Novel Study Offers Clues to Sex Bias in Lupus Incidence

Avery Hurt

September 12, 2022

Systemic lupus erythematosus (SLE), or lupus, shows a marked sex bias, affecting about nine females for every one male, according to Susan Kovats, PhD, who studies sex differences in immunity at the Oklahoma Medical Research Foundation in Oklahoma City. This characteristic of lupus suggests that hormones are involved in the pathogenesis of the disease. It also suggests, Kovats said, that the X chromosome might play a role.

Though studies since the 1970s have indicated a significant role for hormones, the issue is still complex and not well understood, and relatively little research has been done on the molecular mechanisms that might be responsible. This may be because of difficulties with influencing the immune system in vitro, said George A. Robinson, PhD, of University College London's Centre for Rheumatology.

Dr George Robinson

But Robinson and his team found a unique way of investigating the role of sex chromosomes and hormones in the inflammatory profiles across subjects of different sex, gender, age, and disease status. In research published online in The Lancet Rheumatology, Robinson and his team looked at immune cells taken from both cisgender men and women and transgender men and women, and thus were able to "get a more physiological view of what sex hormones are doing to the immune system," he said.

Kovats agreed that it was a useful approach. "The transgender people provided an opportunity to effectively separate sex hormone levels from chromosome content," she said in an interview.

Methods and Findings

Peripheral blood mononuclear cell (PBMC) samples were taken from cisgender individuals with and without juvenile-onset lupus and assessed for 28 immune-cell subsets, including different T-cell, B-cell, and monotype subsets. Subjects included 39 postpubertal cisgender men and women (17 men and 22 women) who did not have juvenile-onset lupus, and 35 postpubertal cisgender men and women (12 men and 23 women) who did have juvenile onset lupus. All were aged 16-25 years. The transgender group included five transgender men and five transgender women (aged 18-19) who were undergoing gender-affirming sex hormone treatment.

The analysis found that one of the key differences between young postpubertal cisgender men and age-matched cisgender women was that the men had significantly elevated frequencies of regulatory T cells (T-reg cells), and the T-reg cells from young cisgender men had greater suppressive capacity in vitro than did those from cisgender women. In addition, RNA sequencing data from isolated T-reg cells showed the transcriptomic signature of the cisgender men's T-regs were significantly enriched for genes in the P13K-AKT signaling pathway. The frequency of T-reg cells was not influenced by sex hormones, but their transcriptomic profile was affected.

"These results are beginning to give us an indication of which genes might be differentially regulated by sex hormones and how these are associated with autoimmunity," Robinson said. "We've also found that, depending on whether you're a cisgender man or woman, you may have a different pathogenic process to developing lupus. It's not necessarily that one mechanism drives the disease across both sexes."

New Approaches, Better insights

Kovats was particularly impressed by the methods of this study. "It was a natural study, the kind of thing we can usually do only in mice," she said.

Dr Susan Kovats

"One problem with studies on the effects of hormones in disease is that historically researchers have not paid that much attention to the actual hormone levels in the humans they studied," she said. "They might look at 100 women and 100 men, roughly between the ages of 20 and 50. We're starting to see more, but there aren't a lot of studies correlating numbers of cells in blood with actual hormone levels in the person. And as we know, just because someone's a certain age doesn't mean that they have a textbook hormone level. Early menopause, birth-control pills, many things can affect those levels."

The researchers hope that these findings will shed light on the mechanisms that create sexual bias in autoimmune diseases, particularly lupus, as well as help researchers to better understand the innate and adaptive immunological differences between men and women. It could also be useful in the clinical setting, Robinson said.

Because of the extreme sex bias in lupus, doctors see far more women with the illness than men. When they do see men with lupus, they need to be able to consider how the patient's sex affects the development and course of the disease. "I think that people need to start looking at patients as clinically different, depending on their sex and gender," he said. Information like that analyzed in this study could help with that. This could be especially important because as Kovats pointed out, although men get lupus far less often than women, when they do have it, they tend to have more severe disease.

Help From Machines

This study was groundbreaking in another area as well. The researchers used machine learning to analyze the data. "We've started working a lot more with these analysis methods to try to answer as much as we can with these smaller data sets," Robinson said. "Rather than the conventional analysis that we would typically perform, we're able to use machine learning and artificial intelligence to try and learn from the data and increase the numbers that we're working with by using a training data set. This allows us to interrogate the data with a lot more precision."

The authors declared no competing interests.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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