title: Deletional tolerance prevents AQP4-directed autoimmunity in mice.
abstract: Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4-specific T cells to the class switch recombination of pathogenic AQP4-specific antibodies and the inflammation of the blood-brain barrier is incompletely understood, as immunogenic naturally processed T-cell epitopes of AQP4 are unknown. By immunizing Aqp4-/-mice with full-length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201-220) as the major immunogenic IAb-restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201-220)-specific T-cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201-220) of Rag1-/-mice reconstituted with the mature T-cell repertoire of Aqp4-/-mice elicits an encephalomyelitic syndrome. Similarly to the T-cell repertoire, the B-cell repertoire of WT mice is "purged" of AQP4-specific B cells, and robust serum responses to AQP4 are only mounted in Aqp4-/-mice. While AQP4(201-220)-specific T cells alone induce encephalomyelitis, NMO-specific lesional patterns in the CNS and the retina only occur in the additional presence of anti-AQP4 antibodies. Thus, failure of deletional T-cell and B-cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Klinikum rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Munich, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Vogel
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Klinikum rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Munich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Knier
authors.affiliation: Department of Biochemistry at the Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lammens
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Sudhakar Reddy
authors.initials: SR
authors.lastname: Kalluri
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurology, School of Medicine, University of Colorado, Aurora, CO, USA.|Department of Ophthalmology, School of Medicine, University of Colorado, Aurora, CO, USA.|Program in Neuroscience, School of Medicine, University of Colorado, Aurora, CO, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Klinikum rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.identifier: 0000-0002-3633-0955
authors.initials: T
authors.lastname: Korn
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology*; D017637:Clonal Deletion / Q000235:genetics; D002999:Clone Cells; D018604:Epitope Mapping; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009471:Neuromyelitis Optica / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012160:Retina / Q000276:immunology*; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II; C474482:I-A(b) antigen, mouse; D016056:Immunodominant Epitopes; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: Aquaporin 4 (AQP4); B cell; Encephalitogenic epitope; Experimental neuromyelitis optica; Optical coherence tomography; T cell; Tolerance