Sex and Immunity: The importance of biological sex in immune responses

Sex and Immunity: The importance of biological sex in immune responses

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By: Anna Podnos and Dr. Gillian Einstein

Male and female organisms differ in terms of social, cultural, and economic roles and expectations (gender), as well as biology (sex), and they experience disease in different ways. The immune system, which detects and protects against disease by recognizing and responding to antigens, is affected by both gender and sex.(1,2) Moreover, the immune system receives regulatory signals from an extended network of cells and tissues, which themselves are affected differently by sex and gender. As therapies targeting the immune system develop to improve outcomes in cancers, viral infections, autoimmune diseases, and transplantation, taking sex differences into account will be ever more crucial for their success.

However, sex differences are seldom the focus of biomedical, and especially immunological research.(1,3) For example, it is rare for animal and cell-based research to use females as experimental subjects.(3) Tellingly, when this was discussed in our Summer 2011 edition (see “Sexism in Biomedical Research”), one student wrote the following response: “I think one should stick to conducting research in one sex to eliminate unnecessary complexity of study design and resource spending. In the field of immunology, there are sex differences in immune responses, but they are not so drastic as to necessitate controlling for sex differences.” This comment reflects a prevalent attitude in biomedical science; however, the evidence is beginning to stack up against it.

Sex-dependent factors influence the susceptibility and progression of diseases. Compared to females, male mice and humans experience higher severity and prevalence of many bacterial, viral, fungal, and parasitic infections.(4) On the other hand, females exhibit more robust immune responses to antigenic challenges, such as infection and vaccination.(5) Although females mount greater immune responses, which can result in faster infection clearance, they more frequently develop immune-mediated pathologies.(7) Females are also at a higher risk for developing many autoimmune and inflammatory diseases than males; 80% of patients with autoimmune diseases are women.(8) In contrast, the risk of death from all malignant cancers is 1.6 times higher for men.(9)

Sex-based differences that affect the competence of the immune system may influence susceptibility to viral or bacterial infection and severity of illness.(1) Females often have lower prevalence and intensity of infections, including malaria, HIV, hepatitis C, and influenza, due to heightened immune responses.(2) The efficacy of antiviral and antibacterial drugs is also different between the two sexes, and adverse reactions to vaccinations are reported more frequently in females.(5,6) This may reflect either a reporting bias, or greater inflammatory responses among women. Heightened inflammatory responses in women are effective for rapid clearance of infections, but can also result in pathology. For example, excessive inflammatory responses are hypothesized to underlie severe outcomes of influenza;10 during the 2009 H1N1 pandemic, Canadian women had a 2.4-fold higher risk of death than men,11 and women worldwide are 2-6 times more likely to die from H5N1 avian influenza, partly due to heightened immune responses.(2)

An increased inflammatory profile in women is evident when looking at the sex distribution of autoimmune disorders. There is a 6-10:1 female:male bias in the prevalence of Sjögren’s syndrome, Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The increased susceptibility of females to such diseases can be shown in animal models, which reveal “profound and complex effects of sex steroid hormones and sex chromosomal complement on immune responses and development of disease.”(8)

The immune system also plays an important role in cancer progression, and sex is an important factor in the diagnosis, pathogenesis, and prognosis of many malignancies.(2) Incidence and mortality rates for a majority of cancers in non-reproductive organs are consistently higher among males than females.(9) Recently, cancer research has been focused on therapies that enhance the patient’s own abilities to fight the tumour, called cancer immunotherapy.(12) But, importantly, the success of these therapies depends, in part, on the sex of the patient. For example, a recent study reported that the combination of having a CD200 receptor (a potential anti-cancer therapeutic target) signaling deficiency and being a female drastically increased immune-mediated pathology in influenza A infection.(13) Since CD200 blocking antibodies are entering clinical trials for cancer treatment, increased inflammation during infections in women as a result of CD200 blocking therapies must be considered as a potentially harmful side-effect.

Some of the differences between the immune system of males and females may be mediated by steroid hormones, like estrogens, progestins, and androgens.(14) There are changes in immune responses between various female reproductive phases.(2) For instance, the activity of regulatory and anti-inflammatory cells increases in pregnant females.(15) Steroid sex hormones regulate a variety of physiological processes in the reproductive, skeletal, cardiovascular, and immune systems. The binding of sex steroids to their receptors on immune cells directly influences cell signaling pathways, which affect the migration of immune cells to sites of inflammation and the production of soluble regulatory molecules that aid in cell communication.

Estrogens can stimulate cell proliferation and differentiation via estrogen receptors in immune cell populations, such as lymphocytes, monocytes, and brain glial cells. Estrogens are associated with inflammation, but they may have different effects in males and females.(16) Progesterone is typically considered to be anti-inflammatory, and progesterone receptors (PR) are differentially expressed between sexes in many immune cells. For example, dendritic cells (DC) from female rodents express higher levels of PR than male DC, and progesterone suppresses inflammation to a greater degree in females.(17) Androgens, like testosterone and dihydrotestosterone, also suppress the activity of immune cells by increasing the production of anti-inflammatory cytokines.(18) Therefore, sex hormones affect the kinetics and magnitude of differential immune responses between males and females.(2)

Other variations in immune responses may be due to genetic, social, and environmental differences between males and females. For example, the X chromosome contains many genes that are involved in immune responses.1 It also contains 10% of all microRNAs (miRNAs) in the human genome, while the Y chromosome does not contain any.(19) miRNAs are critical regulators of the immune response, and this may indicate important sex-based differences in post-transcriptional regulation of expression of molecules involved in immunity.

Social and cultural factors are also important determinants of disease susceptibility, since gender influences patterns of exposure to infections and treatments. Gender roles influence where and how men and women spend their time and the healthcare they receive.(20) For example, in certain societies fatality rates of measles infection are higher for females than for males, since girls remain at home and thus are at a higher risk of infection from siblings inside the home.(1) Also, according to the WHO, important gender differences in access to healthcare may lead to variability in the level of care given to men and women. For instance, a study in Kolkata, India, found that boys with diarrhea were more likely to be rehydrated and taken to qualified health professionals than girls.(20)

The clear differences in immune responses between males and females indicate that therapeutic interventions and research with animal models should take sex into account. For example, sex-based differences in responses to cancer immunotherapies that are already used in clinics should be investigated to optimize patient care. This would offer new directions for treatments that may have sex-based variations in efficacies and side-effect profiles. It’s just good science.

Anna Podnos, MSc candidate
Member of Dr. Reg Gorczynski’s lab

Gillian Einstein, PhD
Director of the Collaborative Graduate Program in Women’s Health,
University of Toronto
Associate Professor,
Psychology and Public Health

References
1 Fish, E. N. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol8, 737-744, doi:10.1038/nri2394 (2008).
2 Klein, S. L. Immune cells have sex and so should journal articles. Endocrinology153, 2544-2550, doi:10.1210/en.2011-2120 (2012).
3 Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev35, 565-572, doi:10.1016/j.neubiorev.2010.07.002 (2011).
4 Klein, S. L. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev24, 627-638 (2000).
5 Klein, S. L., Jedlicka, A. & Pekosz, A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis10, 338-349, doi:10.1016/s1473-3099(10)70049-9 (2010).
6 Cook, I. F. Sexual dimorphism of humoral immunity with human vaccines. Vaccine26, 3551-3555, doi:10.1016/j.vaccine.2008.04.054 (2008).
7 Meier, A. et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid. Nat Med15, 955-959, doi:10.1038/nm.2004 (2009).
8 Voskuhl, R. Sex differences in autoimmune diseases. Biol Sex Differ2, 1, doi:10.1186/2042-6410-2-1 (2011).
9 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 Prev20, 1629-1637, doi:10.1158/1055-9965.epi-11-0246 (2011).
10 de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and. Nat Med12, 1203-1207, doi:10.1038/nm1477 (2006).
11 Zarychanski, R. et al. Correlates of severe disease in patients with 2009 pandemic influenza (H1N1). Cmaj182, 257-264, doi:10.1503/cmaj.091884 (2010).
12 Pardoll, D. M. Immunology beats cancer: a blueprint for successful translation. Nat Immunol13, 1129-1132, doi:10.1038/ni.2392 (2012).
13 Karnam, G. et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS Pathog8, e1002710, doi:10.1371/journal.ppat.1002710 (2012).
14 Bouman, A., Heineman, M. J. & Faas, M. M. Sex hormones and the immune response in humans. Hum Reprod Update11, 411-423, doi:10.1093/humupd/dmi008 (2005).
15 Mao, G. et al. Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg. Endocrinology151, 5477-5488, doi:10.1210/en.2010-0426 (2010).
16 Candore, G. et al. Gender-related immune-inflammatory factors, age-related diseases, and longevity. Rejuvenation Res13, 292-297, doi:10.1089/rej.2009.0942 (2010).
17 Butts, C. L. et al. Inhibitory effects of progesterone differ in dendritic cells from female and male. Gend Med5, 434-447, doi:10.1016/j.genm.2008.11.001 (2008).
18 McKay, L. I. & Cidlowski, J. A. Molecular control of immune/inflammatory responses: interactions between nuclear. Endocr Rev20, 435-459 (1999).
19 Pinheiro, I., Dejager, L. & Libert, C. X-chromosome-located microRNAs in immunity: might they explain male/female. Bioessays33, 791-802, doi:10.1002/bies.201100047 (2011).
20 Anker, M. Addressing sex and gender in epidemic-prone infectious diseases. (2007).