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

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.

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

“…We identified several genes within the NR4A cluster that may facilitate T-B cell interactions including CD69 (which prevents activated lymphocyte egress from SLO), CD86 (a ligand for CD28 on T cells), IL6 (which can promote both APC and T cell interactions), and ICAM1 (which can support B cell interaction with T follicular helper cells) (61). This is also in accord with a recent report showing that tetramer identified ACPA positive B cells in RA blood and synovial fluid express T cell-stimulating ligands and a persistently activated phenotype suggestive of continuous antigenic triggering (62). A key role for B cells in RA flare was also suggested by the recent discovery of a circulating expanded B cell subset (AC2) prior to emergence of a circulating CD45-/CD31-/PDPN+, PRe-Inflammatory MEsenchymal ("PRIME") cell in RA patient blood (21).…”

Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis

“…As the composition of the autoantibody repertoire in serum likely reflects the composition of the autoantibody secreting Bcell compartment (i.e. plasmablasts/plasma cells) [4,42], the predominance of Igλ in the secreted ACPA-IgG repertoire could be explained by selective survival and/or expansion of Igλ-antibody producing B-cell clones. Alternatively, it could be inherent to the citrullinated antigen-binding B-cell repertoire, irrespective of the maturation stage of the B-cell response.…”

B Cells in Rheumatoid Arthritis：Pathogenic Mechanisms and Treatment Prospects

“…Kristyanto H et al. found that ACPA-positive B cells in the blood and synovial fluid of RA patients could secrete the chemokine interleukin 8 to attract neutrophils to the site of inflammation ( 76 ).…”