoimmune mediated neuroinflammation/disease. We seek Original Research, Review, Mini-Review, Methods, Protocols, Perspective and Hypothesis and Theory articles that cover, but are not limited to, the following topics:

1. The modulation of innate immunity by sex hormones.
2. The effects of sex hormones in acquired immunity, i.e. T cells and B cells.
3. Pregnancy-mediated effects of hormones on innate and adapative immune responses.
4. Role and expression of estrogen receptor on different immune cell types.
5. Influence of sex hormones on the expansion of selected microbial lineages in the gut and how hormonal influence of microbiota could contribute to the sexual dimorphism of autoimmune diseases.
6. Autoimmune / inflammatory diseases and sex hormones, including but not limited to: Systemic Lupus Erythematosus, Sjogren’s Syndrome, Rheumatoid Arthritis, Multiple Sclerosis, and autoimmune-mediated neuroinflammation / disease.

Keywords: Sex hormones, Estrogen, Progesterone, Testosterone, Prolactin, Immunity

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