Autoimmune diseases predominantly affect more females than males, but the underlying significance of some of the immunological differences between sexes, which stem from various genetic, hormonal, and environmental factors, is less clearly defined.
In the ACR Convergence session Bringing Sexy Back: Sex Hormone Modulation of Immune Responses in Autoimmunity, two researchers explored how sex hormones influence immune responses and potentially contribute to autoimmunity. Recorded sessions at ACR Convergence 2025 are available on demand to all registered meeting participants through October 31, 2026, by logging in to the meeting website.
Petter Brodin, MD, PhD, the Garfield Weston Chair of Neonatology and Professor of Pediatric Immunology in the Department of Immunology and Inflammation at Imperial College London, United Kingdom, and Professor of Pediatric Immunology at Karolinska Institutet, Sweden, sought to distinguish the root of some of the differences between male and female immune systems by exploring whether they stem from hormones or chromosomes. He said all prior studies comparing male and female immune systems had failed to distinguish the contribution of sex chromosomes from hormones. Therefore, he and his group decided to study individuals assigned female sex at birth and undergoing gender-affirming hormone therapy (GAHT).
“These individuals are assigned one sex at birth, and then they receive hormone therapy that reverses or completely changes their hormone profile to the opposite sex,” Dr. Brodin said. “By following the immune system over the course of this treatment, we can actually look to see which components of these healthy people’s immune system are sensitive to sex hormones.”
He noted that when individuals receive testosterone during GAHT, it appears as if the entire immune system shifts focus. The most significant difference, according to Dr. Brodin, was a reduction in the number of plasmacytoid dendritic cells (pDCs), the principal type I interferon-producing cell.
“There’s clearly a recalibration of the entire, whole system, dampening the type I interferons,” he explained.
He stressed that type I interferons and tumor necrosis factor (TNF) pathways are cross-regulated features.
“If one goes up, the other goes down,” Dr. Brodin said. “That’s something I think we haven’t paid attention to enough in our clinical practices.”
Another question he raised was, when individuals receive testosterone therapy, do these cells directly sense the sex hormone, or is there a secondary effect mediated by another sensing cell? One way to find out, he explained, is to investigate which cells express the receptors for androgens and estradiol.
“It turns out that plasmacytoid dendritic cells, both at the mRNA level and at the protein level, express more androgen receptor and estradiol receptor 2 than any other cell type, suggesting that an unrecognized function of pDCs might actually be a sort of ‘sentinel cell’ for sex hormones that can sense and regulate the other cells accordingly,” Dr. Brodin explained.
Shannon Dunn, PhD, Associate Professor of the Department of Immunology at the University of Toronto, Canada, analyzed sex differences through the lens of obesity, noting that a type I interferon signal intersects with T helper 1 (Th1) cell biology and amplifies it.
“We found that this pathway was upregulated particularly with obesity, both in humans and in mice,” Dr. Dunn said.
In her research, Dr. Dunn first sought to identify which proteins were upregulated with obesity. Her analysis of individuals with obesity showed elevated levels of inflammation, Th1, interleukin-17 (IL-17), interleukin-6 (IL-6), and dendritic cell maturation, as well as activation of interferon regulatory factor by cytosolic pattern recognition receptors.
“These pathways are upregulated in a female and not in a male, and then also many of them were upregulated in MS (multiple sclerosis) as well as in healthy people,” Dr. Dunn explained.
She also highlighted that there is a level of “interferon tone” in the immune system, even in a healthy state, and this tone seems to be higher in females than in males. This increase has downstream effects on T cells.
“In the state of obesity, there seems to be an increase in this type I interferon tone, particularly in a female, and that actually has an impact on the T cell and enhances the ability of that T cell to make interferon gamma,” Dr. Dunn said.
Don’t Miss a Session
If you weren’t able to make it to a live session during ACR Convergence 2025 — or you want to revisit a session from the annual meeting — make plans to watch the replay. All registered participants receive on-demand access to scientific sessions after the meeting through October 31, 2026.