Rabbit Anti-Human IL-13 monoclonal antibody, clone 32I7I6

Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 x 10(-74)), rs6924962 (P = 3.21 x 10(-19)) and rs892666 (P = 1.11 x 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 x 10(-16)) and rs918518 (P = 3.22 x 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 x 10(-13)), IL13 (rs1295685; P = 1.65 x 10(-7)), IL23A (rs61937678; P = 1.82 x 10(-7)) and TNFAIP3 (rs642627; P = 5.90 x 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.

Type I interferon (IFN-alpha/beta) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-alpha/beta-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-alpha/beta signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-alpha/beta-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-alpha/beta signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.