Research has repeatedly shown that women have a stronger immune response to infections than men. Studies from as early as the 1940s have elucidated that women possess an enhanced capability of producing antibodies.
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Even though this builds an effective resistance barrier to infections, women have a higher predisposition to autoimmunity caused by a hyperimmune response. The difference between the immune system in men and women can be due to sex hormones and environmental factors.
MHC gene
The stronger immune response is not beneficial in all cases as it makes women more susceptible to immunopathology such as autoimmunity. This has been linked to immune response components such as specific gene variants of the major histocompatibility complex (MHC).
MHC are molecules that are encoded by a set of highly polymorphic genes. MHC is crucial for the adaptive immune response. A high variety of MHC gene variants is beneficial. A study from Lund University hypothesized that gender differences in immune systems are linked to the levels of MHC diversity.
Sex bias in asthma prevalence
Asthma is characterized by sexual dimorphism which changes throughout life. In children, there is an increased prevalence of asthma in boys compared to girls. However, around puberty, this trend changes resulting in a higher frequency of asthma in girls. This change suggests that sex hormones play a key role in asthma pathogenesis.
Many factors regulate the pathophysiology of asthma including genetics, environment, respiratory mechanisms, sex hormones, and obesity. Understanding sex differences and sex hormones regulation is crucial.
Hepatitis B/C
Hepatitis B is a liver infection that is caused by a virus carried by blood and body fluids. Hepatitis B and hepatitis C are more common in male patients than female patients. Also, female Hepatitis B carriers tend to have a lower viral load than their male counterparts.
There are differences in the pathogenesis of infectious diseases caused by sex differences. Women tend to have a more intense innate, cellular and humoral immune response to vaccinations and infections than men.
Sex hormones influence the immune responses to viruses by binding to the hormone receptor expressed on immune cells. While estrogens have an immune-stimulating effect, androgens have an immune-suppressing effect.
Androgens are hormones related to male traits and reproductive activity. Androgens interact directly with the hepatitis B genome. Estrogen and estradiol receptors help protect the liver cells from inflammatory damage, apoptosis which leads to fibrosis and transformations that precede hepatitis C. The decreased estrogen receptor in men has been linked to the worse outcomes of hepatitis. The combined action of male and female sex hormones coupled with viral factors contribute to the mechanisms of sex differences in the outcome and development of hepatitis infection.
X chromosome and the link to autoimmune disease
Even though women are less vulnerable to some infectious diseases than men they are more likely to develop autoimmune diseases such as hypothyroidism or rheumatoid arthritis. A recent study conducted by researchers at UCLA in mice indicated that the cause of the higher incidence of autoimmune diseases in women is a gene called Kdm6a that is more expressed in women’s immune cells.
In this experiment, mice were bred to develop a disease like multiple sclerosis (MS). In humans, women are three times more likely to develop MS disease than men. Previous research has suggested that having two X chromosomes can account for this difference in the immune system between women and men.
To determine which genes are expressed more frequently in the T cells women’s immune cells the researchers sequenced the RNA of female and male mice and 205 human men and 294 human women. The mice that were bred without the Kdm6a gene showed fewer symptoms of the MS disease and reduced autoimmune activity in spinal cells and a greater number of intact axons.
Also, there were prominent molecular changes that occurred after the deletion of the gene. These changes included increased activity of genes involved in healthy immune response and reduced activity of genes involved in neuroinflammation.
The results from this study help elucidate why females are more prone to developing an autoimmune disease and suggest that modulating the activity Kdm6a in T cells might be a potential therapeutic target for MS and other autoimmune diseases. This also suggests that drugs like metformin, a diabetes medication that has been shown to alter Kdm6a activity, might also deserve further study.
Final remarks
Men and women differ in many aspects ranging from biological, hormonal, physiological and psychological. Recently, more attention has been brought to sex differences in the immune system of men and women.
Research has demonstrated differences in the prevalence of diseases such as asthma and hepatitis. There is also evidence for genetic differences in the expression of immune cells between women and men.
A more comprehensive understanding of the interaction between sex hormones and the immune system’s responses can lead to the development of novel, more effective therapeutic interventions and manage immune-mediated diseases.
References
Moulton, V. (2018). Sex Hormones in Acquired Immunity and Autoimmune Diseasehttps://www.frontiersin.org/articles/10.3389/fimmu.2018.02279/full
Ruggieri, A. et al. (2018). Sex-Dependent Outcome of Hepatitis B and C Viruses Infections: Synergy of Sex Hormones and Immune Responses? https://www.frontiersin.org/articles/10.3389/fimmu.2018.02302/full
Shah, R. & Newcomb, D. (2018). Sex Bias in Asthma Prevalence and Pathogenesis. https://www.frontiersin.org/articles/10.3389/fimmu.2018.02997/full
Taneja, V. (2018). Sex Hormones Determine Immune Response. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119719/
Yuichiro Itoh et al. (2019) The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J Clin Invest. 2019;129(9):3852-3863. https://doi.org/10.1172/JCI126250
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