Abstract
BackgroundAnti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism involved in AQP4-Ab production remains unclear.MethodsWe analyzed the immunophenotypes of patients with NMOSD and other neuroinflammatory diseases as well as healthy controls (HC) using flow cytometry. Transcriptome analysis of B cell subsets obtained from NMOSD patients and HCs was performed. The differentiation capacity of B cell subsets into antibody-secreting cells was analyzed.ResultsThe frequencies of switched memory B (SMB) cells and plasmablasts were increased and that of naïve B cells was decreased in NMOSD patients compared with relapsing–remitting multiple sclerosis patients and HC. SMB cells from NMOSD patients had an enhanced potential to differentiate into antibody-secreting cells when cocultured with T peripheral helper cells. Transcriptome analysis revealed that the profiles of B cell lineage transcription factors in NMOSD were skewed towards antibody-secreting cells and that IL-2 signaling was upregulated, particularly in naïve B cells. Naïve B cells expressing CD25, a receptor of IL-2, were increased in NMOSD patients and had a higher potential to differentiate into antibody-secreting cells, suggesting CD25+ naïve B cells are committed to differentiate into antibody-secreting cells.ConclusionsTo the best of our knowledge, this is the first study to demonstrate that B cells in NMOSD patients are abnormally skewed towards antibody-secreting cells at the transcriptome level during the early differentiation phase, and that IL-2 might participate in this pathogenic process. Our study indicates that CD25+ naïve B cells are a novel candidate precursor of antibody-secreting cells in autoimmune diseases.
Highlights
Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD)
switched memory B (SMB) cells (CD19+CD20+CD27+IgD−) were significantly increased in NMOSD compared with healthy controls (HC), whereas there was no difference in the proportion of total B cells in Peripheral blood mononuclear cells (PBMC) among HCs and disease groups (Fig. 1A; Additional file 1: Fig. S1A)
Changes in the frequencies of B cell subsets in NMOSD were not observed in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD), most of whom were treated with corticosteroids, suggesting that differences in the B cell subsets in NMOSD could not be explained by the effect of the corticosteroid therapy
Summary
Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS) characterized by severe optic neuritis, myelitis, and the presence of anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) [1, 2]. The production of autoantibodies and defects in B cell tolerance are associated with the pathomechanisms of several autoimmune diseases. Many studies have reported that autoreactive naïve B cells are increased in various autoimmune diseases including NMOSD, suggesting defects in early B cell tolerance checkpoints [13, 14]. DN2 cells were reported to be derived from CD27−IgD+CXCR5−CD11c+ cells, termed activated naïve B cells These studies suggested that abnormalities of early B cell development may exist in autoimmune pathology
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