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Background: Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes, including the ocular surface, oral cavity, and genitals. These reactions are very rare but are often associated with inciting drugs, infectious agents, or both., Objective: We sought to identify susceptibility loci for cold medicine-related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement (SMI)., Methods: A genome-wide association study was performed in 808 Japanese subjects (117 patients with CM-SJS/TEN with SMI and 691 healthy control subjects), and subsequent replication studies were performed in 204 other Japanese subjects (16 cases and 188 control subjects), 117 Korean subjects (27 cases and 90 control subjects), 76 Indian subjects (20 cases and 56 control subjects), and 174 Brazilian subjects (39 cases and 135 control subjects)., Results: In addition to the most significant susceptibility region, HLA-A, we identified IKZF1, which encodes Ikaros, as a novel susceptibility gene (meta-analysis, rs4917014 [G vs. T]; odds ratio, 0.5; P = 8.5 × 10(-11)). Furthermore, quantitative ratios of the IKZF1 alternative splicing isoforms Ik1 and Ik2 were significantly associated with rs4917014 genotypes., Conclusion: We identified IKZF1 as a susceptibility gene for CM-SJS/TEN with SMI not only in Japanese subjects but also in Korean and Indian subjects and showed that the Ik2/Ik1 ratio might be influenced by IKZF1 single nucleotide polymorphisms, which were significantly associated with susceptibility to CM-SJS/TEN with SMI., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. They often affect the ocular surface and can result in permanent visual dysfunction., Objectives: We sought to discover genetic markers for SJS/TEN susceptibility., Methods: We performed a genome-wide association study with 60 patients and 300 control subjects. We applied stringent filter and visual assessments for selecting single nucleotide polymorphisms (SNPs) and a high false discovery rate threshold. We fine-mapped the region where a candidate SNP was found and confirmed the results by means of sequencing. We evaluated the function of agonist-activated prostaglandin E receptor 3 (EP3), the gene for which contained several SNPs, in regulating cytokine production in human conjunctival epithelial (CE) cells. The expression levels of EP3 in the CE cells from patients and control subjects were also compared., Results: We identified 3 SNPs that passed the false discovery rate threshold. One (rs17131450) was close to the EP3 gene. Therefore we analyzed the EP3 region in detail and identified 5 other SNPs. We confirmed the association between SJS/TEN and all 6 SNPs. Activated EP3 was expressed in control CE cells, and it suppressed polyI:C-stimulated cytokine production, suggesting that EP3 might help prevent ocular surface inflammation. Concordantly, the EP3 levels were much lower in the CE cells of the patients than in those of the control subjects., Conclusion: We demonstrated, using both genetic and functional analyses, that EP3 could be a key player in the pathogenesis of SJS/TEN accompanied by ocular complications., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Prostaglandin (PG) E(2) exerts a variety of actions through 4 G protein-coupled receptors designated as EP(1), EP(2), EP(3), and EP(4). We have reported that PGE(2) acts on EP(3) in airway epithelial cells and exerts anti-inflammatory actions in ovalbumin-induced murine allergic asthma. Although EP(3) is also expressed in skin and PGE(2) is produced abundantly during skin allergic inflammation, the role of PGE(2)-EP(3) signaling in skin allergic inflammation remains unknown., Objective: We sought to investigate whether PGE(2)-EP(3) signaling exerts anti-inflammatory actions in skin allergic inflammation., Methods: We used a murine contact hypersensitivity (CHS) model and examined the role of EP(3) by using an EP(3)-selective agonist, ONO-AE-248 (AE248), and EP(3)-deficient mice. The inflammation was evaluated by the thickness and histology of the hapten-challenged ear. Inflammation-associated changes in gene expression and effects of AE248 were examined by means of microarray analysis of the skin. Localization of EP(3) was examined by staining for beta-galactosidase knocked in at the EP(3) locus in EP(3)-deficient mice. EP(3) action was also examined in cultured keratinocytes., Results: Administration of AE248 during the elicitation phase significantly suppressed CHS compared with that seen in vehicle-treated mice. Microarray analysis revealed that administration of AE248 inhibited the gene expression of neutrophil-recruiting chemokines, including CXCL1, at the elicitation site. X-gal staining in EP(3)-deficient mice revealed EP(3) expression in keratinocytes, which was further confirmed by anti-EP(3) antibody in wild-type mice. In cultured keratinocytes AE248 suppressed CXCL1 production induced by TNF-alpha., Conclusion: PGE(2)-EP(3) signaling inhibits keratinocytes activation and exerts anti-inflammatory actions in murine CHS.

Background: We previously demonstrated that the prostaglandin E(2) (PGE(2))-EP3 pathway negatively regulates allergic reactions in a murine allergic asthma model., Objectives: We investigated whether the PGE(2)-EP3 pathway also regulates the development of murine experimental allergic conjunctivitis (EAC)., Methods: The expression of EP3 was examined by means of RT-PCR and immunohistochemistry in wild-type mice, as well as by means of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining in mice deficient in EP3 (Ptger3(-/-) mice) carrying the beta-galactosidase gene at the EP3 gene locus. EAC was induced by immunization of mice with short ragweed pollen (RW), followed by challenge with eye drops of RW, and eosinophil infiltration and eotaxin-1 mRNA expression in the conjunctiva were examined. Mice were also treated with a topical application of an EP3-selective agonist during the elicitation phase. Quantitative RT-PCR was used to detect expression of COXs and prostaglandin E synthases, and ELISA was used to measure PGE(2) production in the eyelid., Results: EP3 was constitutively expressed in conjunctival epithelium on the ocular surface. Ptger3(-/-) mice demonstrated significantly increased eosinophil infiltration in conjunctiva after RW challenge compared with wild-type mice. Consistently, significantly higher expression of eotaxin-1 mRNA was observed in Ptger3(-/-) mice. Conversely, treatment of wild-type mice with an EP3-selective agonist resulted in a significant decrease in eosinophil infiltration, which was blunted in Ptger3(-/-) mice. Expression of COX-2 and prostaglandin E synthases was upregulated and PGE(2) content was increased in the eyelids after RW challenge., Conclusion: These data suggest that PGE(2) acts on EP3 in conjunctival epithelium and downregulates the progression of EAC.