Aberrant bone marrow granulopoiesis generates neutrophils that promote B cell activity in neuromyelitis optica spectrum disorder

Bone marrow hematopoietic stem and progenitor cells (HSPCs) sense immune activation and instruct systemic immunity. However, the alterations of HSPCs in autoimmune diseases, which are driven by an active immune response, and their impact on disease activity and progression are not clear. Neuromyelitis optica spectrum disorder (NMOSD) is a B cell-mediated autoimmune neurological disease characterized by pathogenic autoantibodies against aquaporin-4 (AQP4-IgG). We observed aberrant bone marrow granulopoiesis in samples from individuals with NMOSD, which was accompanied by B cell clonal expansion. Aberrant granulopoiesis was mediated by hyperactivated JAK-STAT signaling, leading to an increase in ISG15+ neutrophils that produced B cell-activating factor (BAFF). These BAFF-producing neutrophils were sufficient to drive maturation of antibody-secreting cells and autoantibody production in vitro. Aberrant granulopoiesis was also observed in individuals with NMOSD receiving B cell depletion therapy who experienced relapse; in contrast, belimumab, a monoclonal antibody against BAFF, reduced autoantibody titers and number of relapses. Thus, targeting the bone marrow niche may present a treatment strategy for NMOSD and perhaps other B cell-mediated autoimmune diseases.