Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing

Arthritis Rheumatol. 2019 Apr;71(4):529-541. doi: 10.1002/art.40772. Epub 2019 Feb 23.


Objective: To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA).

Methods: Citrulline- and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays.

Results: Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor α (IL-15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts.

Conclusion: To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / genetics*
  • Autoantibodies / immunology
  • B-Lymphocytes / immunology*
  • Cytokines / blood
  • Cytokines / immunology
  • ErbB Receptors / blood
  • ErbB Receptors / immunology
  • Humans
  • Leukocytes, Mononuclear / immunology
  • Receptors, Interleukin-15 / blood
  • Receptors, Interleukin-15 / immunology
  • Sequence Analysis, RNA
  • Signal Transduction / immunology
  • Transcriptome / immunology*


  • Autoantibodies
  • Cytokines
  • IL15RA protein, human
  • Receptors, Interleukin-15
  • EGFR protein, human
  • ErbB Receptors

Associated data

  • GENBANK/GSE99006