Single-cell sequencing of immune cells from anticitrullinated peptide antibody positive and negative rheumatoid arthritis

TLDR

Anti‑citrullinated peptide antibody (ACPA) status in rheumatoid arthritis (RA) reveals disease heterogeneity with unknown immunopathological mechanisms. The study aims to profile CD45+ hematopoietic cells from peripheral blood or synovial tissues of ACPA+ and ACPA- RA patients using single‑cell RNA sequencing to identify immune cell subsets contributing to RA subtypes. Single‑cell RNA sequencing of CD45+ cells from peripheral blood or synovial tissues of both ACPA+ and ACPA- RA patients was performed to delineate immune cell subsets involved in RA subtypes. The study found that ACPA- RA synovial tissues exhibit up‑regulated CCL13, CCL18, and MMP3 in myeloid cells, reduced HLA‑DRB5 and cytotoxic/exhaustion gene expression, and increased infiltration of CCL13/CCL18‑positive cells, whereas the HLA‑DR15 haplotype is associated with higher disease activity in ACPA+ RA, underscoring distinct pathogenic pathways and the need for ACPA‑guided precision therapy.

Abstract

The presence or absence of anti-citrullinated peptide antibodies (ACPA) and associated disparities in patients with rheumatoid arthritis (RA) implies disease heterogeneity with unknown diverse immunopathological mechanisms. Here we profile CD45+ hematopoietic cells from peripheral blood or synovial tissues from both ACPA+ and ACPA- RA patients by single-cell RNA sequencing and identify subsets of immune cells that contribute to the pathogenesis of RA subtypes. We find several synovial immune cell abnormalities, including up-regulation of CCL13, CCL18 and MMP3 in myeloid cell subsets of ACPA- RA compared with ACPA+ RA. Also evident is a lack of HLA-DRB5 expression and lower expression of cytotoxic and exhaustion related genes in the synovial tissues of patients with ACPA- RA. Furthermore, the HLA-DR15 haplotype (DRB1/DRB5) conveys an increased risk of developing active disease in ACPA+ RA in a large cohort of patients with treatment-naive RA. Immunohistochemical staining shows increased infiltration of CCL13 and CCL18-expressing immune cells in synovial tissues of ACPA- RA. Collectively, our data provide evidence of the differential involvement of cellular and molecular pathways involved in the pathogenesis of seropositive and seronegative RA subtypes and reveal the importance of precision therapy based on ACPA status.