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The influence of sex and gender on the immune response
Abstract
The immune system and its orchestrated response are affected by a multitude of endogenous and exogenous factors, modulators and challenges. One of the most frequent differences described in the immune response is its vigor and activity in females compared to males, leading to the consequent increase in autoimmune conditions seen in the female population as well as differences in the immune response to pathogens and viruses. The following review summarizes our present knowledge on sex differences in the immune response, detailing the hormonal and genetic effects that have been proposed as explanatory mechanisms. Sexual hormones, mostly estrogen but also progesterone and testosterone, affect immune cells quantitatively and qualitatively. Relevant research has focused on the impact of hormones on cytokine production by the different effector cells, as well as impact on immunoglobulin production by B lymphocytes and activity of granulocytes and NK cells. The biological aspects are complemented by research data on the possible modulatory role of the X chromosome. In addition to biological differences, the frequently neglected role of gender as an immunomodulator is introduced and explored. Gender affects all areas of human life and consequently affects the different steps of an immune response. Exposure to various types of antigens, access to health promotion programs and health care, as well as prioritization of health needs and household resource allocation all affect the different response of females and males to immunologic challenges.
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“Inflammatory responses are ste reotypically greater in females, which may be dictated by greater cytokine release due to the location of cytokine and TLR genes on the X-chromosome (Oertelt-Prigione, 2012).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Oertelt-Prigione, 2012
In the citing paper
“Thus, in addition to the immune factors that regulate the complex immunoendocrine network, gender might have a significant function in shaping the immune response [2].”
From Gender-Related Effects of Sex Steroids on Histamine Release and Fc ε RI Expression in Rat Peritoneal Mast Cells (2015) · cites this paper as [2]
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“zolpidem, a sleep medication35, which shows slower drug metabolization and high secondary effects in women, increasing their health risks compared with men34,36,37.”
From Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare (2020) · cites this paper as [37]
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Sex/gender-related differences in inflammaging
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“For example, the action of gonadal hormones up- or down-regulates cytokine levels, cell numbers, and receptor expression for many types of immune cells, and this varies with age [27,28].”
BackgroundRegulation of mi RNA biogenesis and turnover in the immune system
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“Estrogens are steroid hormones that mediate sex differences, but they also affect the function of lymphocytes and monocytes and may contribute to the increased frequency of autoimmune disorders in females (65).”
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“These hormones changed the distribution and function of lymphocyte subsets [26, 27].”
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Kananen, L., Marttila, S., Nevalainen, T., Jylhävä, J., Mononen, N., Kähönen, M. A. P., Raitakari, O. T., Lehtimäki, T. J., & Hurme, M. (2016) · BMC Genomics · doi:10.1186/s12864-016-2421-z · Cited by 85
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MethodMatters of the heart: Cellular sex differences
Walker, C. J., Schroeder, M. E., Aguado, B. A., Anseth, K. S., & Leinwand, L. A. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.04.010 · Cited by 74
Pigrau, M., Rodiño‐Janeiro, B. K., Casado‐Bedmar, M., Lobo, B., Vicario, M., Santos, J., & Alonso, C. (2015) · Neurogastroenterology & Motility · doi:10.1111/nmo.12717 · Cited by 83
Achalasia and Obstructive Motor Disorders Are Not Uncommon in Patients With Eosinophilic Esophagitis
Ghisa, M., Laserra, G., Marabotto, E., Ziola, S., Tolone, S., de Bortoli, N., Frazzoni, M., Mauro, A., Penagini, R., Savarino, V., et al. (2020) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2020.07.056 · Cited by 78
Lorenz, M., Koschate, J., Kaufmann, K., Kreye, C., Mertens, M., Kuebler, W. M., Baumann, G., Gossing, G., Márki, A., Zakrzewicz, A., et al. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.02.018 · Cited by 87
“Although the impact of the expression differences between male and female HUVEC for the in vivo situation remains to be elucidated, our data in endothelial cells are in accordancewith the clinical finding that overall immune reactivity is higher in females than in males [30].”
BackgroundPulmonary group 2 innate lymphoid cells: surprises and challenges
Starkey, M. R., McKenzie, A. N. J., Belz, G. T., & Hansbro, P. M. (2019) · Mucosal Immunology · doi:10.1038/s41385-018-0130-4 · Cited by 77
“Several immune cell lineages, including myeloid cells and lymphocytes express receptors for estrogen, progesterone and androgens (testosterone, dihydrotestosterone and androstenedione) and are hormone regulated and influence both innate and adaptive immune responses.(96) In macrophages, estrogen receptor signaling inh…”
The fate is not always written in the genes: Epigenomics in epidemiologic studies
Langevin, S. M., & Kelsey, K. T. (2013) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21762 · Cited by 75
“Since personal characteristics, behaviors, exogenous exposures, or pathologic states can modulate the circulating immune profile [Cheng et al., 2004; Mehta et al., 2008; Szabo and Mandrekar, 2009; Federico et al., 2010; Kiecolt-Glaser et al., 2010; Oertelt-Prigione, 2012], inter-subject variation in leukocyte distribu…”
Risk factors for immune-related adverse events: what have we learned and what lies ahead?
Liu, X., Shi, Y., Zhang, D., Zhou, Q., Liu, J., Chen, M., Xu, Y., Zhao, J., Zhong, W., & Wang, M. (2021) · Biomarker Research · doi:10.1186/s40364-021-00314-8 · Cited by 74
“Immune system function is known to vary between sexes as a result of hormonal and genetic effects [114].”
BackgroundGender aspects in food allergy
Pali‐Schöll, I., & Jensen‐Jarolim, E. (2019) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000529 · Cited by 72
Sex and gender affect immune aging
Calabrò, A., Accardi, G., Aiello, A., Caruso, C., & Candore, G. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1272118 · Cited by 71
“For example, the transmission of sexually transmitted diseases is faster in women who use oral contraceptives than in men, particularly in the case of HIV infection (Oertelt-Prigione, 2012; Addo and Altfel, 2014).”
BackgroundInfluentialThe limitations and hidden gems of the epidemiology of primary biliary cirrhosis
Podda, M., Selmi, C. F., Lleò, A., Moroni, L., & Invernizzi, P. (2013) · Journal of Autoimmunity · doi:10.1016/j.jaut.2013.06.015 · Cited by 71
Roy, A., Bauer, S. M., & Lawrence, B. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038448 · Cited by 70
“However, the idea that estrogens polarize toward Th2-biased responses is likely an oversimplification of the physiological and pharmacological effects of endogenous and exogenous estrogens on immune function [64], and therefore is probably not an adequate explanation.”
BackgroundTLR7, IFNγ, and T-bet: Their roles in the development of ABCs in female-biased autoimmunity
Rubtsova, K., Marrack, P., & Rubtsov, A. V. (2014) · Cellular Immunology · doi:10.1016/j.cellimm.2014.12.002 · Cited by 69
“It is a welldocumented fact that there are differences in immune responses between males and females [1].”
BackgroundSelf-protection as an adaptive female strategy
Benenson, J. F., Webb, C. E., & Wrangham, R. W. (2021) · Behavioral and Brain Sciences · doi:10.1017/s0140525x21002417 · Cited by 71
Katzav, A., Arango, M., Kivity, S., Tanaka, S., Givaty, G., Agmon‐Levin, N., Honda, M., Anaya, J., Chapman, J., & Shoenfeld, Y. (2013) · Journal of Autoimmunity · doi:10.1016/j.jaut.2013.06.010 · Cited by 66
Wen, C., van Dixhoorn, I. D. E., Schokker, D., Woelders, H., Stockhofe-Zurwieden, N., Rebel, J. M. J., & Smidt, H. (2021) · Animal Microbiome · doi:10.1186/s42523-021-00115-2 · Cited by 65
Dupuis, M. L., Conti, F., Maselli, A., Pagano, M., Ruggieri, A., Anticoli, S., Fragale, A., Gabriele, L., Gagliardi, M. C., Sanchez, M., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01903 · Cited by 64
“The immunomodulatory effects exerted by E2 are, at least partially, responsible for the existing differences between female and male immune systems, with females mounting stronger humoral and cellular immune responses than males (6).”
BackgroundRehberger, K., von Siebenthal, E. W., Bailey, C., Bregy, P., Fasel, M., Herzog, E. L., Neumann, S., Schmidt‐Posthaus, H., & Segner, H. E. (2020) · Environment International · doi:10.1016/j.envint.2020.105836 · Cited by 64
“Since the response of fish to toxicants as well as pathogens may differ between sexes (Koehler 2004, Le Manach et al., 2016, Oertelt-Prigione 2012, Winzer et al., 2002a, Winzer et al., 2002b), we analyzed the data for male and female fish separately.”
BackgroundNormal Values of T, B and NK Lymphocyte Subpopulations in Peripheral Blood of Healthy Cuban Adults
Kokuina, E., Breff-Fonseca, M. C., Valverde, C. A. V., & Díaz, I. M. (2019) · MEDICC Review · doi:10.37757/mr2019.v21.n2-3.5 · Cited by 59
“[36,37] The difference in values of CD3+CD4+ cells can be attributed to the effect of sex hormones on their specifi c receptors expressed in T and B lymphocytes.[38] Sex chromosome genes and sex hormones such as estrogen, progesterone and androgens contribute to male/female differences in immune response.”
BackgroundImpact of progesterone on the immune system in women: a systematic literature review
Zwahlen, M., & Stute, P. (2023) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-023-06996-9 · Cited by 59
Kang, N., Yu, Y., Zheng, X., Luo, Z., Jiao, Z., Liu, X., Wang, Y., Liang, Y., Zhang, Z., Ye, X., et al. (2024) · International Journal of Surgery · doi:10.1097/js9.0000000000001475 · Cited by 61
“Additionally, females often exhibit stronger immune responses, which may affect postoperative in fl ammation and healing processes, thereby increasing the risk of hypoPT [116] .”
BackgroundDragin, N., Nancy, P., Villegas, J. A., Roussin, R., Panse, R. L., & Berrih‐Aknin, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-08631-5 · Cited by 58
The causes and consequences of variation in human cytokine production in health
Schirmer, M., Kumar, V., Netea, M. G., & Xavier, R. J. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.05.012 · Cited by 60
Breach of Tolerance: Primary Biliary Cirrhosis
Wang, L., Chang, C. C.-C., Gershwin, M. E., & Wang, F. (2014) · Seminars in Liver Disease · doi:10.1055/s-0034-1383729 · Cited by 55
Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?
Morris, G., Maes, M. H. J., Murdjeva, M., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1255-x · Cited by 60
Honey bee protein atlas at organ-level resolutionPreprint
Chan, Q. W. T., Chan, M. Y. M., Logan, M., Yuan, F., Higo, H. A., & Foster, L. J. (2013) · Genome Research · doi:10.1101/gr.155994.113 · Cited by 58
“In humans, there are measurable differences between males and females with regard to lipid metabolism (Sugiyama and Agellon 2012), the handling of oxidative stress (Vina et al. 2011), and the immune system (Oertelt-Prigione 2012), to name a few.”
BackgroundMuñoz-Cruz, S., Mendoza-Rodríguez, Y., Nava-Castro, K. E., Yepez-Mulia, L., & Morales-Montor, J. (2015) · Journal of Immunology Research · doi:10.1155/2015/351829 · Cited by 54
“Thus, in addition to the immune factors that regulate the complex immunoendocrine network, gender might have a significant function in shaping the immune response [2].”
BackgroundMusey, P. I., Linnstaedt, S. D., Platts-Mills, T. F., Miner, J. R., Bortsov, A. V., Safdar, B., Bijur, P., Rosenau, A., Tsze, D. S., Chang, A. K., et al. (2014) · Academic Emergency Medicine · doi:10.1111/acem.12529 · Cited by 55
Krementsov, D. N., Noubade, R., Dragon, J. A., Otsu, K., Rincón, M., & Teuscher, C. (2013) · Annals of Neurology · doi:10.1002/ana.24020 · Cited by 54
“In humans, gender influences immunity, although controversial results regarding gender and/or sex hormone treatment in ex vivo studies are frequently reported.(58) p38 MAPK is well known to control proinflammatory functions in human monocytes/macrophages,(6) but to the best of our knowledge, little has been reported o…”
BackgroundReference Values for Peripheral Blood Lymphocyte Subsets in a Healthy Korean Population
Choi, J., Lee, S. J., Lee, Y. A., Maeng, H. G., Lee, J. K., & Kang, Y. W. (2014) · Immune Network · doi:10.4110/in.2014.14.6.289 · Cited by 51
Vercellini, P., Bandini, V., Viganò, P., Stefano, G. D., Merli, C. E. M., & Somigliana, E. (2023) · Human Reproduction · doi:10.1093/humrep/dead229 · Cited by 50
“In addition to local stimulation of eutopic and ectopic endometrium, oestrogens also exert a systemic pro-inflammatory effect (Straub, 2007; Oertelt-Prigione, 2012a,b; Cutolo et al. , 2014; Dodd and Menon, 2022).”
BackgroundSex Disparities in Cancer Mortality: The Risks of Being a Man in the United States
Najari, B. B., Rink, M., Li, P. S., Karakiewicz, P. I., Scherr, D. S., Shabsigh, R., Meryn, S., Schlegel, P. N., & Shariat, S. F. (2012) · The Journal of Urology · doi:10.1016/j.juro.2012.11.153 · Cited by 48
Gender Differences in Cardiovascular Drugs
Stolarz, A. J., & Rusch, N. J. (2015) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-015-6611-8 · Cited by 55
Kutteh, W. H., Stanic, A. K., & Schust, D. J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-47912-7.00013-5 · Cited by 46
Selection for brain size impairs innate, but not adaptive immune responses
Kotrschal, A., Kolm, N., & Penn, D. J. (2016) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2015.2857 · Cited by 45
Metadata
- Authors
- Oertelt-Prigione, S.
- Venue
- Autoimmunity Reviews
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 11
- Issue
- 6-7
- Pages
- A479-A485
- ISSN
- 1568-9972 (ISSN-L)
- OpenAlex
- W2045019335
- Cited by
- 459
- References
- 102
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 38 · 2023: 28 · 2022: 32 · 2021: 43 · 2020: 45 · 2019: 23 · 2018: 28 · 2017: 35 · 2016: 32 · 2015: 36 · 2014: 37 · 2013: 22 · 2012: 7
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Autoimmunity Reviews (publishedVersion)
- PubMed (publishedVersion)
- Publikationen an der Universität Bielefeld (Universität Bielefeld) (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- sex differences in immune response, gender differences, autoimmune disease, sex hormones, estrogen, progesterone, testosterone, cytokine production, antibody production, B cells, granulocytes, natural killer cells, X chromosome, social determinants of health, health care access
- MeSH terms
- B-Lymphocytes, Bone Marrow Cells, Dendritic Cells, Female, Humans, Immunity, Active, Immunologic Factors, Killer Cells, Natural, Male, Sex Factors, Gonadal Steroid Hormones, T-Lymphocytes
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