Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production
- 5 May 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 142 (6), 1598-1615
- https://doi.org/10.1093/brain/awz106
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 naive 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 naive 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 (K-d 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 naive B cells, which develops as a consequence of impaired early B cell tolerance checkpoints in NMOSD patients.Keywords
Funding Information
- Guthy-Jackson Charitable Foundation
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health (AI114780, AI104739, AI130548, AI071087, AI061093, AI110498)
- National Eye Institute
- National Institutes of Health (EY022936)
- Medical Scientist Training Program
- University of Colorado Anschutz Medical Campus (T32 GM008497)
- Onassis Foundation
- Support Program for Scholars' Association Members (R ZO 006/2018-2019)
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