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Sex differences in immune responses to infectious diseases

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Abstract

Purpose

The influence of sex hormones is recognized to account for the susceptibility and distinct outcomes of diverse infectious diseases.

Methods

This review discusses several variables including differences in behavior and exposure to pathogens, genetic, and immunological factors.

Conclusion

Understanding sex-based differences in immunity during different infectious diseases is crucial in order to provide optimal disease management for both sexes.

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References

  1. Garenne M. Demographic evidence of sex differences in vulnerability to infectious diseases. J Infect Dis. 2015;211:331–2.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Klein SL. Sex differences in prophylaxis and therapeutic treatments for viral diseases. Handb Exp Pharmacol. 2012;214:499–522.

    Article  CAS  PubMed  Google Scholar 

  3. Markle JG, Fish EN. SeXX matters in immunity. Trends Immunol. 2014;35:97–104.

    Article  CAS  PubMed  Google Scholar 

  4. Amur S, Parekh A, Mummaneni P. Sex differences and genomics in autoimmune diseases. J Autoimmun. 2012;38:J254–65.

    Article  CAS  PubMed  Google Scholar 

  5. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010;10:594–604.

    Article  CAS  PubMed  Google Scholar 

  6. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8:737–44.

    Article  CAS  PubMed  Google Scholar 

  7. Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays. 2011;33:791–802.

    Article  CAS  PubMed  Google Scholar 

  8. Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune WJ, Somers E, et al. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41:60–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Brooks EG, Schmalstieg FC, Wirt DP, Rosenblatt HM, Adkins LT, Lookingbill DP, et al. A novel X-linked combined immunodeficiency disease. J Clin Invest. 1990;86:1623–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Schmalstieg FC, Goldman AS. Immune consequences of mutations in the human common gamma-chain gene. Mol Genet Metab. 2002;76:163–71.

    Article  CAS  PubMed  Google Scholar 

  11. van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007;2007:89017.

    PubMed Central  PubMed  Google Scholar 

  12. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–31.

    Article  CAS  PubMed  Google Scholar 

  13. Castles CG, Oesterreich S, Hansen R, Fuqua SA. Auto-regulation of the estrogen receptor promoter. J Steroid Biochem Mol Biol. 1997;62:155–63.

    Article  CAS  PubMed  Google Scholar 

  14. Shim GJ, Kis LL, Warner M, Gustafsson JA. Autoimmune glomerulonephritis with spontaneous formation of splenic germinal centers in mice lacking the estrogen receptor alpha gene. Proc Natl Acad Sci USA. 2004;101:1720–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Shim GJ, Wang L, Andersson S, Nagy N, Kis LL, Zhang Q, et al. Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. Proc Natl Acad Sci USA. 2003;100:6694–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005;175:5716–23.

    Article  CAS  PubMed  Google Scholar 

  17. Gourdy P, Araujo LM, Zhu R, Garmy-Susini B, Diem S, Laurell H, et al. Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-gamma production by invariant natural killer T cells. Blood. 2005;105:2415–20.

    Article  CAS  PubMed  Google Scholar 

  18. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock. 2000;14:81–90.

    Article  CAS  PubMed  Google Scholar 

  19. Sader MA, McGrath KC, Hill MD, Bradstock KF, Jimenez M, Handelsman DJ, et al. Androgen receptor gene expression in leucocytes is hormonally regulated: implications for gender differences in disease pathogenesis. Clin Endocrinol (Oxf). 2005;62:56–63.

    Article  CAS  Google Scholar 

  20. Medina KL, Garrett KP, Thompson LF, Rossi MI, Payne KJ, Kincade PW. Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen. Nat Immunol. 2001;2:718–24.

    Article  CAS  PubMed  Google Scholar 

  21. Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix ML, et al. Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS. 2004;18:2361–9.

    PubMed  Google Scholar 

  22. Moore AL, Kirk O, Johnson AM, Katlama C, Blaxhult A, Dietrich M, et al. Virologic, immunologic, and clinical response to highly active antiretroviral therapy: the gender issue revisited. J Acquir Immune Defic Syndr. 2003;32:452–61.

    Article  PubMed  Google Scholar 

  23. Collazos J, Asensi V, Cartón JA. Sex differences in the clinical, immunological and virological parameters of HIV-infected patients treated with HAART. AIDS. 2007;21:835–43.

    Article  PubMed  Google Scholar 

  24. Farzadegan H, Hoover DR, Astemborski J, Lyles CM, Margolick JB, Markham RB, et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 1998;352:1510–4.

    Article  CAS  PubMed  Google Scholar 

  25. Sterling TR. When should highly active antiretroviral therapy be initiated? Hopkins HIV Rep. 2001;13:11.

    Google Scholar 

  26. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009;15:955–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C, Dolan MJ, et al. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood. 2005;106:3524–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Sodora DL, Gettie A, Miller CJ, Marx PA. Vaginal transmission of SIV: assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. AIDS Res Hum Retroviruses. 1998;14:S119–23.

    Article  PubMed  Google Scholar 

  29. Grebely J, Page K, Sacks-Davis R, van der Loeff MS, Rice TM, Bruneau J, et al. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology. 2014;59:109–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Rodríguez-Torres M, Ríos-Bedoya CF, Rodríguez-Orengo J, Fernández-Carbia A, Marxuach-Cuétara AM, López-Torres A, et al. Progression to cirrhosis in Latinos with chronic hepatitis C: differences in Puerto Ricans with and without human immunodeficiency virus coinfection and along gender. J Clin Gastroenterol. 2006;40:358–66.

    Article  PubMed  Google Scholar 

  31. Di Martino V, Lebray P, Myers RP, Pannier E, Paradis V, Charlotte F, et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology. 2004;40:1426–33.

    Article  PubMed  Google Scholar 

  32. McClelland EE, Smith JM. Gender specific differences in the immune response to infection. Archivum Immunologiae et Therapiae Experimentalis. 2011;59:203–13.

    Article  PubMed  Google Scholar 

  33. Narasimhan P, Wood J, Macintyre CR, Mathai D. Risk factors for tuberculosis. Pulm Med. 2013;2013:828939.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Guerra-Silveira F, Abad-Franch F. Sex bias in infectious disease epidemiology: patterns and processes. PLoS one. 2013;8:e62390.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Frieden TR, Lerner BH, Rutherford BR. Lessons from the 1800s: tuberculosis control in the new millennium. Lancet. 2000;355:1088–92.

    Article  CAS  PubMed  Google Scholar 

  36. Clarke WG, Cochrane AL, Miall WE. Results of a chest x-ray survey in the Vale of Glamorgan; a study of an agricultural community. Tubercle. 1956;37:417–25.

    Article  CAS  PubMed  Google Scholar 

  37. Yamamoto Y, Saito H, Setogawa T, Tomioka H. Sex differences in host resistance to Mycobacterium marinum infection in mice. Infect Immun. 1991;59:4089–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Svanberg L. Effects of estrogen deficiency in women castrated when young. Acta Obstet Gynecol Scand Suppl. 1981;106:11–5.

    CAS  PubMed  Google Scholar 

  39. Curtis J, Turk JL. Resistance to subcutaneous infection with Mycobacterium lepraemurium is controlled by more than one gene. Infect Immun. 1984;43:925–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Demkow U, Filewska M, Michalowska-Mitczuk D, Kus J, Jagodzinski J, Zielonka T, et al. Heterogeneity of antibody response to myobacterial antigens in different clinical manifestations of pulmonary tuberculosis. J Physiol Pharmacol. 2007;58:117–27.

    PubMed  Google Scholar 

  41. Pope V, Larsen SA, Rice RJ, Goforth SN, Parham CE, Fears MB. Flow cytometric analysis of peripheral blood lymphocyte immunophenotypes in persons infected with Treponema pallidum. Clin Diagn Lab Immunol. 1994;1:121–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39:400–12.

    Article  CAS  PubMed  Google Scholar 

  43. Bernin H, Lotter H. Sex bias in the outcome of human tropical infectious diseases: influence of steroid hormones. J Infect Dis. 2014;209:S107–13.

    Article  CAS  PubMed  Google Scholar 

  44. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbiological aspects of Trichomonas vaginalis. Clin Microbiol Rev. 1998;11:300–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Liesenfeld O, Nguyen TA, Pharke C, Suzuki Y. Importance of gender and sex hormones in regulation of susceptibility of the small intestine to peroral infection with Toxoplasma gondii tissue cysts. J Parasitol. 2001;87:1491–3.

    Article  CAS  PubMed  Google Scholar 

  46. Karami M, Doudi M, Setorki M. Assessing epidemiology of cutaneous leishmaniasis in Isfahan, Iran. J Vector Borne Dis. 2013;50:30–7.

    PubMed  Google Scholar 

  47. Satoskar A, Alexander J. Sex-determined susceptibility and differential IFN-gamma and TNF-alpha mRNA expression in DBA/2 mice infected with Leishmania mexicana. Immunology. 1995;84:1–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Brabin L, Brabin BJ. Parasitic infections in women and their consequences. Adv Parasitol. 1992;31:1–81.

    Article  CAS  PubMed  Google Scholar 

  49. Degu G, Mengistu G, Jones J. Some factors affecting prevalence of and immune responses to Schistosoma mansoni in schoolchildren in Gorgora, northwest Ethiopia. Ethiop Med J. 2002;40:345–52.

    PubMed  Google Scholar 

  50. Travi BL, Osorio Y, Melby PC, Chandrasekar B, Arteaga L, Saravia NG. Gender is a major determinant of the clinical evolution and immune response in hamsters infected with Leishmania spp. Infect Immun. 2002;70:2288–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Lezama-Dávila CM, Isaac-Márquez AP, Barbi J, Oghumu S, Satoskar AR. 17Beta-estradiol increases Leishmania mexicana killing in macrophages from DBA/2 mice by enhancing production of nitric oxide but not pro-inflammatory cytokines. Am J Trop Med Hyg. 2007;76:1125–7.

    PubMed Central  PubMed  Google Scholar 

  52. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509:282–3.

    Article  PubMed  Google Scholar 

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Acknowledgements

This review was written in honor of Gerd Fätkenheuer’s 60th birthday. He has been our teacher for over a decade and we would like to thank him for his excellent teaching—both in internal medicine and infectious diseases but also in science and politics. He taught us to systematically look for all the puzzle pieces, to find a plausible diagnosis, to never give up, to take responsibility for our decisions, and to never forget the ultimate goal—the best for the patient. CL and JF are supported by the German Centre for Infection Research (DZIF). NR’s research is supported by funding from Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD; funded by the DFG within the Excellence Initiative by the German federal and state governments) and Deutsche Forschungsgemeinschaft (SFB 670).

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The authors have no conflicts of interest.

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Correspondence to Clara Lehmann.

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Fischer, J., Jung, N., Robinson, N. et al. Sex differences in immune responses to infectious diseases. Infection 43, 399–403 (2015). https://doi.org/10.1007/s15010-015-0791-9

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  • DOI: https://doi.org/10.1007/s15010-015-0791-9

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