Why Do Women Develop More Autoimmune Diseases than Men?

What is Autoimmune Disease?

Autoimmune disease is the third most common disease, globally, outpaced only by cancer and heart disease. Autoimmune disease is a condition in which the immune system mistakenly attacks healthy cells and tissues in the body and can significantly influence different organs, such as skin, blood vessels, kidney, central nervous system, etc. Normally, the immune system protects humans from harmful microorganisms like bacteria and viruses. But in autoimmune disease, the immune system mistakenly recognizes a person's own cells and tissues as "intruder" and starts to attack those cells, which leads to immune-mediated inflammation and damage to various organs. The symptoms of autoimmune diseases vary depending on the specific organs or biological processes involved. They may cause joint pain, muscle weakness, skin rashes, fever, and organ dysfunction, which can lead to life-threatening health problems. 

So far, more than 80 known autoimmune diseases have been reported based on different conditions and organs involved. Some common autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, Type 1 diabetes, inflammatory bowel disease, psoriasis, etc. (Figure 1). Since autoimmune diseases cannot be cured, treatments focus on managing symptoms, reducing inflammation, and suppressing abnormal immune responses. But none of the available treatments can truly “kick” the autoimmune disease out of the patient's body. It remains a big challenge for researchers to fully understand the mechanisms of autoimmune diseases and the genetic and immunological factors leading to the diseased states. It’s known that certain genetic predispositions can make people more susceptible to developing autoimmune diseases, as well as some environmental factors, such as infections, hormonal changes, and exposure to chemicals or drugs. However, research on autoimmune diseases is ongoing and better therapeutic strategies are urgently needed. 

Why Do Women Have Higher Risk for Developing Autoimmune Diseases than Men?

A very important question that has intrigued many scientists, physicians, and patients for decades is why women have up to a four-fold increased risk for developing autoimmune diseases than men. It’s clear that 4 out 5 autoimmune disease patients are female. For instance, in systemic lupus erythematosus (SLE) patients, the ratio of sex is 9:1 female to male, and an even higher risk is seen in Sjögren’s Disease, with an observed sex ratio in patients of 19:1 female to male.

What causes this? Researchers have proposed several factors that may play a role. One possible factor is hormones. Female sex hormones, particularly estrogen, modulate the immune response. For example, evidence has shown that estrogen can enhance the activity of immune cells like B cells and T cells and facilitate the immune response. People have proposed that females have stronger immune responses than males, leading to a higher ratio of female autoimmune disease patients, which thought to be due to a difference in T cell expression levels. Also, female hormone levels vary under certain conditions like pregnancy and may lead to the onset of autoimmune diseases. Environmental factors such as infections, stress, and chemicals may also cause autoimmune diseases, but are not likely to cause the large difference in numbers of female versus male patients. 

The most convincing explanation is genetic predisposition, since many autoimmune diseases have genetic components associated with a higher risk. Some of the genetic components are located on the X chromosome. With two X chromosomes in females compared to one X chromosome in males, females are more likely to get autoimmune diseases. Evidence to support this hypothesis is that Klinefelter syndrome patients, who are phenotypically males with two X chromosomes and one Y chromosome, appear to have a higher risk for autoimmune diseases, similar to females. Another finding to support this is that specific X-linked genes like TLR7 can escape X inactivation, which is a contributor to specific autoimmune diseases. In order to understand it better in gene level, researchers have dug deeper into the X chromosome. 

Recently, Chang’s group from Stanford University has reported that Xist ribonucleoproteins (RNP) complex with many autoantigenic components and this is an important driver to sex-biased autoimmunity. (Figure 2) As we know, females have a 46,XX karyotype and males have a 46,XY karyotype. In order to make gene expression output equivalent between males and females, the gene expression of one of the two X chromosomes in females is silenced by a long non-coding RNA (lncRNA) Xist, which is only transcribed from the silenced X chromosome and not expressed in males. Xist can bind to 81 unique binding proteins. Some of them have been proved to be autoantigens and can promote immune response. In order to confirm that Xist ribonucleoproteins (RNP) induces abnormal autoimmune response, they introduced an inducible and non-silencing allele of Xist into male mice, which allows the study of female-specific long non-coding RNA (lncRNA) in male background. By chemically inducing the expression of Xist ribonucleoproteins (RNP), they observed disease damage in the kidney, liver and lungs that can be found in severe SLE patients. Compared to non-treated male mice, the total pathology dramatically increased. This study illustrates the genetic predisposition can be the main cause to the sex-biased autoimmune diseases, especially the gene encoding Xist ribonucleoproteins in females. 

Conclusion and Future Perspectives

Autoimmune disease cases have been increasing over the years, globally. Although it’s a well-known fact that females have a higher chance to get autoimmune diseases than males, limited study has been done on gene levels, leaving the mechanisms behind it not fully clear. The Chang study provides insights into how Xist ribonucleoprotein can work as autoimmune antigenic triggers in females. Understanding genetic and molecular mechanisms underlying autoimmune disease will be very important for developing new treatment methods and supplementing current common therapies, such as B cell depletion. Further studies with larger sample sizes need to be done to confirm these results and identify the exact Xist antigens that cause autoimmune diseases. Hopefully, in the near future, these questions can be answered by scientists and autoimmune diseases can be cured. 

References

Kronzer VL, Bridges SL, Davis JM. Why women have more autoimmune diseases than men: An evolutionary perspective. Evol Appl. 2021 Mar;14(3):629–33.

Dou DR, Zhao Y, Belk JA, Zhao Y, Casey KM, Chen DC, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. 2024 Feb 1;187(3):733-749.e16.

Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010 Aug;10(8):594–604.

Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008 Sep;173(3):600–9.

Smith-Bouvier DL, Divekar AA, Sasidhar M, Du S, Tiwari-Woodruff SK, King JK, et al. A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med. 2008 May 12;205(5):1099–108.

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