Mutagenesis of the aquaporin 4 extracellular domains defines restricted binding patterns of pathogenic neuromyelitis optica IgG.

The Journal of Biological Chemistry
Gregory P OwensJeffrey L Bennett

Abstract

Neuromyelitis optica-immunoglobulin G (NMO-IgG) binds to aquaporin-4 (AQP4) water channels in the central nervous system leading to immune-mediated injury. We have previously demonstrated that a high proportion of CSF plasma cells of NMO patients produce antibody to the extracellular domains of the AQP4 protein and that recombinant IgG (rAb) derived from these cells recapitulate pathogenic features of disease. We performed a comprehensive mutational analysis of the three extracellular loops of the M23 isoform of human AQP4 using both serial and single point mutations, and we evaluated the effects on binding of NMO AQP4-reactive rAbs by quantitative immunofluorescence. Whereas all NMO rAbs required conserved loop C ((137)TP(138) and Val(150)) and loop E ((230)HW(231)) amino acids for binding, two broad patterns of NMO-IgG recognition could be distinguished based on differential sensitivity to loop A amino acid changes. Pattern 1 NMO rAbs were insensitive to loop A mutations and could be further discriminated by differential sensitivity to amino acid changes in loop C ((148)TM(149) and His(151)) and loop E (Asn(226) and Glu(228)). Alternatively, pattern 2 NMO rAbs showed significantly reduced binding following amino acid changes ...Continue Reading

References

Aug 21, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Gregory P OwensDonald H Gilden
Aug 5, 2004·Annals of Neurology·Claudia F LucchinettiHans Lassmann
Aug 10, 2005·The Journal of Experimental Medicine·Vanda A LennonShannon R Hinson
Apr 23, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joseph D HoRobert M Stroud
Nov 26, 2009·Annals of Neurology·Monika BradlHans Lassmann
Nov 26, 2009·Annals of Neurology·Jeffrey L BennettBernhard Hemmer
Sep 9, 2010·Multiple Sclerosis : Clinical and Laboratory Research·John D E Parratt, John W Prineas
Jan 8, 2011·The Journal of Biological Chemistry·Francesco PisaniMaria Svelto
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Jan 25, 2012·Annals of Neurology·Lukmanee TradtrantipA S Verkman
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Sep 23, 2014·The Journal of Biological Chemistry·Francesco PisaniGrazia Paola Nicchia

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Citations

May 6, 2016·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Satoshi OgasawaraYukinari Kato
Jun 22, 2016·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Satoshi OgasawaraYukinari Kato
Aug 16, 2016·International Journal of Molecular Sciences·Hiroko Ikeshima-Kataoka
May 4, 2018·The Neurologist·I Vanessa Marin CollazoW Oliver Tobin
May 6, 2019·Brain : a Journal of Neurology·Elizabeth CotzomiKevin C O'Connor
Apr 16, 2020·Acta Neuropathologica Communications·Irina TsymalaMonika Bradl
Apr 9, 2019·The Journal of Clinical Investigation·John SoltysJeffrey L Bennett
Jul 31, 2020·Cellular & Molecular Immunology·Alicia ZouFabienne Brilot
Oct 24, 2020·Nature Reviews. Disease Primers·Sven JariusBrigitte Wildemann
Jun 26, 2021·Neurology. Neuroimmunology and Neuroinflammation·Jie LiGregory C Ippolito

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Methods Mentioned

BETA
FACS
light scattering
PCR
transfection
ELISA
protein assay
fluorescence microscopy

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QUEST
Jmol Viewer
IMGT
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