Background/Purpose: Males and females have altered immune responses resulting in variation in autoimmune risk. Sex differences exist in the frequency and activity of immune-cell subsets but mechanisms underlying sexual dimorphism remain unknown. Our previous work identified a link between immune cell function and lipid metabolism. We hypothesised that sex hormones could influence immune cell differentiation via changes in lipid metabolism and this could be altered in autoimmune diseases such as juvenile-onset systemic lupus erythematosus (JSLE) that emerges during puberty and has a strong female prevalence.

Methods: Flow cytometry and qPCR were used to measure metabolic marker expression on 44 immune cell subsets from 39 teenage healthy controls (HCs, 17 male, 22 female, mean age 19), 35 age matched JSLE patients (12 male, 23 female, mean age 19), pre puberty HCs (10 males and 10 females, mean age 8) and individuals with gender dysphoria undergoing cross-sex hormone therapy (10 biologic males and 10 biologic females). Analysis of metabolic biomarkers including lipoprotein composition was performed on matching serum using nuclear magnetic resonance.

Results: HC responder (Tresp) and regulatory (Treg) T-cell subsets displayed the strongest immune profile differences by sex with significantly increased Tregs (p= 0.036) and reduced Tresp (p= 0.001) frequencies in males compared to females. HC Male Tregs had an increased suppressive capacity, IL-4 production (p= 0.019) (supported by increased GATA-3 expression) and plasma membrane glycosphingolipid (GSL) expression (p= 0.038) compared to Tregs from HC females. GSL changes were mirrored by increased expression of GSL synthesis enzyme UGCG (p= 0.042) in male Tregs, suggesting a sex-specific alteration in lipid metabolism related to Treg function.

Metabolomic lipoprotein analysis of matching serum revealed that teenage HC males had significantly reduced atheroprotective high density lipoprotein subsets and increased atherogenic very low density lipoprotein (VLDL) subsets compared to HC females. These differences were not observed pre-puberty but were induced appropriately by sex hormone treatment in gender dysphoria individuals; suggesting that sex hormones regulate lipid metabolism in vivo.

VLDL subsets from HC males were preferentially enriched with triglycerides and correlated positively with activated Treg subsets compared to VLDL from HC females where no such relationship was seen. Furthermore, Tregs cultured with VLDL isolated from either HC males or females recapitulated the male and female Treg phenotype respectively. Strikingly, sex differences in Treg frequency, phenotype, lipid metabolism and serum lipoproteins were lost in patients with JSLE. This loss of sexual dimorphism in JSLE patients involved the development of a more atherogenic metabolomic profile and pro-inflammatory T-cell phenotype in females.

Conclusion: Potential defects in sex hormone signalling in patients with JSLE may lead to a loss of differential male/female lipid taxonomy. Defective lipoprotein metabolism in JSLE could alter immune cell plasma membrane lipids and immune cell function and contribute to increased cardiovascular risk in female JSLE patients.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-differences-in-autoimmunity-and-cardiovascular-risk-could-be-associated-with-altered-treg-phenotype-and-lipoprotein-metabolism/