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Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis
  1. Maximilian F Konig1,
  2. Jon T Giles2,
  3. Peter A Nigrovic3,4,
  4. Felipe Andrade1
  1. 1Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, New York, USA
  3. 3Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
  4. 4Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Felipe Andrade, Division of Rheumatology, Johns Hopkins University School of Medicine, Mason F Lord Building Center Tower, Suite 6000, 5200 Eastern Avenue, Baltimore MD 21224, USA; andrade{at}


Background Anti-citrullinated protein antibodies (ACPAs) are the hallmark of rheumatoid arthritis (RA). Protein citrullination is believed to drive autoantigen selection in RA. Nonetheless, several autoantigens in RA are targeted as native (unmodified) proteins. Here, the study of hnRNP A2/B1 (RA33) provides a framework to understand the humoral response to native and citrullinated autoantigens in RA.

Methods RA synovial fluid (SF) cells were analysed by immunoblotting and mass spectrometry. RA33 was cloned from RASF cells and splice variants expressed as recombinant proteins. Antibodies against native and citrullinated RA33 were characterised by ELISA, immunoblotting and immunoprecipitation.

Results RA33 is citrullinated in the rheumatoid joint and targeted either as a citrullinated or native protein in distinct patient subsets with RA. A novel splice variant (hnRNP B1b) previously associated with disease initiation in experimental arthritis was identified in the RA joint and acts as the major target of the anti-RA33 response. Antibodies exclusively targeting citrullinated RA33 were positively associated with disease duration and erosive disease. In contrast, anti-(native) RA33 antibodies were detected almost exclusively in early RA and identified patients with low radiographic erosion scores. Finally, a unique subset of double-reactive patients demonstrated intermediate severity, but rapid disease progression, suggesting a transitional disease phase in the evolution of an anti-native protein antibody to ACPA response in RA.

Conclusions These data suggest that native and citrullinated proteins targeted by autoantibodies in RA may be part of a single antibody system and challenge the paradigm of citrullination as the unifying principle underlying loss of tolerance in RA.

  • Rheumatoid Arthritis
  • Ant-CCP
  • Autoantibodies

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  • Handling editor Tore K Kvien

  • Contributors Each author has contributed to one or more of the following aspects of the manuscript—conception and design, acquisition, analysis and interpretation of data, drafting and revising the article.

  • Funding This work was supported by The Jerome L Greene Foundation, The Donald B and Dorothy L Stabler Foundation (FA), the Rheumatology Research Foundation (JTG) and the Fundación Bechara (PAN).

  • Competing interests None declared.

  • Ethics approval Johns Hopkins Institutional Review Board, Partners Healthcare Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data relevant for this study have been included in the manuscript. Any additional data referred to as not shown will be available through direct contact with the corresponding author. Reagents derived from this project will be available upon request through material transfer agreements.