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

Nat Commun. 2021 Aug 17;12(1):4977. doi: 10.1038/s41467-021-25246-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Citrullinated Protein Antibodies / genetics*
  • Anti-Citrullinated Protein Antibodies / immunology
  • Anti-Citrullinated Protein Antibodies / metabolism*
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Autoantibodies / immunology
  • Cell Line
  • Chemokines, CC
  • Cohort Studies
  • Genetic Predisposition to Disease
  • HLA-DR Serological Subtypes
  • Humans
  • Killer Cells, Natural
  • Leukocyte Common Antigens
  • Matrix Metalloproteinase 3
  • Monocyte Chemoattractant Proteins
  • Myeloid Cells
  • Synovial Membrane / metabolism*
  • T-Lymphocytes
  • Up-Regulation


  • Anti-Citrullinated Protein Antibodies
  • Autoantibodies
  • CCL13 protein, human
  • CCL18 protein, human
  • Chemokines, CC
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • Monocyte Chemoattractant Proteins
  • Leukocyte Common Antigens
  • MMP3 protein, human
  • Matrix Metalloproteinase 3