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Activated B cells could hold key to early-stage autoimmunity in rheumatoid arthritis

Science Translational Medicine
Reuters Health - 23/11/2020 - B cells that contain anticitrullinated protein antibodies (ACPAs), a major risk factor for rheumatoid arthritis (RA), are most active in early-stage disease but also proliferate in ACPA-positive patients with arthralgia who have not yet developed synovial inflammation, researchers say.

"Silencing these (autoreactive) B cells could be a target for novel therapies," Dr. Hans Scherer of Leiden University Medical University Medical Center told Reuters Health by email. "The ultimate goal is the induction of 'immunological remission,' which we think is required for cure."

A possible reason that RA often flares when treatment is stopped, he said "is that most current treatments efficiently suppress inflammation while leaving the underlying immunological processes unaffected. Hence, patients frequently reach clinical remission, but not immunological remission."

As reported in Science Translational Medicine, the team studied samples of blood and synovial fluid from inflamed joints. They found that B cells with ACPAs were most active in patients with early-stage RA, but were also abundant in samples from patients with joint pain who had not yet developed the disease.

Further analyses revealed that ACPA-positive B cells from RA patients strongly expressed T cell-stimulating ligands; produced large amounts of proinflammatory cytokines; deactivated the immune-suppressing receptor CD32; and attracted neutrophils to joints through the secretion of IL-8. As Dr. Scherer noted, this activated autoreactive B cell response persisted in patients who achieved clinical remission with conventional treatment.

"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," the authors conclude.

In addition to targeting these cells for therapy, Dr. Scherer said, "the activation state of the autoreactive B cell response we described can serve as a biomarker for immunological disease activity, which is what we currently miss in the clinic. This biomarker could guide the choice and the intensity of the treatment, and could also guide the decision on when to stop medication."

Dr. Stuart Kaplan, chief of rheumatology at South Nassau Communities Hospital in Oceanside, New York called the study "groundbreaking." He told Reuters Health, "The findings support the widely-held notion that B cells are responsible for the inflammation associated with RA, not primarily through their production of autoantibodies but, rather, via their effect on T cell stimulation and their production of proinflammatory cytokines."

"This study was also notable in that it compared ACPA-positive B cells from patients with various degrees of disease activity from arthralgia through established RA," he said by email. "The results confirmed the concept that RA is a continuous antigen-driven process and that immunological activity may persist even in the face of clinical remission."

"Most importantly," he noted, "the data indicates that RA entails continuous antigenic triggering of autoreactive B cells and therefore, may be immunologically active even when clinically stable. This may translate into the need to continue treatment even when the patient appears to be in remission, especially if high levels of autoantibodies are still being produced."

"Further research is needed to elucidate the complete role of ACPA-positive B cells and to identify additional targets for intervention," he said. "In addition, it would be very helpful to study autoreactive B cells from the same patient over an extended period of time as their RA progresses."

SOURCE: https://bit.ly/2J8INow Science Translational Medicine, online November 18, 2020.

By Marilynn Larkin


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