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.
Highlights
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
Using unsupervised graph-based clustering, we identified 25 clusters in peripheral blood mononuclear cells (PBMCs), which consisted of three major populations, B cells, T/Natural Killer (NK) cells, and myeloid cells, by examining the expression of canonical markers CD3D, CD79A, CD14, FCER1A, FCGR3A, IL3RA, NKG7, PPBP, and MZB1 (Fig. 1b, Supplementary Fig. 1a)
We identified a total of four clusters of B cells in PBMCs from all individuals by comparing the expression of IGHD, CD27, IGHM, IGHG1, IGHG3, IGHA1, and MZB1; these B cell clusters included naïve B cells, memory-unswitched B cells, memory-switched B cells, and plasma B cells (Supplementary Fig. 1b)
Summary
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. 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 apply single-cell RNA sequencing (scRNA-seq) to characterize the cell composition, proportion, gene expression signature, and developmental trajectories of CD45+ cells in the peripheral blood and synovial membrane of ACPA+ and ACPARA patients. We present this single-cell immunological landscape and identify immune cell types in ACPA- RA that might contribute to disease development
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