B cells drive the immunopathology of autoimmune neurological diseases. Bone marrow hematopoietic stem and progenitor cells (HSPCs) sense immune activation and instruct systemic immunity. However, the alterations of HSPCs in B cell-mediated neuroinflammation and their impact on disease progression remain unknown. Neuromyelitis optica spectrum disorder (NMOSD) is a B cell-mediated autoimmune neurological disease. Herein, we show aberrant bone marrow granulopoiesis in NMOSD patients, accompanied by B cell clonal expansion. This aberrant granulopoiesis was mediated by hyperactivated JAK-STAT signaling, leading to a dramatic increase of ISG15+ neutrophils that produced BAFF to drive maturation of antibody-secreting cells and autoantibody production. This effect was also observed in NMOSD patients receiving B cell depletion therapy and experienced relapse. In NMOSD patients, belimumab, a monoclonal antibody against BAFF, reduced disease relapse and autoantibody titer. Thus, targeting bone marrow niche may present a new treatment strategy for NMOSD and perhaps other autoimmune neurological diseases.
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