title: A PD-1 polymorphism is associated with disease progression in multiple sclerosis.
abstract: T cells are considered to play a pivotal role in orchestrating the self-reactive immune responses in multiple sclerosis (MS). Programmed death 1 (PD-1) is a member of the B7/CD28 superfamily of costimulatory molecules exerting inhibitory functions on T cells. Recently, an intronic 7146G/A polymorphism within the PD-1 gene was described and suggested to be associated with autoimmunity. We investigated whether this genetic polymorphism is a genetic modifier for risk and progression of MS. Blood samples from 939 German MS patients (mean age, 39 years; range, 13-71; 566 patients [60%] with relapsing-remitting MS, 279 (30%) with secondary, and 94 (10%) with primary progressive MS) and 272 healthy white controls were tested. Genotyping was performed by polymerase chain reaction and restriction enzyme digestion; results were confirmed by automatic sequencing. A significant association of the mutated allele with a progressive disease course was detected (44% 7146G vs 56% 7146A, chi(2) p = 0.002). Consequences of the PD-1 mutation for T-cell function were assessed ex vivo in some patients using microsphere-stimulated peripheral blood lymphocytes and purified CD4 cells. Importantly, PD-1-mediated inhibition of T-cell cytokine secretion (interferon-gamma) is impaired in patients carrying the PD-1 polymorphism. In conclusion, our data suggest that PD-1 polymorphism is a genetic modifier of the progression of MS, possibly through inducing a partial defect in PD-1-mediated inhibition of T-cell activation.
authors.affiliation: Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Department of Neurology, Bayerische Julius-Maximilians Universität, Würzburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mehling
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Mathias
authors.initials: M
authors.lastname: Mäurer
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor; D012307:Risk Factors
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor