Trends in Immunology
Volume 35, Issue 3, March 2014, Pages 97-104
Journal home page for Trends in Immunology

Review
SeXX matters in immunity

https://doi.org/10.1016/j.it.2013.10.006Get rights and content

Highlights

  • Sex-dependent factors affect susceptibility to and severity of infection and autoimmunity.

  • Sex-specific factors influence the transcriptome, the microbiome, and immunophenotype.

  • Sex hormones influence the effector functions of different immune cell populations.

  • The critical role of sex in shaping an immune response cannot be ignored.

The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed.

Section snippets

Sex: a major determinant of an immune response

Accumulating evidence supports a role for sex-based differences in susceptibility to and severity of infectious diseases, in response to vaccination and medications, and in both the incidence and pathogenesis of autoimmune diseases 1, 2. Sex bias in the immune response could result from direct effects of an individual's sex chromosome complement, for example, X- or Y-linked genes, from indirect effects of the sex chromosomes, for example, sex hormones, or from environmental risk factors that

Sex bias in infectious diseases

It has long been known that, in general, males are more susceptible to infectious diseases than females. Multiple studies have documented this sex bias in susceptibility to certain bacterial, parasitic, and viral infections (Box 1); both in humans and in a variety of other species (reviewed in [4]). Although epidemiological data on human sex bias in infectious diseases incite interesting questions, biological effects may be obscured by variables such as sex-specific behaviors that may modify

Mechanisms determining sex-specific immunity

Sex hormones exert potent effects on immune cell subsets. The global gene expression profile of peripheral blood mononuclear cells (PBMCs) from young and elderly men and women has revealed age- and sex-dependent alterations in immune cell transcriptomics [26]. The ways in which sex-dependent immune cell phenotypes are influenced by sex hormones is an emerging field, and accumulating data are providing new insights. Sex steroid hormones exert their functions by binding to nuclear receptors that

Environmental, epigenetic, and pregnancy-related modification of sex-specific immunity

There is emerging evidence that epigenetic and environmental (particularly, microbiome-related) factors influence the expression of sex-specific immune phenotypes. In addition, dramatic changes in sex hormone levels during pregnancy may simultaneously promote tolerance to the fetus, while creating vulnerability to pathogens. Some recent progress in these fields is discussed below.

Concluding remarks

Recent advances in our understanding of how sex influences the immune response include evidence that the microbiome and epigenetic phenomena, including expression levels of miRs, contribute significantly to defining an immune response. Moreover, recent data further specify the direct effects of sex hormones on individual immune cell subsets. Age-dependent changes in the transcriptome, hormone levels, and immune cell responsiveness, all contribute to the sex differential in susceptibility to and

Acknowledgments

ENF is a Tier 1 Canada Research Chair. JGM is supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research.

References (85)

  • P. Gourdy

    Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-gamma production by invariant natural killer T cells

    Blood

    (2005)
  • M. Kisiela

    Hydroxysteroid dehydrogenases (HSDs) in bacteria: a bioinformatic perspective

    J. Steroid Biochem. Mol. Biol.

    (2012)
  • L. Yurkovetskiy

    Gender bias in autoimmunity is influenced by microbiota

    Immunity

    (2013)
  • I. Bianchi

    The X chromosome and immune associated genes

    J. Autoimmun.

    (2012)
  • E.C. Baechler

    The emerging role of interferon in human systemic lupus erythematosus

    Curr. Opin. Immunol.

    (2004)
  • J. Banchereau

    Autoimmunity through cytokine-induced dendritic cell activation

    Immunity

    (2004)
  • A.H. Sawalha

    Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes

    J. Autoimmun.

    (2009)
  • M.N. Edelmann et al.

    Epigenetic impact of simulated maternal grooming on estrogen receptor alpha within the developing amygdala

    Brain Behav. Immun.

    (2011)
  • R. Dai et al.

    microRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases

    Transl. Res.

    (2011)
  • S.M. Blois

    Decidualization and angiogenesis in early pregnancy: unravelling the functions of DC and NK cells

    J. Reprod. Immunol.

    (2011)
  • J.H. Rowe

    Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens

    Cell Host Microbe

    (2011)
  • H. Farzadegan

    Sex differences in HIV-1 viral load and progression to AIDS

    Lancet

    (1998)
  • M. Roivainen

    Entry of coxsackievirus A9 into host cells: specific interactions with alpha v beta 3 integrin, the vitronectin receptor

    Virology

    (1994)
  • T.J. Wickham

    Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment

    Cell

    (1993)
  • C.C. Whitacre

    Sex differences in autoimmune disease

    Nat. Immunol.

    (2001)
  • E.N. Fish

    The X-files in immunity: sex-based differences predispose immune responses

    Nat. Rev. Immunol.

    (2008)
  • F. Guerra-Silveira et al.

    Sex bias in infectious disease epidemiology: patterns and processes

    PLoS ONE

    (2013)
  • R.J. Engler

    Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses

    Arch. Intern. Med.

    (2008)
  • C.C. Whitacre

    A gender gap in autoimmunity

    Science

    (1999)
  • D.J. McCarty

    Incidence of systemic lupus erythematosus. Race and gender differences

    Arthritis Rheum.

    (1995)
  • G.J. Rainey

    Receptor-specific requirements for anthrax toxin delivery into cells

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • M. Butterworth

    Influence of sex in immunoglobulin levels

    Nature

    (1967)
  • M.F. Doran

    Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period

    Arthritis Rheum.

    (2002)
  • B.G. Weinshenker

    Natural history of multiple sclerosis

    Ann. Neurol.

    (1994)
  • S. Makino

    Effect of castration on the appearance of diabetes in NOD mouse. Jikken dobutsu

    Exp. Anim.

    (1981)
  • H.S. Fox

    Androgen treatment prevents diabetes in nonobese diabetic mice

    J. Exp. Med.

    (1992)
  • B.F. Bebo

    Gender differences in experimental autoimmune encephalomyelitis develop during the induction of the immune response to encephalitogenic peptides

    J. Neurosci. Res.

    (1998)
  • R.R. Voskuhl

    Gender differences in autoimmune demyelination in the mouse: implications for multiple sclerosis

    Ann. Neurol.

    (1996)
  • S.A. Ahmed et al.

    The influence of testosterone on the development of autoimmune thyroiditis in thymectomized and irradiated rats

    Clin. Exp. Immunol.

    (1982)
  • M.S. Harbuz

    A protective role for testosterone in adjuvant-induced arthritis

    Br. J. Rheumatol.

    (1995)
  • J.R. Roubinian

    Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice

    J. Exp. Med.

    (1978)
  • S. Marttila

    Transcriptional analysis reveals gender-specific changes in the aging of the human immune system

    PLoS ONE

    (2013)
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