The effect of sexual dimorphisms on the immune phenotype of both healthy individuals and those with autoimmunity were assessed in a study published in The Lancet Rheumatology.
According to the study authors, the current study is the first to report on the immune-cell phenotype by comparing sex and gender differences among young postpubertal cisgender men and cisgender women, both with and without juvenile-onset systemic lupus erythematosus (SLE), as well as in transgender individuals undergoing gender-affirming sex hormone treatment without juvenile-onset SLE.
Groups eligible for study participation included healthy postpubertal cisgender individuals aged 16 to 25 years; healthy prepubertal individuals aged 6 to 11 years; transgender individuals aged 18 to 19 years undergoing gender-affirming treatment (ie, testosterone in individuals who were assigned female sex at birth and estradiol in individuals who were assigned male sex at birth); and postpubertal cisgender individuals aged 14 to 25 years with juvenile-onset SLE who were age-matched with cisgender individuals without juvenile-onset SLE.
The frequencies of 28 immune-cell subsets (eg, different T-cell, B-cell, and monocyte subsets) were measured in peripheral blood mononuclear cells via flow cytometry. RNA-sequencing was used to compare sex and gender differences in regulatory T (Treg) cell phenotypes among individuals with juvenile-onset SLE, age-matched cisgender participants without juvenile-onset SLE, and age-matched transgender individuals undergoing gender-affirming sex hormone treatment.
From September 5, 2012, through November 6, 2019, peripheral blood was collected from 39 participants in the postpubertal group (17 cisgender men; mean age, 18.76 years and 22 cisgender women; mean age, 18.59 years); 14 children in the cisgender prepubertal group (7 cisgender boys; mean age, 8.90 years and 7 cisgender girls; mean age, 8.40 years); 10 individuals in the transgender group (5 transgender men; mean age, 18.20 years and 5 transgender women; mean age, 18.70 years); and 35 participants in the juvenile-onset SLE group (12 cisgender men; mean age, 18.58 years and 23 cisgender women; mean age, 19.48 years).
Results of the study showed that statistically significantly elevated frequencies of Treg cells were a key immune-cell feature distinguishing young prepubertal cisgender men from cisgender women in a similar age-group (P =.0097). In addition, Treg cells from young cisgender men vs women showed a statistically significantly increased suppressive capacity in vitro, along with a distinct transcriptomic signature significantly enriched for genes in the PI3K-AKT signaling pathway.
Further, gender-affirming sex hormones among transgender men and women resulted in multiple statistically significantly changes in the Treg-cell transcriptome, many of which enriched functional pathways that overlapped with those altered among cisgender men and women, thus underscoring a hormonal influence on Treg-cell function according to gender.
Although sex differences in Treg-cell frequency were absent and suppressive capacity was reversed in participants with juvenile-onset SLE, sex differences in Treg-cell transcriptional signatures were significantly more pronounced in those with vs without juvenile-onset SLE, implying that sex hormone signaling might be dysregulated in autoimmunity.
One of the study limitations included the difficulty involved in enrolling and collecting larger volumes of blood from rare cohorts of young individuals, particularly transgender individuals and children, which limited the ability to evaluate the phenotype and function of Treg cells. In addition, researchers did not conduct a follow-up of transgender individuals, which prevented studying the long-term effects of hormone therapy on Treg cells.
The study authors concluded, “This information helps us to understand the mechanistic pathogenesis of autoimmune disease and the bias toward cisgender women. Our study will help inform the future consideration of sex as a biological variable in inflammatory research and clinical trials.”
Robinson GA, Peng J, Peckham H, et al. Investigating sex differences in T regulatory cells from cisgender and transgender health individuals and patients with autoimmune inflammatory disease: a cross-sectional study. Lancet Rheumatol. Published online August 31, 2022. doi:10.1016/S2665-9913(22)00198-9