The immune system is an elegant and highly refined network of cells, organs, and proteins, but in approximately 10% of the world’s population, it goes haywire. Autoimmune diseases occur when your body’s own immune system, normally responsible for protecting against invading pathogens, turns on itself. This phenomenon can be described as a loss of self-tolerance, a term that refers to a highly controlled process during the development of your immune cells that teaches your cells what to attack and what to leave alone; what is foreign and what is self. Autoimmunity occurs when this tolerance is lost – the immune system mistakenly attacks your own body, resulting in significant damage.
After decades of research, scientists are beginning to uncover why autoimmune diseases occur, but many questions remain. One of these questions is why females get more autoimmunity than males. It is estimated that approximately 80% of diagnosed individuals are females, with many autoimmune diseases exhibiting a clear sex bias. For example, the male-to-female ratio is 1:3 in Multiple Sclerosis, 1:7 in Hashimoto’s Disease, and 1:9 in Systemic Lupus Erythematosus. While it is an ongoing effort to understand this sex bias in autoimmune disease, there are several factors that likely play a role.
Sex Hormones Beyond Reproduction
Most people know of estrogen as a female sex hormone primarily responsible for the development and regulation of reproductive systems, but this hormone plays a major role in the immune response. In fact, many immune cells have the necessary proteins that allow them to respond to estrogen. This means that estrogen can control the development, survival, and activity of both the non-specific, rapid arm of the immune response (innate immunity), as well as the specific, targeted arm (adaptive immunity). As a result, females exhibit stronger innate and adaptive immune responses to pathogens compared to males. For example, responses to vaccines, which rely on adaptive immunity, are stronger in females. Some scientists have theorized that this is an evolutionarily conserved feature – estrogen promoting strong immune responses would protect offspring from infectious disease, which was historically a leading cause of death for much of human history. Testosterone, the male reproductive hormone, tends to regulate the immune response rather than activate it. Interestingly, in many autoimmune diseases, the female bias becomes increasingly apparent after puberty, when the levels of reproductive hormones increase dramatically. For example, pediatric Multiple Sclerosis exhibits a 1:1 male-to-female ratio, which climbs to 1:3 following the onset of puberty. This suggests that high levels of estrogen in females can activate the immune system, leading to autoimmunity if self-tolerance is lost. Ultimately, differences in sex hormones may partially explain why females are at a higher risk for autoimmune diseases than males.
Sex Chromosomes Do More Than Determine Sex
Female sex is characterized by XX chromosomes, while male sex is characterized by XY chromosomes. The X chromosome contains many of the genes responsible for producing the large number of proteins that your body needs to function. Since females have two X chromosomes while males only have one, the body has developed a clever way to control the levels of gene expression, ensuring that the doses of genes are equal between the two sexes. X chromosome inactivation is a process that randomly selects and silences one X chromosome in female cells, allowing only the genes from the other X chromosome to be expressed. However, this mechanism sometimes fails, with 15% of genes on the silenced X chromosome escaping inactivation and being expressed on both X chromosomes. This means that some genes are expressed at a level that is higher in females than in males. This becomes a concern because the X chromosome contains the highest number of immune-related genes in the whole human genome. In fact, genes that have been identified to commonly escape X chromosome inactivation are primarily related to activation of the immune response and have been linked to a higher risk of developing autoimmune diseases. Ultimately, overexpression of immune-related genes on X chromosomes in females is another factor driving the sex bias in autoimmune diseases.
The Environment: An Outside Influence
While hormones and genetics can explain some of the sex disparity in autoimmune diseases, they are not the only culprits. Scientists conduct twin studies, where they examine sets of identical twins with the same DNA and monitor who develops an autoimmune disease. They found that if one twin develops an autoimmune disease, the other twin only has a 20–40% chance of also developing an autoimmune disease, with exact rates varying for each disease condition. Thus, external environmental factors must also be involved in this process. Some environmental and lifestyle factors that have been linked to a higher risk of developing autoimmunity include smoking, obesity, and viral infections, like Epstein-Barr Virus (EBV) and SARS-CoV-2.Although the exact mechanisms can vary, environmental factors can lead to DNA damage, alter gene expression, change the structure of proteins, and disrupt the body’s natural protective barriers. The overall outcome is often abnormal activation of both the innate and adaptive immune responses. For females who are genetically and hormonally predisposed to overactivation of the immune response, these environmental triggers can increase the risk of autoimmune diseases even further.
The Research Road Ahead
Clearly, the female bias in autoimmune diseases is a complex interaction of genetic, hormonal, and environmental factors. While progress has been made on this topic, there is still much work to be done. It wasn’t until the 1990s that females were routinely included in clinical trials – only about 30 years ago, despite females experiencing the greatest burden of autoimmune diseases. As a result, much of the information about these conditions has been shaped by research that underrepresented females. We now know that females can differ from males in disease symptoms, immune responses, and responses to treatment plans. This can result in delayed diagnosis or even misdiagnosis and inappropriate treatment because males have been used as the framework for symptom identification and treatment plans. Ongoing research brings us closer to understanding why autoimmune diseases affect females and males differently and how we can use that knowledge to improve care for everyone.
Carmen Ucciferri
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