New research explains differences between men's and women's immune systems

It has long been known that there are gender differences in our immune system. These differences are regulated both by genetics and by sex hormones. However, immunological comparisons between men and women can never fully distinguish the significance of genetic versus hormonal variations. 

Now, a Swedish research group led by Karolinska Institutet and Uppsala University has conducted a unique study analysing the regulation and adaptation of the immune system over time in 23 trans men who have undergone gender-affirming testosterone treatment. 

“We have followed individuals who were assigned female sex at birth and later received testosterone treatment in adulthood. Their genetic profile remains unchanged, while their hormone profile shifts entirely from typically female to male hormone levels,” says Petter Brodin, paediatrician and professor of paediatric immunology at the Department of Women's and Children's Health, Karolinska Institutet, who led the study together with Nils Landegren, assistant professor at Uppsala University. “This unique change allows us, for the first time, to identify which parts of a person's immune system are directly regulated by sex hormones rather than genetic sex differences.”

The researchers can now demonstrate that increased testosterone levels and the accompanying reduction in estrogen particularly affect the balance between two crucial immune signaling systems: antiviral interferon type 1 (IFN-1) and proinflammatory signals such as tumour necrosis factor alpha (TNFα). 

The immune system changes throughout life

They also have a hypothesis about why the immune system needs to be dynamically regulated by hormones throughout life.

“All individuals must be able to adjust their immune systems over the course of their lives to be optimally regulated for the conditions and challenges we face. During puberty and sexual maturation, new demands arise, and the immune system must be regulated differently to enable pregnancy in women and muscle growth in men,” says Petter Brodin.

By regulating these key functions via sex hormones, this can be achieved, and in women, it is dynamically controlled even during a menstrual cycle,” he adds.

The results of the study open an entirely new field of research, according to Petter Brodin.

“The newfound knowledge will help us better influence people's immune systems even without using sex hormones. For example, new drugs can be developed to impact these regulatory mechanisms and thus rebalance the immune response, especially for women with the autoimmune rheumatic disease SLE,” he explains.

However, the results also have a more direct implications for transgender individuals.

“This research is also of crucial for transgender individuals undergoing gender-affirming hormone therapy, and I believe that this group deserves significantly more scientific attention and follow-up to ensure their long-term health,” says Petter Brodin.

The research was funded by the Knut and Alice Wallenberg Foundation, the Swedish Society for Medical Research, the Swedish Research Council, Karolinska Institutet and the European Research Council (ERC).

Forskargruppen bakom studien. Från vänster: Ziyang Tan, Jun Wang, Hugo Barcenilla, Laura Gonzalez, Petter Brodin, Kanth Tadepally, Anette Johnsson, Rikard Forlin. Foto: Linnea Bengtsson

Publication: "Immune system adaptation during genderaffirming testosterone treatment", Tadepally Lakshmikanth, Camila Consiglio, Fabian Sardh, Rikard Forlin, Jun Wang1, Ziyang Tan, Hugo Barcenilla, Lucie Rodriguez, Jamie Sugrue, Peri Noori, Margarita Ivanchenko, Laura Piñero Páez, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Henrik Ryberg, Åsa Hallgren, Christian Pou, Yang Chen, Jaromír Mikeš, Anna James, Per Dahlqvist, Jeanette Wahlberg, Anders Hagelin,  Mats Holmberg, Marie Degerblad, Magnus Isaksson, Darragh Duffy, Olle Kämpe, Nils Landegren, Petter Brodin, Nature online September 4, 2024. 

Facts: Men's and women's immune systems differ 

Men are more severely affected by certain infectious diseases such as COVID-19, HIV and tuberculosis. Additionally, women generally respond better to vaccinations, but also experience side effects more frequently.

On the other hand, almost all autoimmune diseases disproportionately affect women, which is most evident in conditions like Sjögren's syndrome and systemic lupus erythematosus (SLE), where nine out of ten affected individuals are women.

Source: Petter Brodin