title: Defective autoimmune regulator-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy.
abstract: Chronic inflammatory demyelinating polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking Ags, and pathogenic effector mechanisms are not well defined. The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-Ags and deletion of self-reactive T cells. In this study, we used mice with hypomorphic Aire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets myelin protein zero, an Ag for which expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4(+) T cells are sufficient to transfer disease in mice and produce IFN-γ in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to myelin protein zero initiates an autoimmune Th1 effector response toward peripheral nerves.
authors.affiliation: Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA. masu@email.unc.edu
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
authors.forename: Dan
authors.initials: D
authors.lastname: Davini
authors.forename: Philip
authors.initials: P
authors.lastname: Cheng
authors.forename: Karen
authors.initials: K
authors.lastname: Giang
authors.forename: Una
authors.initials: U
authors.lastname: Fan
authors.forename: Jason J
authors.initials: JJ
authors.lastname: DeVoss
authors.forename: Kellsey P A
authors.initials: KP
authors.lastname: Johannes
authors.forename: Lorelei
authors.initials: L
authors.lastname: Taylor
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Shum
authors.forename: Mariella
authors.initials: M
authors.lastname: Valenzise
authors.forename: Antonella
authors.initials: A
authors.lastname: Meloni
authors.forename: Helene
authors.initials: H
authors.lastname: Bour-Jordan
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D008969:Molecular Sequence Data; D018993:Myelin P0 Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000097:blood / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D018993:Myelin P0 Protein; D014157:Transcription Factors; D000096927:AIRE Protein