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.

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

“…PD-1 has been shown to be important for selftolerance because spontaneous autoimmune diseases develop in PD-1 −/− mice (2)(3)(4). A single-nucleotide polymorphism that affects PD-1 expression is associated with autoimmune diseases in humans, such as systemic lupus erythematosus (5), type I diabetes (6), rheumatoid arthritis (7), and multiple sclerosis (MS) (8), suggesting that PD-1 deficiency may be a genetic factor involved in the development of autoimmunity.…”

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

“…Following this line, such changes in expression levels of immune-regulatory molecules or adhesion molecules with their consequences with regard to T-cell invasion into the CNS might also account for so far unexplained decreases in the individual treatment response during the course of therapy, as observed in the context of natalizumab treatment. In this context, it is important to note that the B7-H1/PD-1 pathway is obviously key to susceptibility and disease type/course of several autoimmune disorders, including MS (41)(42)(43), which puts our findings into the overriding context of what functional consequences certain risk genes can have. This study demonstrates that single immune regulatory molecules affecting the activation status of (encephalitogenic) T cells can influence lesion distribution, which is associated with an altered capacity of these cells to elicit transient focal EC dysfunction and barrier dysfunction as essential steps for lesion development.…”

Association between a PD-1 gene polymorphism and antisperm antibody-related infertility in Iranian men

“…Moreover PD 1.3 SNP has been reported in different autoimmune settings, including rheumatoid arthritis [14], Type I diabetes [11], Multiple sclerosis [15], Ankylosing spondylitis [16] and Allergy [17].…”

“…To date, more than 30 SNPs have been identified in human PD-1 gene [10,11]. Prokunina et al reported that the allele A of a SNP named PD1.3 (PD1.3A) in intron 4 is associated with the development of SLE in Europeans (relative risk=2.6) and Mexicans (relative risk=3.5) [12] To date, Single Nucleotide Polymorphism association with PD 1.3 has been reported in several auto-antibody associated autoimmune diseases; including psoriasis [13], rheumatoid arthritis [14], Type I diabetes [11], Multiple sclerosis [15], Ankylosing spondylitis [16] and Allergy [17].…”