Women autoimmune disease risk has long puzzled scientists because disorders like lupus, rheumatoid arthritis, and multiple sclerosis affect women far more often than men. A major new study analyzing more than 1.27 million immune cells now suggests the answer may lie in sex-specific genetic programming inside the immune system itself.
The study, published May 7, 2026, in the American Journal of Human Genetics, examined blood samples from 982 healthy adults in the OneK1K cohort, including 564 women and 418 men.
Scientists Mapped Immune Differences One Cell at a Time
Researchers used single-cell RNA sequencing to profile peripheral blood mononuclear cells (PBMCs) with the 10x Genomics Chromium platform and Illumina NovaSeq 6000. In total, they analyzed 1,267,758 individual immune cells across 75 sequencing batches.
Each participant also underwent genome-wide genotyping using the Illumina Global Screening Array. This allowed scientists to directly connect DNA variants with gene activity inside specific immune cell populations.
The team classified immune cell types using the Azimuth PBMC reference pipeline and mapped sequencing reads to the GRCh37/hg19 human genome reference with STAR through the Cell Ranger Suite. They then applied SCTransform normalization and Seurat batch correction to minimize technical noise.
This high-resolution approach mattered because older bulk-tissue studies averaged signals across mixed cell populations, often masking subtle but biologically important sex differences.
Female Immune Cells Showed Stronger Inflammatory Signatures
A striking pattern emerged across multiple immune-cell types.
Genes more active in women were strongly enriched for TNF-ฮฑ signaling pathways molecular circuits that drive inflammation and immune activation. TNF-ฮฑ plays a central role in diseases such as lupus, rheumatoid arthritis, and multiple sclerosis.
Men, by contrast, showed stronger expression of genes involved in ribosomal and translational activity, the core cellular machinery responsible for protein production.
The findings suggest female immune systems may exist in a more โprimedโ inflammatory state even under healthy conditions. That heightened readiness could improve protection against infections while simultaneously increasing the risk of autoimmune misfires.
The cellular composition of the immune system also differed by sex. Women carried higher frequencies of B cells and showed stronger inflammatory and cytotoxic T-cell responses after repeated stimulation. Men had larger populations of circulating natural killer (NK) cells.
Researchers Identified More Than 1,000 Sex-Specific Genetic Switches
To determine whether DNA itself drives these immune differences, the researchers performed extensive expression quantitative trait locus (eQTL) mapping.
These analyses identify genetic variants that function like regulatory โvolume knobs,โ increasing or decreasing gene activity inside particular cell types.
The team first analyzed all participants together, then repeated the analysis separately by sex after statistically balancing sample sizes between women and men.
To classify a variant as truly sex-specific, researchers imposed strict criteria:
- The variant had to appear absent not merely weaker in the opposite sex
- Effect sizes had to differ significantly between males and females
- Variants then had to pass a formal genotype-by-sex interaction test with FDR < 0.05
The analysis uncovered more than 1,000 sex-specific eQTLs on autosomes, plus 51 validated sex-interacting eQTLs where the same DNA variant produced dramatically different effects depending on sex.
Surprisingly, these sex-dependent regulatory effects were more common on autosomes than on the X or Y chromosomes. That finding challenges the long-standing assumption that sex differences in immunity are driven mainly by sex chromosomes.
Lupus Risk Variants Were Especially Powerful in Women
Among the most clinically important discoveries were two lupus-associated variants showing strong female-biased effects.
The variant rs2099684 increased expression of FCGR3A in natural killer cells specifically in women. Another variant, rs760462, amplified expression of ITGB2 in female monocytes.
Both genes are heavily involved in immune activation and inflammatory signaling. Previous genome-wide association studies had already linked these variants to systemic lupus erythematosus (SLE), a disease affecting women roughly nine times more often than men.
The new findings provide a direct mechanistic explanation for how identical genetic risk variants can produce much stronger disease effects in female immune systems.
Why Autoimmune Drugs May Not Work the Same in Men and Women
One of the studyโs central conclusions is that many sex-specific immune mechanisms remained invisible in older research methods that averaged cells together without accounting for cell type or biological sex.
The authors argue that sex-dependent regulatory variation on autosomes may be just as important โ or even more important โ than sex chromosome biology in shaping immune differences between women and men.
The results also raise major implications for medicine. Drugs targeting inflammatory pathways such as TNF-ฮฑ signaling may not behave identically across sexes because the immune cells themselves are genetically regulated differently.
Researchers say the new cell-type-resolved map of sex-biased eQTLs provides a valuable framework for interpreting autoimmune disease genetics through a sex-aware lens and could help guide the design of future clinical trials and personalized therapies.
Reference
Yazar, S., Alquicira-Hernandez, J., Wing, K., 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), 1006โ1023. https://doi.org/10.1016/j.ajhg.2026.04.003
