by University College London

Credit: Journal of Experimental Medicine (2025). DOI: 10.1084/jem.20241253

Women have a higher proportion of key immune cells between puberty and menopause, which may be linked to the sex hormone estrogen and explain why they are less susceptible to certain infectious diseases than men, according to a new study led by researchers at UCL.

The study, published in the Journal of Experimental Medicine, is one of the first to explore how sex chromosomes and sex hormones combine to influence the immune systems of healthy individuals across a wide range of ages and gender profiles.

Explaining the importance of the paper, Dr. Elizabeth Rosser, a senior author of the study from UCL Division of Medicine and at the Center for Adolescent Rheumatology at UCL, said, “Sex and gender are frequently overlooked in medical research, despite evidence that many females typically produce ‘stronger’ immune responses to infections such as COVID-19 than males, while also having a greater risk of developing autoimmune conditions such as lupus and rheumatoid arthritis.

“The primary sex hormones—estrogen in females and testosterone in males—are thought to play a role in these differences, as are the sex chromosomes (XX in people registered female at birth, and XY in people registered male at birth).

“However, very little is known about how immune health outcomes may change during puberty or menopause, or for transgender individuals in receipt of gender-affirming or puberty-suppressing hormone treatments.”

In order to examine how hormones and biological sex influence the production of 31 different immune cell types, the team analyzed blood samples from 283 individuals between the ages of 6 and 84 years.

Of these, 203 were cisgender females and cisgender males, including post-menopausal women receiving hormone replacement therapy (HRT). They also analyzed samples from 80 transgender females and males receiving gender-affirming or puberty-suppressing hormone treatments.

The results indicated that cisgender females (XX chromosomal background) have higher levels of specific white blood cells, known as class-switched memory B cells, than cisgender males (XY chromosomal background).

Class-switched memory B cells, which are a major component of the immune system, have undergone a process known as “class-switching” that makes them highly efficient at fighting infections that the body has encountered before. But these “specially trained” B cells may also lead to more severe symptoms if the person has an autoimmune disorder, where a person’s immune system attacks their own healthy tissues.

Crucially, researchers found that these sex differences were only seen between individuals who had completed puberty, but not yet (in the case of cisgender females) gone through menopause. Along with the fact that B cells have receptors for estrogen, this finding suggests that estrogen, which is found at much lower levels in females before puberty and after menopause, may be associated with the increase in class-switched memory B cells.

Professor Coziana Ciurtin, principal investigator of the study from UCL Division of Medicine and the Center for Adolescent Rheumatology at UCL, said, “Our study has identified some evidence that estrogen plays an important role in the abundance of class-switched memory B cells in females, but more research is required to fully understand the biological mechanisms at play.

“However, these findings could partially explain the sex differences we see in many infectious diseases, vaccine responses, and autoimmune disorders, and add to the growing evidence that sex and gender are critical factors to be considered in immunological studies.”

The authors say that despite the differences in class-switched memory B cells observed in the different groups, it is not possible to conclude that these differences are “good” or “bad” in terms of overall health.

While cisgender females do have better protection against infectious diseases such as COVID-19 and hepatitis B, this is balanced out by being more susceptible to autoimmune conditions such as lupus. For groups whose B cell populations more closely resemble those in cisgender males, the opposite could be true. Future research would be needed to address this.

The team found that in transgender males (XX chromosomal background) receiving treatment to block their production of estrogen, levels of class-switched memory B cells were significantly reduced when compared to cisgender females of the same age. These levels were comparable to those seen in cisgender males.

However, when they analyzed samples from transgender females (XY chromosomal background) who were taking estrogen to affirm their gender, their levels of class-switched memory B cells were comparable with those seen in cisgender males.

Professor Lucy Wedderburn from the UCL Great Ormond Street Institute of Child Health and Director of the Center for Adolescent Rheumatology at UCL, said, “The X chromosome carries numerous genes that are important for human immune responses, so it was critical to find out whether the effects of estrogen would be the same in cisgender females and transgender males with two X chromosomes, versus cisgender males and transgender females with only one X chromosome.

“This data from our Center demonstrates that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.”

In the samples from cisgender females aged 40–60 years who were receiving HRT, estrogen was associated with a significant increase in class-switched memory B cells. This further suggests that estrogen is only associated with this increase in people with two copies of the X chromosome.

The authors say that the research highlights the need for further high-quality, long-term studies to examine the impact of hormonal treatment on infection and autoimmunity risk across a range of sex chromosomal backgrounds and stages of life.

Dr. Hannah Peckham, first author of the study from UCL Division of Medicine, UCL Great Ormond Street Institute of Child Health, and the Center for Adolescent Rheumatology at UCL, said. “Our study demonstrates that improvements in diversity and inclusion practices within medical research will not only advance our scientific understanding of sex-biases in disease outcomes, but potentially shed light on novel strategies for personally tailored health care and potentially mitigate against health inequalities.”

More information: Hannah Peckham et al, Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes, Journal of Experimental Medicine (2025). DOI: 10.1084/jem.20241253

Journal information:Journal of Experimental Medicine

Provided by University College London

---

Explore further

Testosterone tied to incidence, progression of metabolic syndrome

https://meet.google.com/call?authuser=0&hl=en-GB&mc=KAIwAZoBFDoScGludG9fdGxncmFtZXBqb3cyogE7GgIQADICUAA6AhABSgQIARABWgIIAGoCCAFyAggBegIIAogBAJIBAhABmgEEGAEgAKIBAhAA4gECCACyAQcYAyAAKgEwwgECIAHYAQE&origin=https%3A%2F%2Fmail.google.com&iilm=1742905604441