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The first study to document sex differences in TLR4 activation and disease outcome.
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The first documentation of sex differences in innate lymphoid cells, with direct implications for sex differential susceptibility to an autoimmune disease.
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This systems biology study identifies a testosterone- sensitive gene cluster involved in lipid biosynthesis that correlates with lower protective antibody responses to seasonal influenza vaccination in men.
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This paper reviews the major mechanisms responsible for higher immune activity in females as compared with men.
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A mouse study of two models of autoimmune disease providing the first evidence that the XX chromosome complement confers greater susceptibility to autoimmunity than the XY sex chromosome complement.
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One of the first papers to hypothesize that X-linked miRNAs play a major part in the sex differences in immunity between males and females.
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A rigorous evaluation of oestrogenic effects on DC differentiation and ER expression.
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An excellent review of oestrogenic effects on immune cells and immune-mediated diseases, with exceptional details about in vitro and in vivo studies, concentrations of oestrogen and identification of the biopotential effects of oestrogens on immune responses.
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An excellent example of the molecular mechanisms mediating how sex steroids, specifically oestrogens, regulate the functioning of immune cells in vivo.
Dai, R. et al. Suppression of LPS-induced Interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood 112, 4591–4597 (2008).
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One of the first papers describing direct effects of sex steroids, specifically oestrogens, affecting a specific T cell population.
Dinesh, R. K., Hahn, B. H. & Singh, R. P. Gender and sex hormones influence CD4 regulatory T cells and their expression of FoxP3 in healthy people and in SLE. Arthritis Rheum. Abstr. 62 (Suppl. 10), 1257 (2010).
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Mechanistic details about how progesterone signalling through progesterone receptors affects DC maturation and function.
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A detailed in vivo examination of the molecular mechanisms through which androgens affect T cell responses and the outcome of an autoimmune disease.
Khulan, B. et al. Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia. Hum. Mol. Genet. 21, 2086–2101 (2012).
A double-blind controlled trial of maternal micronutrient supplementation demonstrating that peri-conceptional nutrition has sex- differential epigenetic effects on genes involved in immunity.
Tobi, E. W. et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Mol. Genet. 18, 4046–4053 (2009).
Sinha, A., Madden, J., Ross-Degnan, D., Soumerai, S. & Platt, R. Reduced risk of neonatal respiratory infections among breastfed girls but not boys. Pediatrics 112, e303 (2003).
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Jensen, K. J. et al. The effects of vitamin A supplementation with measles vaccine on leucocyte counts and in vitro cytokine production. Br. J. Nutr. 115, 619–628 (2016).
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A mouse-based study demonstrating that the gut microbiota alters sex hormone levels, which in turn protect mice male from type 1 diabetes. Transfer of male microbiota to susceptible females provided robust protection against type 1 diabetes.
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Bolnick, D. I. et al. Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat. Commun. 5, 4500 (2014).
This paper demonstrates that diet affects the microbiota differently in males and females in humans and fish, suggesting that treatment of dysbiosis may need to be sex specific.
Bolnick, D. I. et al. Individuals' diet diversity influences gut microbial diversity in two freshwater fish (threespine stickleback and Eurasian perch). Ecol. Lett. 17, 979–987 (2014).
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Goldenberg, R. L. et al. The Alabama Preterm Birth Study: intrauterine infection and placental histologic findings in preterm births of males and females less than 32 weeks. Am. J. Obstet. Gynecol. 195, 1533–1537 (2006).
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Liu, C. A. et al. Prediction of elevated cord blood IgE levels by maternal IgE levels, and the neonate's gender and gestational age. Chang Gung Med. J. 26, 561–569 (2003).
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Leposavic, G., Perisic, M. & Pilipovic, I. Role of gonadal hormones in programming developmental changes in thymopoietic efficiency and sexual diergism in thymopoiesis. Immunol. Res. 52, 7–19 (2012).
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Yang, Y. & Kozloski, M. Sex differences in age trajectories of physiological dysregulation: inflammation, metabolic syndrome, and allostatic load. J. Gerontol. A Biol. Sci. Med. Sci. 66, 493–500 (2011).
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Giefing-Kroll, C., Berger, P., Lepperdinger, G. & Grubeck-Loebenstein, B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 14, 309–321 (2015).
This paper reviews the interplay between sex hormones and the aging immune system, suggesting that elderly women remain immune-privileged even in the face of declining sex hormone levels post menopause.
Castelo-Branco, C. & Soveral, I. The immune system and aging: a review. Gynecol. Endocrinol. 30, 16–22 (2014).
Hirokawa, K. et al. Slower immune system aging in women versus men in the Japanese population. Immun. Ageing 10, 19 (2013).
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Voskuhl, R. Sex differences in autoimmune diseases. Biol. Sex Differ. 2, 1 (2011).
Voskuhl, R. R. et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 35–46 (2016).
A clinical trial using oestrogen (specifically the placental oestrogen, oestriol) to mitigate the debilitating effects of severe multiple sclerosis, showing that oestrogens can be used therapeutically to treat immune-mediated diseases.
Gold, S. M., Chalifoux, S., Giesser, B. S. & Voskuhl, R. R. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J. Neuroinflammation 5, 32 (2008).
Cook, M. B. et al. Sex disparities in cancer incidence by period and age. Cancer Epidemiol. Biomarkers Prev. 18, 1174–1182 (2009).
Cook, M. B., McGlynn, K. A., Devesa, S. S., Freedman, N. D. & Anderson, W. F. Sex disparities in cancer mortality and survival. Cancer Epidemiol. Biomarkers Prev. 20, 1629–1637 (2011).
Lista, P., Straface, E., Brunelleschi, S., Franconi, F. & Malorni, W. On the role of autophagy in human diseases: a gender perspective. J. Cell. Mol. Med. 15, 1443–1457 (2011).
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Vom Steeg, L. G. & Klein, S. L. SeXX Matters in infectious disease pathogenesis. PLoS Pathog. 12, e1005374 (2016).
A current review of sex differences in infectious diseases, with a detailed analysis of the mechanistic causes of sex differences in the outcome of infectious diseases in humans.
Fischer, J., Jung, N., Robinson, N. & Lehmann, C. Sex differences in immune responses to infectious diseases. Infection 43, 399–403 (2015).
Sawyer, C. C. Child mortality estimation: estimating sex differences in childhood mortality since the 1970s. PLoS Med. 9, e1001287 (2012).
This study used data from multiple sources to estimate sex ratios of mortality among children worldwide, demonstrating key differences in different regions of the world.
Flanagan, K. L. & Jensen, K. J. in Sex and Gender Differences in Infection and Treatments for Infectious Diseases (eds Klein, S. L. & Roberts, C. W.) 273–312 (Springer, 2015).
This book chapter provides a comprehensive review of sex-based differences in immunity to vaccines and infections in under-5-year-old children.
Griesbeck, M. & Altfeld, M. in Sex and Gender Differences in Infection and Treatments for Infectious Diseases (eds Klein, S. L. & Roberts, C. W.) 103–181 (Springer, 2015).
Cook, I. F. Sexual dimorphism of humoral immunity with human vaccines. Vaccine 26, 3551–3555 (2008).
A comprehensive review of studies demonstrating sex-based differences in antibody responses to vaccines. Multiple vaccines were implicated, highlighting the need to consider sex as a variable in vaccine immunogenicity studies.
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