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Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica
John Soltys, … , Gregory P. Owens, Jeffrey L. Bennett
John Soltys, … , Gregory P. Owens, Jeffrey L. Bennett
Published April 8, 2019
Citation Information: J Clin Invest. 2019;129(5):2000-2013. https://doi.org/10.1172/JCI122942.
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Research Article Inflammation Neuroscience Article has an altmetric score of 13

Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica

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Abstract

Neuromyelitis optica (NMO) is an autoimmune CNS disorder mediated by pathogenic aquaporin-4 (AQP4) water channel autoantibodies (AQP4-IgG). Although AQP4-IgG–driven complement-dependent cytotoxicity (CDC) is critical for the formation of NMO lesions, the molecular mechanisms governing optimal classical pathway activation are unknown. We investigated the molecular determinants driving CDC in NMO using recombinant AQP4–specific autoantibodies (AQP4 rAbs) derived from affected patients. We identified a group of AQP4 rAbs targeting a distinct extracellular loop C epitope that demonstrated enhanced CDC on target cells. Targeted mutations of AQP4 rAb Fc domains that enhance or diminish C1q binding or antibody Fc-Fc interactions showed that optimal CDC was driven by the assembly of multimeric rAb platforms that increase multivalent C1q binding and facilitate C1q activation. A peptide that blocks antibody Fc-Fc interaction inhibited CDC induced by AQP4 rAbs and polyclonal NMO patient sera. Super-resolution microscopy revealed that AQP4 rAbs with enhanced CDC preferentially formed organized clusters on supramolecular AQP4 orthogonal arrays, linking epitope-dependent multimeric assembly with enhanced C1q binding and activation. The resulting model of AQP4-IgG CDC provides a framework for understanding classical complement activation in human autoantibody–mediated disorders and identifies a potential new therapeutic avenue for treating NMO.

Authors

John Soltys, Yiting Liu, Alanna Ritchie, Scott Wemlinger, Kristin Schaller, Hannah Schumann, Gregory P. Owens, Jeffrey L. Bennett

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Figure 5

Super-resolution microscopy of membrane-bound AQP4 rAb clustering on M23-AQP4 OAPs.

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Super-resolution microscopy of membrane-bound AQP4 rAb clustering on M23...
(A) Representative images showing M23-AQP4 and AQP4 rAb and ASA scores. Image scale: pixel = 19.5 × 19.5 nm; scale bar: 100 nm. (B) The magnitude of cluster spread for the average resolvable rAb cluster was grouped by epitope-binding dependence and compared using ANOVA with Tukey’s test for multiple comparisons. Each data point represents the mean from at least 3 images throughout. (C) Theoretical depiction of the ASA scoring scale. A hypothetical antibody distribution is displayed schematically to illustrate the relative size of AQP4 rAb and the image pixel. Pixel groups containing a higher concentration of rAb signal (bottom) are considered to have a higher probability of clustering and forming multivalent contacts with C1q. (D) A hierarchal clustering analysis of ASA scores was performed for His151/Leu154-independent rAbs (red), His151/Leu154-dependent rAbs (blue), and E345R Fc-mutated rAbs (black) on CHO cells expressing M23-AQP4 and M1-AQP4. The mean ASA score is plotted against levels of (E) bound rAb and (F) C1q at CDC EC50.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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