title: The co-inhibitory molecule PD-1 modulates disease severity in a model for an inherited, demyelinating neuropathy.
abstract: We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule "programmed death" (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phenotype of CD8+ T-lymphocytes in the P0 myelin mutants. PD-1 deficiency in P0+/- mice leads to a stronger increase of CD8+ T-lymphocytes and a substantially aggravated histological phenotype in the PNS compared to P0+/- mice expressing PD-1. Correspondingly, functional down-stream features, such as electrophysiological parameters, walking coordination and mechano-sensation are more affected than in PD-1-expressing myelin mutants. Our study demonstrates that a monogenic nerve disorder can be substantially modified by immune-controlling mechanisms. Thus, understanding the implication of disease-modifiers in inherited demyelination could be of pivotal interest for limiting the detrimental impact of primarily genetically-mediated myelin disorders by fostering immuno-regulatory pathways.
authors.affiliation: Department of Neurology, University of Wuerzburg, Wuerzburg.
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schwab
authors.forename: Chi Wang
authors.initials: CW
authors.lastname: Ip
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002607:Charcot-Marie-Tooth Disease; D002678:Chimera; D003711:Demyelinating Diseases / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020235:Gait Apraxia / Q000503:physiopathology; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010523:Peripheral Nervous System Diseases / Q000276:immunology / Q000503:physiopathology*; D061026:Programmed Cell Death 1 Receptor; D052097:Quadriceps Muscle / Q000294:innervation; D012584:Sciatic Nerve / Q000503:physiopathology / Q000648:ultrastructure; D013126:Spinal Nerve Roots / Q000503:physiopathology / Q000648:ultrastructure; D018709:Statistics, Nonparametric; D014110:Touch / Q000502:physiology
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma