To uncover how naive B-cell development is functionally related to auto-IgG serostatus, steroid treatment and relapse occurrence in neuromyelitis optica spectrum disorder (NMOSD).

NMOSD is a rare yet severe autoimmune disease characterized by antibody-driven inflammation of mainly the ocular nerves and/or spinal cord. Although naive B cells are key players, it remains unknown whether their composition and outgrowth differ between serological subgroups.

Frequencies of transitional/early emigrant (CD38^highCD27^-CD24^high) and naive mature (CD38^-/dimCD27^-IgM⁺) B cells were analyzed in the blood from 15 AQP4-IgG-positive NMOSD and 12 MOG-IgG-positive (MOGAD) patients with and without corticosteroid therapy. Naive mature B cells were cultured under T-bet- and IL-21/CD40L-inducing conditions for development into (auto)IgG-producing plasmablasts (FACS/ELISA/CBA).

Under complete treatment-naive circumstances, naive mature/transitional B-cell ratios were reduced in AQP4-IgG-positive NMOSD vs MOGAD, multiple sclerosis and healthy control groups. This was caused by increased proportions of transitional B cells, which were extremely high in 2 AQP4-IgG-positive cases with relapses (35% and 44% of the total B-cell pool). Transitional B-cell proportions were strongly diminished in 9 steroid-treated patients. For naive B cells from 7 relapsing NMOSD patients, TLR9 ligand (CpG-ODN) synergized with IFN-γ to enhance plasmablast formation in vitro. This was not found for 11 non-relapsing patients or 9 healthy controls. IFN-γ- and CpG-ODN-induced naive B cells showed increased IgG secretion especially for patients with relapses in the NMOSD group. In vitro AQP4-IgG secretion was detected for 3 relapsing but not in 6 non-relapsing patients, which was enhanced by IFN-γ/CpG-ODN (2 out of 3 relapsing cases). MOG-IgG was not detected in naive B-cell culture supernatants of 4 relapsing and 4 non-relapsing patients with MOGAD.

Naive B-cell homeostasis is different and selectively targeted by steroid therapy in NMOSD patients. This supports further exploration of naive B cells in TLR9-inducing in vitro systems to predict NMOSD activity.