Background/Purpose: Sex differences in the immune system may contribute to o an increased incidence of autoimmunity in women and an increased susceptibility to infection and cancer in men. Human neutrophils, which have a putative role in systemic lupus erythematosus (SLE) disease initiation, propagation and tissue injury, display sexual dimorphism. This is characterized in healthy controls by female neutrophils exhibitingheightened type I-interferon (IFN) response and enhanced activation and NET formation compared to males, while men have less mature and activated neutrophils compared to women. SLE has a significant female bias (9:1 ratio). However, men with SLE often have very severe disease. It is not currently well understood if there are different immunological drivers in lupus between men and women and if sex differences in immune cells are present in SLE. There is a subset of neutrophils in SLE called low density granulocytes (LDGs) that have been reported to have important pathogenic roles in the disease but whether these cells exhibit sexual dimorphism is also not known. Understanding sex differences in immune cell subsets in SLE may improve understanding of disease heterogeneity and could provide insight for sex- specific treatment targets.

Methods: Age matched male and female patients with SLE were recruited from a comprehensive lupus clinic. Peripheral blood mononuclear cells (PBMC), LDGs and normal dense neutrophils (NDN) were purified and then subjected to cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) via the 10x platform. Downstream analysis was performed with Cell Ranger and the Seurat package in R. Functional assays were performed.

Results: Six patients with SLE (3 male and 3 female) have been analyzed thus far. The average age in years was 36.7 and 36.3 for males and females, respectively. Average SLEDAI was 6.7 and 4.7 male and female, respectively. All patients were on less than or equal to 15 mg of daily prednisone. There was significant heterogeneity between males and females in neutrophil analysis by CITE-Seq compared to other immune cells. Overall, females had an increased proportion of a type I IFN-stimulated gene (ISG)^hi LDG cluster compared to males. Female LDGs had a higher IFN-I signature score. Female NDNs were similarly enriched in the ISG^hi cluster and also had a higher IFN-I score compared to males. Male LDGs and NDNs were enriched in less mature neutrophil clusters. Other cell types did not display as much heterogeneity.

Conclusion: These preliminary results show sex differences in SLE by single cell transcriptomics with much of the heterogeneity arising from the neutrophils. More patients are currently being recruited to further understand neutrophil heterogeneity and functional implications in male and female lupus. This information may provide insight into SLE heterogeneity between sexes and could lead to stratified lupus treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophils-in-systemic-lupus-erythematosus-demonstrate-heterogeneity-based-on-sex/