Persistently activated, proliferative memory autoreactive B cells promote inflammation in rheumatoid arthritis

Science Translational Medicine, vol. 12

Abstract

Autoreactive B cells mediate autoimmune pathology, but exactly how remains unknown. A hallmark of rheumatoid arthritis (RA), a common autoimmune disease, is the presence of disease-specific anticitrullinated protein antibodies (ACPAs). Here, we showed that ACPA-positive B cells in patients with RA strongly expressed T cell-stimulating ligands, produced abundant proinflammatory cytokines, and were proliferative while escaping inhibitory signals. This activated state was found at different degrees in different stages of disease: highest in patients with recent-onset RA, moderate in patients with established RA, and far less pronounced in ACPA-positive individuals "at risk" for developing disease. The activated autoreactive B cell response persisted in patients who achieved clinical remission with conventional treatment. ACPA-positive B cells in blood and synovial fluid secreted increased amounts of the chemoattractant interleukin-8, which attracted neutrophils, the most abundant immune cell in arthritic joints. Tetanus toxoid-specific B cells from the same patients exhibited properties of memory B cells without the activation and proliferation phenotype, but these cells transiently acquired a similar proliferative phenotype upon booster vaccination. Together, these data indicated that continuous antigenic triggering of autoreactive B cells occurs in human autoimmune disease and support the emerging concept of immunological activity that persists under treatment even in clinical remission, which may revise our current concept of treatment targets for future therapeutic interventions. In addition, our data pointed to a pathogenic role of ACPA-positive B cells in the inflammatory disease process underlying RA and favor approaches that aim at their antigen-specific inactivation or depletion.

Authors 14

1. Hendy Kristyanto Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

2. Nienke J. Blomberg Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

3. Linda M. Slot Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

4. Ellen I. H. van der Voort Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

5. Priscilla F. Kerkman Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, Netherlands

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

6. Aleida M. Bakker Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

7. Leonie E. Burgers Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

8. Robin M. ten Brinck Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

9. Annette H M van der Helm–van Mil Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

10. Hergen Spits

    Amsterdam UMC Location University of Amsterdam · AIMM Therapeutics (Netherlands) · Amsterdam University Medical Centers

    Affiliation as printed

    AIMM Therapeutics, 1045BA Amsterdam, Netherlands

    Department of Experimental Immunology and Amsterdam Institute of Infection and Immunity, Amsterdam University Medical Center, location AMC, 1105AZ Amsterdam, Netherlands

11. Dominique Baeten

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · UCB Pharma (Belgium)

    Affiliation as printed

    Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Center, location AMC, 1105AZ Amsterdam, Netherlands

    UCB Pharma, 1070 Brussels, Belgium

12. Tom W. J. Huizinga Aachen Department of Rheumatology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

13. René E. M. Toes Aachen Department of Rheumatology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands

14. Hans Ulrich Scherer corresponding Aachen Department of Rheumatology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands