Mayumi Ueta

Our previous study of polymorphisms in the HLA-class I genes of 71 Japanese SJS/TEN patients with ocular surface complications and 113 Japanese healthy controls showed that in the Japanese, HLA-A*0206 was strongly associated with SJS/ TEN. In this study, we examined 118 Japanese SJS/ TEN patients with ocular surface complications and a new control group consisting of 220 healthy Japanese volunteers, and investigated the association between HLA class I antigens, HLA-A, B, C, and the SJS/ TEN. For HLA genotyping we enrolled 118 Japanese patients with SJS/TEN in the chronic or sub-acute phase at Kyoto Prefectural University of Medicine; all presented with ocular surface complications. We also enrolled 220 healthy Japanese volunteers. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO). Results : HLA-A*0206 was most strongly associated with Japanese SJS/TEN patients with ocular surface complications (carrier frequency: p = 0.0000000002, OR = 5.2; gene frequency : p = 0.000000007, OR = 4.2). HLA-A* 0206 is strongly associated with Japanese SJS/TEN patients with ocular surface complications.

Prostaglandin F2α (PGF2α) analogues eye drops are regarded as a first choice for the treatment of glaucoma. The hypotensive action of PGF2α analogues is thought to be attributed to an increase in uveoscleral outflow.1 However, the underlying mechanisms have yet to be well defined. The purpose of this present study was to examine prostaglandin F receptor (FP) localisation in ocular tissue. All experiments were conducted in accordance with the principles set forth in the Declaration of Helsinki. The expression of FP was examined by X-gal staining in ocular tissues of FP knockout mice carrying the β-galactosidase gene at the FP loci ( Ptgfr−/− mice)2 and reverse transcription PCR of human conjuncitival and scleral fibroblasts (see supplementary methods, published online only). First, FP localisation was examined using Ptgfr−/− mice in which the β-galactosidase gene was ‘knocked-in’ at the FP gene. …

To clarify the characteristic appearances of early-stage Acanthamoeba keratitis (AK) and to investigate the effects of topical steroids on those appearances. This study involved 25 eyes of 24 patients diagnosed as early-stage AK at Kyoto Prefectural University of Medicine between October 2002 and June 2008. All patients were contact lens wearers, and 23 patients (96%) were referred from other hospitals. Clinical findings in the medical records of all patients were analyzed retrospectively. Radial keratoneuritis was observed in 20 of 25 eyes (80%), and pseudodendritic lesions were observed in 15 eyes (60%). Only 1 eye (4%) showed neither of these two findings. Of the 10 eyes treated with topical steroids until the first presentation at our hospital, 6 eyes manifested radial keratoneuritis and/or pseudodendritic lesions after the discontinuation of that treatment. The visual prognosis was good in both groups, with or without topical steroid treatment. We found that radial keratoneuritis and pseudodendritic lesions are characteristic appearances of early-stage AK, and that topical steroid treatment might mask these characteristic findings.

Ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation, whereas immune competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs), induce inflammation, and, thereby, exclude microbes. The difference between macrophages and ocular surface epithelial cells could be due to their dissimilarity in coexistence with commensal bacteria. The unique innate immune response of the ocular surface epithelium might contribute to its coexistence with commensal bacteria. Moreover, we suspect that some ocular surface inflammatory disorders might be caused by abnormality of the mucosal innate immunity. We considered the possibility that there is an association between Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)-a severe variant of SJS-and a disordered innate immune response. In gene expression analysis of CD14⁺ cells, we found that interleukin-4 receptor (IL-4R) gene expression was different between patients with SJS/TEN and normal control subjects upon lipopolysaccharide (LPS) stimulation: it was downregulated in the former and slightly upregulated in the latter. Furthermore, expression of mRNA specific for IκBζ and interleukin (IL)-1α was lower in patients with SJS/TEN than in normal controls after 1-hour culture. We next performed single nucleotide polymorphism (SNP) association analysis of IL-4R, IκBζ, and IL1α genes and TLR2 and TLR3-genes associated with innate immunity-in 80 Japanese patients with SJS/TEN and 160 Japanese healthy volunteers. IL4R SNP Gln551Arg (rs.1801275) (P = 0.0004), TLR3 rs.3775296T/G SNP (P = 0.0001) and TLR3 rs.3775290A/G SNP (P = 0.009) showed a significant association with SJS/TEN. IκBζ SNP rs.595788G/A showed a weak inverse association (P = 0.04). Genetic and environmental factors may play a role in an integrated etiology of SJS/TEN, and there is possibly an association between SJS/TEN and a disordered innate immunity.

Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute severe blistering diseases of the skin and also two of the most devastating ocular surface diseases leading to corneal damage and loss of vision. The extreme rarity of cutaneous and ocular surface reactions to drug therapies led us to suspect individual susceptibility. SJS/TEN patients in the acute stage were reported to manifest increased serum levels of Fas Ligand (FasL). Thus, we performed SNP association analysis of the FasL gene. Methods: In 76 Japanese SJS/TEN patients with ocular surface complications and 160 Japanese healthy controls, we examined four SNPs of FasL reported in the Japanese Single Nucleotide Polymorphisms (JSNP) database by sequencing. Results: The SNP rs.3830150 A/G showed a significant strong inverse association with SJS/TEN. Analysis of the genotype pattern of SNPs rs.3830150 and rs.2639614 (rs.3830150 A/A–rs.2639614 G/G) also manifested a strong inverse association with SJS/TEN. Conclusion: FasL gene polymorphisms might be associated with SJS/TEN.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents or inciting drugs. The authors previously reported an association between SJS/TEN and IL-4R gene polymorphism that is essential for IL-4 and IL-13 signaling. To examine IL-4 and IL-13 gene polymorphisms and the combination of these polymorphisms with IL-4R polymorphism, the authors performed polymorphism analysis. In 76 Japanese SJS/TEN patients with ocular surface complications and 160 healthy controls, the authors analyzed polymorphisms of the promoter -590C/T in the IL-4 gene and of the promoter -1111C/T and Arg110Gln in the IL-13 gene and assessed Gln551Arg in the IL-4R gene. Because Arg110Gln affects serum IL-13, plasma IL-13 levels were also examined. In the SJS/TEN patients, the Arg110Gln SNP of IL-13 was significantly associated with the disease, and the frequency of Arg110 alleles was significantly higher than that in the controls. Plasma IL-13 tended to be lower in SJS/TEN patients than in the controls. Analysis of the genotype pattern of IL-4R SNP Gln551Arg and IL-13 SNP Arg110Gln showed that the Gln551Gln(A/A)-Arg110Arg(G/G) genotype pattern was also associated with SJS/TEN. IL-13 gene polymorphisms might be associated with SJS/TEN with ocular surface complications. The present findings suggest that SJS/TEN is different from allergic diseases such as atopy and asthma because the ratio of each allele in the IL-13 SNP Arg110Gln was the opposite of the ratio in those diseases. They also reveal that combined polymorphisms in the IL-13/IL-4R signaling pathway were associated with SJS/TEN with ocular surface complications.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. Although the pathobiological mechanisms underlying the onset of SJS/TEN have not been fully established, the extreme rarity of cutaneous and ocular surface reactions to drug therapies led us to suspect individual susceptibility. Our previous study of polymorphisms in the HLA-class I genes of 40 Japanese SJS/TEN patients with ocular surface complications showed that in the Japanese, HLA-A*0206 was strongly associated with SJS/TEN. In this study, we investigated the association between HLA class II antigens in addition to HLA class I antigens and SJS/TEN. We studied the histocompatibility antigen genes, HLA-A, B, C, DRB1, and DQB1, of 71 Japanese SJS/TEN patients with ocular complications. We also genotyped 113 healthy volunteers for HLA-A, B, C, DRB1, and DQB1. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. HLA-A*0206 was strongly associated with SJS/TEN. HLA-A*1101 was inversely associated. HLA-B*5901 exhibited a high odds ratio for SJS/TEN with ocular complications. However, when we corrected the p-value for the number of alleles detected (n=29), the results ceased to be significant. There was no association between HLA-C and SJS/TEN. There was also no significant association between HLA-DRB1 and SJS/TEN. HLA-DQB1*0502 was negatively and weakly associated with SJS/TEN although correction of the p-value for the number of alleles detected rendered the result not significant. Because our findings are completely different from data reported on Caucasian patients, they suggest strong ethnic differences in the HLA-SJS associations.