In a recent OPIG antibody meeting, the topic of immune system differences between men and women came up. I thought this was cool and something I hadn’t read about, so what a brilliant topic for a blog most. This post is a high-level overview – I’ve listed the papers I’ve used at the bottom of this post so please consult them for more details!
Differences between males and females can lead to pretty big disparities in disease prevalence and outcomes. For example, non-reproductive cancers occur predominantly in males, whilst the majority of autoimmune disease occurs in females. Many factors may be impacting this, including environmental, genetic and hormonal influences, and much more research is required to fully understand these processes. Here I focus on sex-based biology, rather than gender, though both can influence the immune response.
Evidence suggests that females generally have stronger and faster immune responses, including higher numbers of B cells and CD4+ T cells and greater antibody production in response to antigens. Unfortunately, this doesn’t result in females having disease-fighting superpowers; an overactive immune response can lead to autoimmune disease, where the immune system erroneously attacks the body. Additionally, females report more side effects in most vaccine trials – this could be a reporting bias, or may be due to a greater inflammatory response leading to adverse reactions. This increased response is not always consistent and seems depends on age and the antigen involved. One vaccine study suggested elderly males had a stronger antibody response to influenza vaccination than elderly females, and in infant studies females responded better to HSV-2 vaccination whereas males responded better to BCG and rubella vaccination.
Three hypotheses about why sex-differences occur in immune responses suggest the roles of X-chromosomes, sex hormones and the microbiome. Firstly, females with two X chromosomes have one X chromosome inactivated, but this process is not perfect and some immune regulatory genes may be transcribed from both X chromosomes, contributing to a greater immune response (compared to males with only one X chromosome). Secondly, and perhaps the most well understood so far, is the influence of the sex hormones. Females have higher estrogen levels and males have higher androgen levels, such as testosterone. Estrogen receptors are present on many cells throughout the body including many immune cells, and estrogen can modulate the immune system by affecting B cell development and T helper cell function, generally triggering an inflammatory response. In contrast, androgen hormones often have immunosuppressive functions – a study showed males with higher levels of testosterone had a reduced immune response to influenza vaccine. A third hypothesis for the immune response differences between males and females involves the gut microbiome, and increasing amounts of research links microbes in the gut to human health and disease. Gut microbes differ depending on the geographical location, diet, and also sex of the person (sex hormones are known the influence the microbiome).
Sex-based research has already led to the revision of diagnostic protocols for heart attacks, due to the different symptoms experienced by men and women. In the future, we might also see altered dosage and timings in vaccination programs. The immune system is incredibly complex but this research highlights the importance of sex-aggregating data (reporting data for male and female groups separately – see my previous blog post on Invisible Women ) during clinical studies and disease reporting. Failure to do so means differences between sexes may not be recognised, insights into disease pathogenesis may be missed and opportunities to improve healthcare outcomes can be overlooked.
Papers used to write this blog post:
Aaby, P., et al. (2020) The non-specific and sex-differential effects of vaccines. Nature Reviews Immunology, 20(8) 464-470.
Harper, A., & Flanagan, K. L. (2018). Effect of sex on vaccination outcomes: important but frequently overlooked. Current opinion in pharmacology, 41, 122-127.
Klein, S.L. and Flanagan, K.L., (2016). Sex differences in immune responses. Nature Reviews Immunology, 16(10), 626.
Mauvais-Jarvis, F., et al. (2020). Sex and gender: modifiers of health, disease, and medicine. The Lancet, 396(10250) 565-582.
