Functional impairment of CD19(+)CD24(hi)CD38(hi) B cells in neuromyelitis optica spectrum disorder is restored by B cell depletion therapy

Abstract

The role of B cells in immune response regulation is context dependent. In some cases, bystander B cell activation leads to interleukin-10 (IL-10) production, suppressing inappropriate immune responses. However, the role of B cells in regulation of autoimmune diseases, including neuromyelitis optica spectrum disorder (NMOSD), is incompletely understood. NMOSD is an autoimmune disease of the central nervous system with a relapsing-remitting course in which acute attacks lead to severe disability. B cell depletion therapy (BCDT) has shown clinical efficacy in NMOSD by eliminating pathogenic B cells; however, its effect on regulatory B (B-reg) cells remains elusive. Here, we evaluated the B cell subsets, B-reg cell function, and the effect of BCDT on these cells in patients with NMOSD. We showed that CD24(hi)CD38(hi) B cells from patients with NMOSD did not inhibit CD4(+) T cell production of interferon-gamma (IFN-gamma), IL-17, or IL-21 and failed to inhibit follicular helper T cell expansion or induce regulatory T cells. This cellular impairment in patients with NMOSD can be explained by deficient B-reg cell numbers and B-reg cell-intrinsic deficits in IL-10 production specifically in response to B cell bystander activation. Using cross-sectional and 3-year longitudinal studies, we showed that BCDT treatment restored the numerical deficiency of B-reg cells. Moreover, the post-BCDT repopulated CD24(hi)CD38(hi) B cells restored IL-10 production and suppressed IFN-gamma and IL-17 production by CD4(+) T cells. Our results suggest that both numerical deficiency of CD24(hi)CD38(hi) B cells and their impaired regulatory function contribute to NMOSD pathophysiology, and function is restored after BCDT.