3%) and in 7 of 61 (11.5%) patients without inhibitors, corresponding to an OR of 5.4 (95% CI; 2.1–13.7, P < 0.001). TNF-α is an important mediator of inflammatory responses and has crucial immunomodulatory activities. The TNF-α locus is located in the HLA class III region of the MHC complex and several polymorphic sites have been described [17–19]. The most extensively studied polymorphism PD98059 in vitro with pathophysiological effects is a bi-allelic polymorphism at position -308 in the

promoter region of the TNF-α gene consisting of a substitution of an A (allele 2, A2) instead of a G (allele 1, A1). The polymorphism induces increased levels of TNF-α [20,21]. In the MIBS study, 142 patients (86.6%) were allele A1 carriers and 86 (52.4%) were allele A2 carriers compared with frequencies of 97% and 76% of alleles A1 and A2, respectively [10]. The most common genotype A1/A1 was identified in 78 (47.6%) of the patients, and homozygocity for the A2 allele (A2/A2) in 22 individuals (13.4%). Thirty-one of the 78 subjects (39.7%) with the A1/A1 genotype had inhibitors compared with 30 of 64 patients (46.9%; ns) with the A1/A2 genotype. Sixteen of 22 patients (72.7%) homozygous for allele 2 had inhibitors yielding an OR of 4.0 (95% CI 1.4–11.5, P = 0.008) with A1/A1 as the reference group. The association between the genotype A2/A2 and the development of inhibitors was consistent in subgroup analysis of the

124 patients with severe haemophilia A (OR 19.2, 95% CI 2.4–156.5, P < 0.001), as well as in the smaller group of 75 patients with inversions (OR 11.8, 95% CI 1.3–105.1, P = 0.013). Logistic regression SCH772984 manufacturer analysis revealed that the TNF-α genotype A2/A2 was associated with inhibitors after adjustment for the presence of allele 134 in the IL-10.G microsatellite in the entire cohort (OR 4.0, 95% CI 1.3–11.8, P = 0.013) as well as in the subgroup of patients with severe haemophilia (OR 19.3, 95% CI 2.3–162.1, P = 0.007). Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) is a receptor mainly displayed on activated T-cells. It mediates a down-regulation of the T-cell activity by competing with CD28 for the binding of the B7 molecules

[20,21]. Consequently, selleck screening library blockade of this interaction by CTLA-4-antibodies enhances T-cell proliferation and B-cell activity. Several polymorphisms in the CTLA-4 gene have been found to modulate the immune response in antibody-mediated autoimmune diseases, including two single nucleotide polymorphisms (SNPs) [22–26]. The first of these SNPs is located in the promoter region of the gene at position -318 (C or T). The T-allele has been associated with an up-regulation of the CTLA-4 activity on the activated T-cells, thereby counteracting the co-stimulatory signal provided by the B7-CD28 interaction required to elicit an immune response. The second SNP is located at position +49 in the coding sequence (CDS) 1 (A or G) encoding a threonine to alanine substitution in the leader peptide.