Sex and the immune system

Society would have us believe that men and women are vastly different from one another, that the bridge between these binaries causes confusion, hurt, and pain. Although, the term “Men come from Mars and Women come from Venus” has been critically analysed time and time again, when looking at the workings of the immune system, between the sexes, it couldn’t be more accurate.

The immune system informs the way in which we respond to disease, vaccination, and the susceptibility of autoimmune conditions. Although, people generally contain the same immune workings and cells, there are stark differences between the sexes in how the innate and adaptive immune system work with one another.

Beyond the binary classification, intersex individuals concrete the evidence that these immune differences are caused by differing genetic and hormonal profiles. Worryingly, even though these differences are well researched, there is little to no change in clinical advice when our eventual hope is to personalise medicine for better patient outcomes.

Two sides of the same coin: Adaptive and Innate immune system

The immune system protects us from a wide range of disease-causing agents, and it is split up into adaptive and innate systems (Figure 1)1 which mirrors the different approaches required for different kinds of biological threats.  

Figure 1: Shows the different approaches that the innate and the adaptive arms of the immune system use to clear infections. Although the eventual removal of the infectious agent is the primary outcome of both pathways adaptive responses are more specific and forms the basis of the memory response.

Generally, the innate system is seen as our “first line of defence” and the cells which fall under this classification can successfully control common bacterial infections2. Although, this part of the immune system is very powerful, these cells cannot always clear chronic infections coming from viruses.

This means that a more specific and robust response is required that is provided by the adaptive immune arm of the system. The adaptive immune response is one of the most powerful ways in which the cells of our body aim to overcome and clear infections. Not only does the adaptive response actively kill pathogens, but it also facilitates a memory response which is the underlying principle of vaccination.

Worlds apart

Proteins that are able recognise bacterial molecular structures are known as toll-like-receptors (TLR) and play a large role in informing the innate immune response within humans3. Interestingly, the amount of toll-like-receptor 7 (TLR7) is higher within binary females, when compared to their male counterparts4.

These proteins are integral structures to the immune system as it triggers the clearance of various pathogens, including influenza A and Hepatitis C5. Furthermore, TLR7 can shape and inform the adaptive immune response which is integral to human health and vaccination response.

One of the most important cell types in the adaptive arm of the immune system are T-cells. These cells are ultimately responsible for the establishment, maintenance, and memory functions of the immune system. T-cells form a wide range of subcategories (Figure 2)6 that have distinctive functions from one another.

Figure 2: Shows how immature T-cells come to maturity though various pathways and signals provided by dendritic cells. Once these T-cells reach maturity they can form different subsets which coordinates the response to clear infection.

CD4+ and CD8+ T-cells are of particular importance as CD8+ cells can directly kill infected cells, whereas, CD4+ cells can regulate the immune response7.

Surprisingly, even the type of T-cells between the sexes can differ greatly.

Across nearly every ethnic group, females generally have a higher CD4+ T cell count and higher CD4/CD8 ratio when compared to their similarly aged males4. It is important to note that a higher CD4/CD8 ratio is hallmarked as having a robust immune system.

Cause…and effect

These differences in the adaptive and innate immune systems have a wide range effects on how women and men respond to disease, infection, and vaccination.

Of particular importance, TLRs plays a distinctive role in the way females have a stronger reaction to immune stimulatory molecules within vaccines8. This is thought to be one of the many reasons why females generally have more frequent and adverse reactions to immunisation9. Furthermore, a study found that women receiving a half dose of a flu vaccine generated a higher immune response compared to males who had a full dose, presenting that these sex differences pervade into how disease is managed within society10.

Although, TLR7 is important in controlling the clearance of viruses, it is also a key progressor of systemic lupus erythematosus (SLE) where the immune system attacks its own tissues, causing wide scale inflammation11. As females have a greater amount of TL7R, it is unsurprising to hear that SLE affects women nine times more frequently than men12.

It is a well-documented phenomenon that the outcome of Hepatitis B, HIV and influenza infections differ between the sexes. For example, death from the 2009 influenza outbreak in North America was two times greater within women, even though they have a lower exposure rate compared to men13. Although, it is expected that a robust immune system, marked by the high CD8/CD4 ratio, should clear the infection without difficulty, it is thought that this increases the development of symptoms associated with the disease14.

It’s hormonal and genetic

The biggest genetic difference between men and women are their sex chromosome characterisation which has a wide influence on the immune system.

Binary women have a XX sex chromosome characteristic, whereas binary men have a XY characteristic (Figure 3)14.  During early embryo development, XX females undergo a process called X-inactivation where a random X chromosome becomes silenced15.

Figure 3: Shows the binary XX and XY sex chromosomes which determines an individual’s sex.

The process of X-inactivation is important within XX females as without this process the second X chromosome can “double up” the number of genes16.  

However, this silencing is not perfect as 15 to 23% of X-linked human genes can escape this inactivation meaning the genes are able to be expressed at the same time17. Of particular importance, TLR7 can escape this silencing which is thought to be the reasoning to why TLR7 proteins are so much higher within females compared to males10.

Away from genetic differences, the hormonal profile of biological men and women differ greatly, and they can influence and shape the immune system. The sex hormone predominately within men, testosterone, suppresses the immune system whereas, oestrogen, within females, enhances the effects the immune system18. However, especially within binary women, there is an added layer of complexity as the hormonal states can fluctuate during the menstrual cycle and even menopause19,20.

Breaking away from binary

When making these general observations about how sex, chromosomes, and hormones can affect immunity it is important to note that some individuals break away from binary sex classification. Biological sex can transcend this dualistic organisation of XX or XY sex chromosomes 20.

Individuals with Klinefelter Syndrome have male traits however, due to a random error during fertilisation, they can carry an extra X chromosome meaning their sex chromosome characterisation is XXY21.

People that carry an extra X chromosome respond like binary females as they have a characteristic higher CD4+ T cell number and higher CD4/CD8 T cell ratio when compared to XY males22.  Interestingly, the immunological profile that people with Klinefelter Syndrome have can be reversed by testosterone therapy, further presenting the importance of how sex hormones can influence the immune system22.

Not only do these findings strengthen the argument that these immune differences are due to differing genetic and hormonal profiles, but it also suggests medical interventions, such as hormone therapy, can have large effects on an individual’s immune system.

Widening horizons

Despite the well-researched sex differences in how the immune system works, clinical and vaccination decisions have not addressed these distinctions. This is incredibly concerning as the susceptibility and outcome of infections, diseases and even vaccination has shown sex bias.

This utopia of addressing different treatment courses based on sex requires primary research to funnel resources and funding towards more sex-inclusive studies. Inappropriate dosing recommendations, which put women in danger of various side-effects, may be due to pre-clinical studies not separating their data by sex or even including female specimens within their studies23. Separating sex data is important as further analysis could be made about any differences therefore, going to inform policy change to address these issues24.

Going even further, researchers alongside clinicians, need to include those who transcend our society’s thoughts on sex and gender. Although, there has been more effort to conclude the effects of hormone therapy on bone density within transgender individuals, more effort should be made in how hormone therapy may influence the workings of the immune system25.

While it is important to consider how sex influences the immune system, other factors such as diet, the microbiome, and age also play a part in the responsiveness and robustness of the immune response. This presents great complexity into researching human immune sex differences26,27.

The sooner that sex and gender is considered as a human variables within studies, clinical trials, and healthcare the sooner tailored interventions can produce effective results focusing on the these factors4,20.

Note: In this article when I am referring to “sex” these are biologically defined using sex chromosomes, hormones, and characteristics. This is separate from “gender” which is more societal and mostly refers to behaviours and or roles. This is not a discussion into whether these are separate or even exist and any hateful comments will be deleted.

References:

1.         Akiko Iwasaki. BioRender. https://app.biorender.com/biorender-templates/t-5f176d764f5fad00a77918e1-innate-and-adaptive-immunity.

2.         Charles A Janeway, J., Travers, P., Walport, M. & Shlomchik, M. J. Principles of innate and adaptive immunity. Immunobiol. Immune Syst. Health Dis. 5th Ed. (2001).

3.         Kawasaki, T. & Kawai, T. Toll-Like Receptor Signaling Pathways. Front. Immunol. 5, (2014).

4.         Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

5.         Fischinger, S., Boudreau, C. M., Butler, A. L., Streeck, H. & Alter, G. Sex differences in vaccine-induced humoral immunity. Semin. Immunopathol. 41, 239–249 (2019).

6.         Anna Lazaratos. BioRender Templates. https://app.biorender.com/illustrations/edit/608a898ad0a9d300a33da08b.

7.         Robins, H., Emerson, R., Sherwood, A. & Desmarais, C. CD4+ and CD8+ T cell β antigen receptors have different and predictable V and J gene usage and CDR3 lengths (115.10). J. Immunol. 188, 115.10-115.10 (2012).

8.         Fischinger, S., Boudreau, C. M., Butler, A. L., Streeck, H. & Alter, G. Sex differences in vaccine-induced humoral immunity. Semin. Immunopathol. 41, 239–249 (2019).

9.         Klein, S. L., Marriott, I. & Fish, E. N. Sex-based differences in immune function and responses to vaccination. Trans. R. Soc. Trop. Med. Hyg. 109, 9–15 (2015).

10.       Engler, R. J. M. et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 168, 2405–2414 (2008).

11.       Souyris, M. et al. TLR7 escapes X chromosome inactivation in immune cells. Sci. Immunol. 3, (2018).

12.       Rider, V. et al. Gender Bias in Human Systemic Lupus Erythematosus: A Problem of Steroid Receptor Action? Front. Immunol. 9, (2018).

13.       Zarychanski, R. et al. Correlates of severe disease in patients with 2009 pandemic influenza (H1N1) virus infection. CMAJ Can. Med. Assoc. J. J. Assoc. Medicale Can. 182, 257–264 (2010).

14.       Klein, S. L. Immune Cells Have Sex and So Should Journal Articles. Endocrinology 153, 2544–2550 (2012).

15.       Graves, J. Sex, genes, the Y chromosome and the future of men. The Conversation http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893.

16.       DISTECHE, C. M. & BERLETCH, J. B. X-chromosome inactivation and escape. J. Genet. 94, 591–599 (2015).

17.       Kalantry, S. Recent Advances in X-Chromosome Inactivation. J. Cell. Physiol. 226, 1714–1718 (2011).

18.       Souyris, M., Mejía, J. E., Chaumeil, J. & Guéry, J.-C. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin. Immunopathol. 41, 153–164 (2019).

19.       Taneja, V. Sex Hormones Determine Immune Response. Front. Immunol. 9, (2018).

20.       Bhatia, A., Sekhon, H. K. & Kaur, G. Sex Hormones and Immune Dimorphism. Sci. World J. 2014, (2014).

21.       Gameiro, C. M., Romão, F. & Castelo-Branco, C. Menopause and aging: changes in the immune system–a review. Maturitas 67, 316–320 (2010).

22.       Differences, I. of M. (US) C. on U. the B. of S. and G., Wizemann, T. M. & Pardue, M.-L. The Future of Research on Biological Sex Differences: Challenges and Opportunities. Exploring the Biological Contributions to Human Health: Does Sex Matter? (National Academies Press (US), 2001).

23.       Los, E. & Ford, G. A. Klinefelter Syndrome. in StatPearls (StatPearls Publishing, 2021).

24.       Koçar, I. H. et al. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin. Exp. Immunol. 121, 448–452 (2000).

25.       Ravindran, T. S., Teerawattananon, Y., Tannenbaum, C. & Vijayasingham, L. Making pharmaceutical research and regulation work for women. BMJ 371, m3808 (2020).

26.       Vijayasingham, L., Bischof, E. & Wolfe, J. Sex-disaggregated data in COVID-19 vaccine trials. The Lancet 397, 966–967 (2021).

27.       Stevenson, M. O. & Tangpricha, V. Osteoporosis and Bone Health in Transgender Persons. Endocrinol. Metab. Clin. North Am. 48, 421–427 (2019).

28.       Lambring, C. B. et al. Impact of the Microbiome on the Immune System. Crit. Rev. Immunol. 39, 313–328 (2019).

29.       Montecino-Rodriguez, E., Berent-Maoz, B. & Dorshkind, K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest. 123, 958–965 (2013).

Image credit:

Legs hanging photo by Dương Nhân from Pexels

Coin photo by Joey Kyber from Pexels

Brainstorm chalkboard photo by Andrea Piacquadio from Pexels

Swirl and two figures photo by cottonbro from Pexels

Stand out photo by João Jesus from Pexels

Test tubes photo by Martin Lopez from Pexels

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