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Brain. 2019 Jun 1;142(6):1598-1615. doi: 10.1093/brain/awz106.

Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production.

Author information

1
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
3
Departments of Neurology and Ophthalmology and Neuroscience Program, University of Colorado, Denver, CO, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
5
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT, USA.
6
Department of Neurology, Johns Hopkins, School of Medicine, Baltimore, MD, USA.

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) constitute rare autoimmune disorders of the CNS that are primarily characterized by severe inflammation of the spinal cord and optic nerve. Approximately 75% of NMOSD patients harbour circulating pathogenic autoantibodies targeting the aquaporin-4 water channel (AQP4). The source of these autoantibodies remains unclear, but parallels between NMOSD and other autoantibody-mediated diseases posit compromised B cell tolerance checkpoints as common underlying and contributing factors. Using a well established assay, we assessed tolerance fidelity by creating recombinant antibodies from B cell populations directly downstream of each checkpoint and testing them for polyreactivity and autoreactivity. We examined a total of 863 recombinant antibodies. Those derived from three anti-AQP4-IgG seropositive NMOSD patients (n = 130) were compared to 733 antibodies from 15 healthy donors. We found significantly higher frequencies of poly- and autoreactive new emigrant/transitional and mature naïve B cells in NMOSD patients compared to healthy donors (P-values < 0.003), thereby identifying defects in both central and peripheral B cell tolerance checkpoints in these patients. We next explored whether pathogenic NMOSD anti-AQP4 autoantibodies can originate from the pool of poly- and autoreactive clones that populate the naïve B cell compartment of NMOSD patients. Six human anti-AQP4 autoantibodies that acquired somatic mutations were reverted back to their unmutated germline precursors, which were tested for both binding to AQP4 and poly- or autoreactivity. While the affinity of mature autoantibodies against AQP4 ranged from modest to strong (Kd 15.2-559 nM), none of the germline revertants displayed any detectable binding to AQP4, revealing that somatic hypermutation is required for the generation of anti-AQP4 autoantibodies. However, two (33.3%) germline autoantibody revertants were polyreactive and four (66.7%) were autoreactive, suggesting that pathogenic anti-AQP4 autoantibodies can originate from the pool of autoreactive naïve B cells, which develops as a consequence of impaired early B cell tolerance checkpoints in NMOSD patients.

KEYWORDS:

AQP4; B cells; autoantibodies; neuromyelitis optica spectrum disorder (NMOSD); tolerance

PMID:
31056665
PMCID:
PMC6536857
[Available on 2020-06-01]
DOI:
10.1093/brain/awz106

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