New Study Provides Genetic Clues to Autoimmune Disease Risk in Women

Women are disproportionately affected by many autoimmune diseases, but the biological reasons behind these differences are still not fully understood. A new study, published in May 2026, has identified sex-specific differences in immune cell populations, gene activity, and genetic regulation that may help explain why female immune systems are more prone to autoimmune disease.

Researchers analyzed more than 1.25 million immune cells from 982 healthy individuals using single-cell RNA sequencing.

This approach allowed them to examine individual types of immune cells rather than averaging signals across whole blood samples, revealing differences that can be hidden in bulk analyses.

They found that males and females differed in the proportions of several immune cell types.

Females had higher proportions of B cells, CD4+ naive T cells, regulatory T cells, and one type of natural killer cell, while males had higher proportions of CD14+ monocytes, dendritic cells, several memory T cell populations, and other natural killer cells.

Differences also appeared in gene activity.

Female-biased genes across several immune cell types were enriched in pathways involved in inflammation, including TNF-alpha signaling, while male-biased genes were more strongly associated with ribosomal functions such as protein production and RNA processing. The researchers found that most of these sex-biased genes were located on autosomes rather than the X or Y chromosomes, suggesting that differences between male and female immunity extend well beyond the sex chromosomes.

The team also examined expression quantitative trait loci, or eQTLs, genetic variants that influence how strongly particular genes are expressed. They identified more than 1,000 sex-specific eQTLs, along with additional genetic variants whose effects differed between males and females. Many of these regulatory differences were specific to particular immune cell types.

Two findings were particularly relevant to autoimmune disease.

The researchers identified female-biased expression and sex-specific genetic regulation involving FCGR3A in natural killer cells and ITGB2 in monocytes. Both genes have previously been associated with systemic lupus erythematosus or related autoimmune pathways. Lupus is one of the autoimmune diseases with the strongest sex imbalance, occurring far more often in women than in men.

Importantly, the study looked at immune cells under baseline conditions rather than during infection or active disease.

The researchers suggest that these underlying differences may create distinct starting points for male and female immune responses, which could become more pronounced when the immune system is activated.

The findings add to growing evidence that sex can influence immune function at the cellular and genetic levels. Understanding these differences could ultimately help researchers better explain sex-related differences in autoimmune disease susceptibility and develop more individualized approaches to studying and treating autoimmune conditions.

Citation

Yazar, S., Alquicira-Hernandez, J., Wing, K., Senabouth, A., Andersen, S., Fairfax, K. A., Hewitt, A. W., Powell, J. E., & Ballouz, S. (2026). The impact of sex on the immune system explored at the single-cell level. American journal of human genetics, 113(5), 1006–1023. https://doi.org/10.1016/j.ajhg.2026.04.003