Many diseases don’t discriminate, but autoimmune disorders are more common in women than in men. While the exact distribution varies for each disease, women represent about 90% of lupus, Sjögren’s syndrome, and Hashimoto’s thyroiditis cases (1). Understanding the biological basis of this disparity could be the key to developing drugs to treat these disorders.
Susan Kovats, an immunologist at the Oklahoma Medical Research Foundation, examines the role that sex hormones play in regulating the immune system. To do so, she studies changes in immunity in male and female mice that have undergone surgical removal of reproductive organs or genetic knockout of specific hormone receptors on immune cells.
Kovats and her colleagues discovered that androgens, a class of hormones present in higher quantities in males, bind to receptors on type 2 innate lymphoid (ILC2) cells to preserve their immune regulatory function (2, 3). She is interested in exploring how androgens alter gene expression patterns in ILC2 cells and how this affects sex differences in autoimmunity and infection.
Why do some autoimmune diseases preferentially occur in women?
There are two main ideas, and one is chromosomal. Males only have one copy of the X chromosome, so only one copy of a gene on the X chromosome can be expressed. Females have two copies of the X chromosome, so they might have two copies of each gene. In each cell, one of those X chromosomes is generally shut off. But X inactivation is somewhat incomplete, and there are some regions where the inactive X is not completely inactive, which allows that second copy of the gene to be expressed.
Some genes involved in the immune system are in regions where the X chromosome is not completely shut off. One gene that we’re interested in, Toll-like receptor 7, is involved in responding to viruses. Female cells have higher triggering of this receptor. That can lead to more type I interferon, which is actually a driver in several of those female-biased diseases like lupus.
The other school of thought centers on the sex hormones themselves. Sex hormones may seem like a bunch of messy molecules running around in the body, but they actually regulate gene expression. They help to control the accessibility of genes by regulating chromatin conformation or DNA methylation status. Immune cells express receptors for androgens, estrogens, and progesterone to various degrees, and researchers are learning about how these receptors regulate genes. Some of the genes in the type I interferon pathway are regulated by estrogen receptors, so estrogens might push those pathways forward.
How can researchers use this information to develop drugs for autoimmune diseases that disproportionately affect women?
Are there selective estrogen receptor modulators — small molecules that bind estrogen receptors — that could alter the function of the immune cells to shut them off? Can we change estrogen receptor signaling in those particular cells in a way that's analogous to using estrogen receptor blockers to prevent breast cancer from growing? That is tricky, because we don't want to cause side effects in other tissues, especially in someone with a chronic autoimmune disease who might have to take this drug for the rest of her life.
Another possibility focuses on differences in gene expression because of X chromosome inactivation or estrogen regulation of genes. Toll-like receptor 7 is overexpressed in females, so we may be able to find a drug to shut off its signaling. Of course, we don’t want to shut signaling off completely, because this is the same molecule that people need to fight off infections.
What are the greatest challenges in studying sex differences in autoimmunity?
Humans are messy. We have different sex hormone levels at different times in our lives. Women can be at different stages of their cycles. They may be on birth control. They may have had a hysterectomy or an ovariectomy. Researchers need to pay more attention to the hormonal and organ status of the people they study.
If we deprive mice of hormones by gonadectomy or receptors through gene knockouts, we see effects all over the body. Sometimes it's hard to pinpoint those effects to any one particular kind of cell, and that leads to a certain amount of messiness and inconclusiveness. It's important to be as focused as possible when knocking out a receptor to avoid changing hormone metabolism in the whole mouse.
What influence would you like your research to have?
I hope that people will take possible sex differences into account and think about the fact that pathways could operate differently in males and females. The development of drugs, therapies, or solutions might need to be sex specific or age specific in cases like post- or premenopausal women. Everyone is interested in personalized medicine, but sometimes they don't personalize it in that somewhat obvious way. It's my hope that what we're learning about how the immune system might work differently in females and males and how it's regulated by hormones could help inform treatment someday.
This interview has been condensed and edited for clarity.
References
- Natri, H., Garcia, A.R., Buetow, K.H., Trumble, B.C. & Wilson, M.A. The pregnancy pickle: Evolved immune compensation due to pregnancy underlies sex differences in human diseases. Trends Genet 35, 478–488 (2019).
- Kadel, S. et al. A major population of functional KLRG1– ILC2s in female lungs contributes to a sex bias in ILC2 numbers. ImmunoHorizons 2, 74-86 (2018).
- Kovats, S. et al. Androgen receptor activity underlies sex differences in lung-resident ILC2 functional responses during influenza virus infection. J Immunol 204 (2020).
