title: Patterns of antibody binding to aquaporin-4 isoforms in neuromyelitis optica.
abstract: BACKGROUND
  Neuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform.
  
  
  RESULTS
  The aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses.
  
  
  CONCLUSIONS
  Our results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration.
authors.affiliation: Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Simone
authors.initials: S
authors.lastname: Mader
authors.forename: Andreas
authors.initials: A
authors.lastname: Lutterotti
authors.forename: Franziska
authors.initials: F
authors.lastname: Di Pauli
authors.forename: Bettina
authors.initials: B
authors.lastname: Kuenz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schanda
authors.forename: Fahmy
authors.initials: F
authors.lastname: Aboul-Enein
authors.forename: Michael
authors.initials: M
authors.lastname: Khalil
authors.forename: Maria K
authors.initials: MK
authors.lastname: Storch
authors.forename: Sven
authors.initials: S
authors.lastname: Jarius
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kristoferitsch
authors.forename: Thomas
authors.initials: T
authors.lastname: Berger
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051401:Aquaporin 4 / Q000276:immunology*; D002460:Cell Line; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000145:classification / Q000276:immunology*; D020033:Protein Isoforms / Q000276:immunology; D012307:Risk Factors; D013194:Staining and Labeling; D014162:Transfection; D055815:Young Adult
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020033:Protein Isoforms; D049452:Green Fluorescent Proteins
references.citation: Arch Neurol. 2008 Nov;65(11):1443-8
references.pmid: 18779415
references.citation: J Neuroinflammation. 2008 May 29;5:22
references.pmid: 18510734
references.citation: Brain. 2008 Nov;131(Pt 11):3072-80
references.pmid: 18945724
references.citation: Neurology. 1999 Sep 22;53(5):1107-14
references.pmid: 10496275
references.citation: Ann Neurol. 2005 Dec;58(6):840-6
references.pmid: 16283615
references.citation: Neurology. 2003 Mar 11;60(5):848-53
references.pmid: 12629245
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):13052-6
references.pmid: 7528931
references.citation: Biochemistry. 1999 Aug 24;38(34):11156-63
references.pmid: 10460172
references.citation: J Exp Med. 2005 Aug 15;202(4):473-7
references.pmid: 16087714
references.citation: Neuroscience. 2010 Jul 28;168(4):892-902
references.pmid: 19699275
references.citation: Nat Clin Pract Rheumatol. 2008 Sep;4(9):491-8
references.pmid: 18756274
references.citation: Neurologist. 2007 Jan;13(1):2-11
references.pmid: 17215722
references.citation: Brain. 2007 May;130(Pt 5):1235-43
references.pmid: 17449477
references.citation: Glia. 2009 Oct;57(13):1363-73
references.pmid: 19229993
references.citation: Int MS J. 2008 Sep;15(3):99-105
references.pmid: 18808744
references.citation: Brain. 2007 May;130(Pt 5):1194-205
references.pmid: 17282996
references.citation: Ann Neurol. 2006 Mar;59(3):566-9
references.pmid: 16453327
references.citation: Neuropathology. 2007 Jun;27(3):245-56
references.pmid: 17645239
references.citation: Tohoku J Exp Med. 2006 Dec;210(4):307-13
references.pmid: 17146196
references.citation: Neurology. 2002 Jan 8;58(1):143-6
references.pmid: 11781423
references.citation: Neurology. 2007 Mar 27;68(13):1076-7
references.pmid: 17287449
references.citation: Brain. 2007 May;130(Pt 5):1224-34
references.pmid: 17405762
references.citation: Nat Clin Pract Neurol. 2008 Apr;4(4):202-14
references.pmid: 18334978
references.citation: Lancet. 2004 Dec 11-17;364(9451):2106-12
references.pmid: 15589308
references.citation: Arch Neurol. 2007 Jun;64(6):899-901
references.pmid: 17562942
references.citation: Arch Neurol. 2008 Jan;65(1):78-83
references.pmid: 18195142
references.citation: Neurology. 2006 May 23;66(10):1485-9
references.pmid: 16717206
references.citation: Neurology. 2005 Apr 12;64(7):1270-2
references.pmid: 15824362
references.citation: Curr Neurol Neurosci Rep. 2008 Sep;8(5):427-33
references.pmid: 18713580
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13609-14
references.pmid: 14597700
references.citation: Ann Neurol. 2009 Nov;66(5):630-43
references.pmid: 19937948