Autoimmune diseases encompass around 80 different deleterious disorders that predominantly affect women. Such diseases greatly affect the quality of life in individuals and is a leading cause of death in both young and middle-aged women.

Due to the complexity of the disease, it is difficult to understand exactly how auto-immune conditions arise. Ongoing research aims to understand how autoimmune conditions come about and, importantly, why they disproportionately affect women.

What is an autoimmune disease?

As mentioned, autoimmune disease is an umbrella term given to the more than 80 conditions which are currently identified. This includes rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis

A person’s body with an autoimmune condition attacks its own cells and tissues. This is because their immune system does not recognise its own cells as ‘self’, but rather, as foreign entities, just as it would recognise a virus or bacteria. Hence, the immune system attempts to destroy the cells it targets as it would fight off an infection.

The immune surveillance system is highly precise and complex. However, when it malfunctions, it can be extremely detrimental to the individual. Depending on the type of cell the immune system attacks, it can result in a myriad of issues. These can range from mild to severe symptoms and greatly affect the quality of life of individuals with the condition.

Who are more susceptible to autoimmune conditions?

Around 8% of the world’s population have autoimmune conditions, with 78% of this disproportionately affecting women. The reason for this staggering statistic is largely unknown. But research is being done to try and understand the underlying biological basis for this.

We will briefly run through some of the potential theories as to how autoimmune conditions arise and explore the reasons why women are more affected than men.

Role of genetics

Autoimmune conditions are multifactorial. This means there could be many different reasons as to why the onset of the disease is triggered. Genetics, both in men and women, play a crucial part in determining one’s susceptibility to disease.

Genes are passed down from both mother and father to make up the unique genome of the individual. However, there is not one ‘autoimmune gene’, meaning it is often difficult to analyse the hereditary nature of the disease.

Research shows that certain autoimmune diseases demonstrate a strong hereditary link, with individuals showing a much higher risk of acquiring the disease if their relatives have been diagnosed. This is seen in the case of multiple sclerosis and SLE.

X chromosome inactivation

Females possess two X chromosomes—one inherited from the mother and one from the father. The X-chromosome contains vital information required in numerous processes, including the production of sex hormones and immune responses.

As females have two X chromosomes, the activity of certain genes on one of them is permanently switched off during early development. This is to ensure that there isn’t ‘double’ the activity and, hence, excessive gene activity. This process of switching off can go wrong and, therefore, the activity of certain immune-related genes can be skewed.

An example of this can be seen in patients with Scleroderma, an autoimmune condition which affects the skin or vasculature of individuals. The disease results in the over-production of connective tissue. A study shows a clear and significant correlation between X chromosome inactivation and the disease in female patients.

The X chromosome contains the largest number of immune-related genes. A comprehensive review in the International Journal of Molecular Sciences explores the concept of X chromosome inactivation and autoimmunity in females. The detailed review explores how the overexpression of specific immune-related genes may promote autoimmunity in females.

Recent findings on female sex-biased autoimmunity

A breakthrough study published on February 1^st  2024 establishes an exciting new finding. They found that proteins, called XIST, coating the RNA on the X chromosome, promote autoimmunity in females. The study is an exciting step in understanding why autoimmune diseases are so prevalent in women.

But there are other factors which could also contribute to the development of autoimmune conditions in women.

Role of female sex hormones

One of the most obvious differences between the biology of men and women is the presence of the female sex hormones, particularly estrogen and progesterone. It is thought that the drastic changes in these hormones, e.g., during puberty and menopause, can make women more susceptible to autoimmune conditions.

A study in Taiwan analysed the prevalence of acquiring SLE in young girls. They found that the likelihood of girls acquiring SLE increased from 0.65 per 100,000 girls at age 1 to 34.6 at age 15. This is compared to an increase from around 0 cases per 100,000 to only 7.8 at age 15 in boys.

This remarkable difference in statistics indicates an important shift in immune responses during the onset of puberty in females compared to males. Sex hormones such as estrogen have an important role in regulating immune responses. The hormones play a key part in inducing the development, activation and maintenance of specific immune cells, e.g., B and helper T cells.

Previous research tries to understand how the presence of these hormones, e.g., estrogen, can dictate how susceptible women are to developing autoimmune conditions. Conflicting results show that in some autoimmune conditions, such as multiple sclerosis and rheumatoid arthritis, estrogen plays a protective role against the disease. However, in other cases, it may cause autoimmune diseases such as SLE.

Future work

More research is needed to understand the role of female sex hormones in autoimmune conditions, and how this interacts with other factors such as genetics and the environment. This may help in understanding why autoimmune disorders are much more prevalent in women than men.

Research published in MDPI journals, including Biomedicines explores research on autoimmune disorders. If you would like to read more or submit your work, please see MDPI’s full list of journals here.