Functional impairment of CD19CD24CD38 B cells in neuromyelitis optica spectrum disorder is restored by B cell depletion therapy.

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) cells remains elusive. Here, we evaluated the B cell subsets, B cell function, and the effect of BCDT on these cells in patients with NMOSD. We showed that CD24CD38 B cells from patients with NMOSD did not inhibit CD4 T cell production of interferon-γ (IFN-γ), 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 cell numbers and B 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 cells. Moreover, the post-BCDT repopulated CD24CD38 B cells restored IL-10 production and suppressed IFN-γ and IL-17 production by CD4 T cells. Our results suggest that both numerical deficiency of CD24CD38 B cells and their impaired regulatory function contribute to NMOSD pathophysiology, and function is restored after BCDT.