title: T-cell responses to distinct AQP4 peptides in patients with neuromyelitis optica (NMO).
abstract: BACKGROUND
  Although antibodies to aquaporin-4(AQP4) are strongly associated with Neuromyelitis optica (NMO), the sole transfer of these antibodies is not sufficient to induce an NMO-like disease in experimental animals and T-cells and complement are also needed. Initial data indicating the presence of T-cell responses to AQP4 in patients with NMO, have beeen recently reported.
  
  
  OBJECTIVE
  To evaluate the T-cell responses to specific AQP4 peptides/epitopes in patients with NMO and multiple sclerosis (MS).
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were obtained from 14 patients fulfilling the criteria for definite NMO and the proliferation responses to one of 15 distinct pentadecapeptides of AQP4, spanning the whole protein (except of its transmembrane parts) were tested by a standard [H3]-thymidine uptake assay and compared with those of 9 healthy controls and 7 MS patients. A cytometric bead array assay (CBA) and flow cytometry were used to evaluate cytokine (IFNγ, IL17, IL2, IL4, IL5, IL10 and TNFα) and chemokine (CXCL8, CCL5, CXCL10, CXCL9, CCL2) secretion by PHA-stimulated PBMCs and AQP4-specific T-cell lines.
  
  
  RESULTS
  Four main immunodominant epitopes of the AQP4 protein (p137-151, p222-236, p217-231 and the p269-283) were identified in the NMO group. The first two epitopes (assigned as peptides 3 and 9) showed the highest sensitivity (~60% positivity), whereas the latter two (assigned as peptides 8 and 11), the higher specificity. Longitudinal follow up of 5 patients revealed changes in the epitope-specificities during the course of NMO. T-cell lines specific for the AQP4 peptides, produced from NMO patients (but not healthy donors) secreted mainly IL-17 and IL-10 and less IFNγ.
  
  
  CONCLUSIONS
  Our findings indicate that T-cells bearing characteristics of both Th1 and Th17 T-cells and targeting specific immunodominant epitopes of the AQP4 protein might be involved in the pathogenesis of NMO.
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Vaknin-Dembinsky
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Livnat
authors.initials: L
authors.lastname: Brill
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Kassis
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Petrou
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Tamir
authors.initials: T
authors.lastname: Ben-Hur
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Abramsky
authors.affiliation: Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Karussis
mesh_terms: D000328:Adult; D000368:Aged; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D055815:Young Adult
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D018984:Epitopes, T-Lymphocyte; C508609:IL10 protein, human; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: Aquaporin-4; Multiple sclerosis; Neuromyelitis optica; T cells