Sexual dimorphisms account for differences in clinical manifestations or incidence of infectious or autoimmune diseases and malignancy between females and males. Females develop enhanced innate and adaptive immune responses than males and are less susceptible to many infections of bacterial, viral, parasitic, and fungal origin and malignancies but in contrast, they are more prone to develop autoimmune diseases. The higher susceptibility to infections in males is observed from birth to adulthood, suggesting that sex chromosomes and not sex hormones have a major role in sexual dimorphism in innate immunity. Sex-based regulation of immune responses ultimately contributes to age-related disease development and life expectancy. Differences between males and females have been described in the expression of pattern recognition receptors of the innate immune response and in the functional responses of phagocytes and antigen presenting cells. Different factors have been shown to account for the sex-based disparity in immune responses, including genetic factors and hormonal mediators, which contribute independently to dimorphism in the innate immune response. For instance, several genes encoding for innate immune molecules are located on the X chromosome. In addition, estrogen and/or testosterone have been reported to modulate the differentiation, maturation, lifespan, and effector functions of innate immune cells, including neutrophils, macrophages, natural killer cells, and dendritic cells. In this review, we will focus on differences between males and females in innate immunity, which represents the first line of defense against pathogens and plays a fundamental role in the activation, regulation, and orientation of the adaptive immune response.
Innate immunity Sexual dimorphisms Sex hormones X-linked immunodeficiency
This is a preview of subscription content, log in to check access.
The contribution of Ministero della Salute (RF-2013-02355470), Ministry of Education, University and Research (PRIN 2015YYKPNN), and the Associazione Italiana Ricerca sul Cancro (MFAG 2016 ID 18475) is gratefully acknowledged.
Compliance with Ethical Standards
Conflicts of Interest
The authors declare that they have no conflict of interest.
Ethical Approval and Informed Consent
This article does not contain any studies with human participants or animals performed by any of the authors.
Asai K, Hiki N, Mimura Y, Ogawa T, Unou K et al (2001) Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. Shock 16(5):340–343PubMedCrossRefGoogle Scholar
Berghofer B, Frommer T, Haley G, Fink L, Bein G et al (2006) TLR7 ligands induce higher IFN-alpha production in females. J Immunol 177(4):2088–2096PubMedCrossRefGoogle Scholar
Seillet C, Rouquie N, Foulon E, Douin-Echinard V, Krust A et al (2013) Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha. J Immunol 190(11):5459–5470. https://doi.org/10.4049/jimmunol.1203312PubMedCrossRefGoogle Scholar
McGowan JE Jr, Barnes MW, Finland M (1975) Bacteremia at Boston City Hospital: occurrence and mortality during 12 selected years (1935-1972), with special reference to hospital-acquired cases. J Infect Dis 132(3):316–335PubMedCrossRefGoogle Scholar
Bone RC (1992) Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 268(24):3452–3455PubMedCrossRefGoogle Scholar
Fourrier F, Jallot A, Leclerc L, Jourdain M, Racadot A et al (1994) Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock. Circ Shock 43(4):171–178PubMedGoogle Scholar
Barrow RE, Herndon DN (1990) Incidence of mortality in boys and girls after severe thermal burns. Surg Gynecol Obstet 170(4):295–298PubMedGoogle Scholar
Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F (1998) Gender differences in human sepsis. Arch Surg 133(11):1200–1205PubMedCrossRefGoogle Scholar
Christeff N, Benassayag C, Carli-Vielle C, Carli A, Nunez EA (1988) Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem 29(4):435–440PubMedCrossRefGoogle Scholar
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C et al (2006) Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12(9):1065–1074PubMedCrossRefGoogle Scholar
Carlino C, Stabile H, Morrone S, Bulla R, Soriani A et al (2008) Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 111(6):3108–3115PubMedCrossRefGoogle Scholar
Ray A, Prefontaine KE, Ray P (1994) Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem 269(17):12940–12946PubMedGoogle Scholar
Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH (1996) Mechanism of immunosuppression in males following trauma-hemorrhage. Critical role of testosterone. Arch Surg 131(11):1186–1191 discussion 1191-1182PubMedCrossRefGoogle Scholar
Hughes GC, Thomas S, Li C, Kaja MK, Clark EA (2008) Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol 180(4):2029–2033PubMedCrossRefGoogle Scholar
Tora L, White J, Brou C, Tasset D, Webster N et al (1989) The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 59(3):477–487PubMedCrossRefGoogle Scholar
Lanzavecchia A, Sallusto F (2001) The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 13(3):291–298PubMedCrossRefGoogle Scholar
Paharkova-Vatchkova V, Maldonado R, Kovats S (2004) Estrogen preferentially promotes the differentiation of CD11c+ CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol 172(3):1426–1436PubMedCrossRefGoogle Scholar
Siracusa MC, Overstreet MG, Housseau F, Scott AL, Klein SL (2008) 17beta-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. J Immunol 180(3):1423–1431PubMedCrossRefGoogle Scholar
Salamonsen LA, Dimitriadis E, Jones RL, Nie G (2003) Complex regulation of decidualization: a role for cytokines and proteases—a review. Placenta 24(Suppl A):S76–S85PubMedCrossRefGoogle Scholar
Garlanda C, Maina V, Martinez de la Torre Y, Nebuloni M, Locati M (2008) Inflammatory reaction and implantation: the new entries PTX3 and D6. Placenta 29(Suppl B):129–134PubMedCrossRefGoogle Scholar
Leonard S, Murrant C, Tayade C, van den Heuvel M, Watering R et al (2006) Mechanisms regulating immune cell contributions to spiral artery modification—facts and hypotheses—a review. Placenta 27(Suppl A):S40–S46PubMedCrossRefGoogle Scholar
Salamonsen LA, Zhang J, Brasted M (2002) Leukocyte networks and human endometrial remodelling. J Reprod Immunol 57(1–2):95–108PubMedCrossRefGoogle Scholar
Martinez de la Torre Y, Buracchi C, Borroni EM, Dupor J, Bonecchi R et al (2007) Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc Natl Acad Sci U S A 104(7):2319–2324PubMedPubMedCentralCrossRefGoogle Scholar
Salustri A, Garlanda C, Hirsch E, De Acetis M, Maccagno A et al (2004) PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization. Development 131(7):1577–1586PubMedCrossRefGoogle Scholar
Cetin I, Cozzi V, Pasqualini F, Nebuloni M, Garlanda C et al (2006) Elevated maternal levels of the long pentraxin 3 (PTX3) in preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol 194(5):1347–1353PubMedCrossRefGoogle Scholar
Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD et al (2002) Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 62(7):2141–2150PubMedGoogle Scholar