TY - JOUR
T1 - Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder
AU - Li, Jie
AU - Bazzi, Sam A.
AU - Schmitz, Florian
AU - Tanno, Hidetaka
AU - McDaniel, Jonathan R.
AU - Lee, Chang Han
AU - Joshi, Chaitanya
AU - Kim, Jin Eyun
AU - Monson, Nancy
AU - Greenberg, Benjamin M.
AU - Hedfalk, Kristina
AU - Melamed, Esther
AU - Ippolito, Gregory C.
N1 - Funding Information:
The Article Processing Charge was funded by the authors.
Funding Information:
This work was supported by funding from the Owens Medical Research Foundation (E.M., G.I.), Dell Medical School startup funds (E.M.), NIH grant no. R01NS102417 (N.M.), and the Swedish Brain Foundation FO2018-0231 (K.H.). Sample acquisition costs were funded in part by the UT Southwestern CONQUER Program, and the Guthy-Jackson Charitable Foundation for NMO. H.T. was supported by UTHealth Innovation for Cancer Prevention Research Training Program Post-Doctoral Fellowship (Cancer Prevention and Research Institute of Texas grant no. RP160015). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas.
Publisher Copyright:
© American Academy of Neurology.
PY - 2021/9/24
Y1 - 2021/9/24
N2 - ObjectiveTo determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD.MethodsWe combined high-Throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro.ResultsMultiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01).ConclusionsThe composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.
AB - ObjectiveTo determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD.MethodsWe combined high-Throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro.ResultsMultiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01).ConclusionsThe composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.
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U2 - 10.1212/NXI.0000000000001034
DO - 10.1212/NXI.0000000000001034
M3 - Article
C2 - 34168058
AN - SCOPUS:85109395036
SN - 2332-7812
VL - 8
JO - Neurology: Neuroimmunology and NeuroInflammation
JF - Neurology: Neuroimmunology and NeuroInflammation
IS - 5
M1 - e1034
ER -