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A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 2005 Jul;58(1):50-7



Pubmed ID




Scopus ID

2-s2.0-21844451620 (requires institutional sign-in at Scopus site)   198 Citations


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.

Author List

Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Mäurer M, Wiendl H


Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antigens, CD
Antigens, Surface
Apoptosis Regulatory Proteins
Base Sequence
CD4-Positive T-Lymphocytes
Disease Progression
Flow Cytometry
Gene Frequency
Lymphocyte Activation
Middle Aged
Multiple Sclerosis
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Programmed Cell Death 1 Receptor
Risk Factors