Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 12, Issue 570, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaz5327
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Funding
- Netherlands Organization for Scientific Research (NWO) Gravitation Program from the Institute for Chemical Immunology [00019]
- NWO [435000033, 91214031]
- EU/EFPIA Innovative Medicines Initiative Joint Undertaking (IMI-JU) BeTheCure grant [1151422]
- IMI2-JU RTCure grant [777357]
- NWO-ZonMW clinical fellowship [90714509]
- NWO-ZonMW VENI grant [91617107]
- ZonMW Enabling Technology Hotels grant [435002030]
- Dutch Arthritis Foundation [15-2-402, 18-1-205]
- European Research Council (ERC) under the European Union [714312]
- NWO-ZonMW VICI grant
- ERC
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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 recentonset 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.
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