Failure of Early B Cell Tolerance and possible BCR Signaling Dysregulation Underlie NF155-Mediated Autoimmune Nodopathies

Defects in B-cell tolerance checkpoints have been implicated in several autoimmune diseases, including MuSK-positive myasthenia gravis (MG), another IgG4 autoantibody-mediated disease. Here, we investigated whether tolerance defects exist in neurofascin-155-mediated AIN (NF155-AIN), using a well-established assay, by generating recombinant antibodies from new emigrant (NE) and mature naïve (MN) B cells from three NF155-AIN patients, and tested them for polyreactivity and autoreactivity.

Additionally, we analyzed the transcriptome of peripheral blood mononuclear cells with a special focus on naïve B cells and CD4+ T cells at the single-cell level, along with characterization of cell-cell interactions. NF155-AIN patients have an elevated frequency of polyreactive B cells in the NE (37.4% compared to 9.7% in healthy controls (HCs), p = 0.03) and MN (31.5% compared to 10.5% in HCs, p = 0.03) compartments, consistent with a breach in early B cell tolerance checkpoints.