To clarify the relationship between the bone marrow, auto-reactive B lymphocytes and the disease evolution, and thus to provide new ideas for precise immune intervention in the treatment of neuromyelitis optica spectrum disorder （NMOSD）.

B cells drive the immunopathology of NMOSD. Bone marrow niche can sense immune activation and generate hematogenous cells to orchestrate inflammation. Yet the alterations of bone marrow hematopoietic cells in NMOSD and their potential impact on disease progression remain unknown.

We collected bone marrow and peripheral blood samples from 22 NMOSD patients and 8 sex- and age-matched healthy individuals to performed single-cell transcriptome and immune repertoire sequencing. In vitro, bone marrow samples from controls and active NMOSD patients were collected and CD34⁺ cells were sorted and induced differentiation to assess myeloid colony-forming units and the changes after JAK inhibitor treatment; Neutrophils and B-cells from the peripheral blood of active NMOSD patients and healthy were also collected and co-cultured in vitro to evaluate the alterations in B cell function by blocking BAFF. We also identified the source of G-CSF and GM-CSF in the bone marrow of NMOSD patients by flow cytometry. In 14 NMOSD patients, we validated the therapeutic effect of the BAFF neutralizing antibody Beliuzumab.

We show remarkably augmented granulopoiesis in bone marrow of NMOSD patients, accompanied by expansion of B cell clones. This aberrant granulopoiesis was mediated by JAK-STAT pathway and led to dramatic production of BAFF that drives the production of antibody-secreting cells and AQP4-IgG, which is also observed in NMOSD patients with relapse after receiving rituximab. In an open-label, single-arm trial of belimumab, a monoclonal antibody against BAFF, in 14 NMOSD patients, belimumab prevented relapse in these patients and reduced the production of antibody-secreting cells and AQP4-IgG.

Targeting bone marrow niche may present a new avenue to treat NMOSD.