Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1‐keratin 5–specific transgenic mice

Ueta, Mayumi; Hamuro, Junji; Nishigaki, H; Nakamura, Nobutaka; Shinomiya, Katsuhiko; Mizushima, Katsura; Hitomi, Yuki; Tamagawa‐Mineoka, Risa; Yokoi, Norihiko; Naito, Yuji; Tokunaga, Katsushi; Katoh, Norito; Sotozono, Chie; Kinoshita, Shigeru

doi:10.1111/all.13308

Cited by 13 publications

(22 citation statements)

References 33 publications

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“…43 It is possible that multiple susceptibility genes for CM-SJS/TEN with SOC are involved in forming functional networks. We documented that EP3 suppresses the TLR3 ligand and PolyI:C-induced cytokine production, 48,49,53,54 and that IKZF1 was upregulated by the TLR3 ligand polyI:C. 51 An imbalance in these genes may trigger the mucocutaneous inflammation seen in patients with CM-SJS/TEN with SOC ( Fig. 7a).…”

Section: Strategies For the Futurementioning

confidence: 87%

“…6b). Histologic analysis showed not only dermatitis but also tissue inflammation in the blepharoconjunctiva, tongue, and paronychia 51 as with patients in the acute state of SJS/TEN with SOC. 2 Our findings suggest that IKZF1 plays a critical role in maintaining mucocutaneous homeostasis 2 and that it might be implicated in the aggravation of mucocutaneous inflammation seen in the presence of CM-SJS/TEN with SOC.…”

Section: Ikzf1mentioning

confidence: 91%

“…44 In epidermal keratinocytes and conjunctival epithelial cells, polyI:C, a TLR3 ligand, upregulated the expression of IKZF1 mRNA. 51 We produced K5-Ikzf1-EGFP transgenic (Ikzf1-Tg) mice by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva. 51 Mucocutaneous inflammation was exacerbated in these mice; they developed dermatitis; some developed blepharoconjunctivitis 51 (Fig.…”

Section: Ikzf1mentioning

confidence: 99%

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Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Ueta

2018

Invest. Ophthalmol. Vis. Sci.

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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We found that cold medicines, including multi-ingredient cold medications and nonsteroidal antiinflammatory drugs, were the main causative drugs especially in patients with SJS/TEN with SOC. Cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC was strongly associated with HLA-A*02:06 in the Japanese populations, and significantly associated with HLA-B*44:03 in the Japanese and in Indian and Brazilian populations. Single nucleotide polymorphism association analysis showed that the Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKZF1 gene were significantly associated with CM-SJS/TEN with SOC and that they could regulate mucocutaneous inflammation including that of the ocular surface. As we found several HLA-SNP sets with a high odds ratio, we postulated that they may help to predict the possible development of SJS/TEN with SOC. From our findings we suggest that besides microbial infection and cold medicines, a combination of multiple gene polymorphisms and their interactions contribute strongly to the onset of CM-SJS/TEN with SOC.

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Section: Strategies For the Futurementioning

confidence: 87%

Section: Ikzf1mentioning

confidence: 91%

Section: Ikzf1mentioning

confidence: 99%

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Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Ueta

2018

Invest. Ophthalmol. Vis. Sci.

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“…For GeneChip analysis and quantitative RT-PCR, in vivo human conjunctival epithelium was harvested from conjunctival tissue obtained during ocular surface reconstruction or conjunctivochalasis surgery by overnight immersion at 4°C in 1.0 U/mL purified dispase (Roche Diagnostic, Basel, Switzerland) 13…”

Section: Methodsmentioning

confidence: 99%

“…Human conjunctival tissue samples were from patients with SJS/TEN undergoing ocular surface reconstruction. The controls were nearly normal conjunctival tissue samples from operated patients with conjunctivochalasis 11–14…”

Section: Methodsmentioning

confidence: 99%

Gene expression analysis of conjunctival epithelium of patients with Stevens-Johnson syndrome in the chronic stage

et al. 2019

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ObjectiveTo investigate the pathology underlying the ocular surface complications of patients with Stevens-Johnson syndrome (SJS) in the chronic stage.Methods and analysisUsing oligonucleotide microarrays, we performed comprehensive gene expression analysis of the conjunctival epithelium of patients with SJS in the chronic stage (n=3). The controls were patients with conjunctival chalasis (n=3). We confirmed the downregulation and upregulation of transcripts of interest by quantitative real-time PCR (RT-PCR) assay. The expression of ocular surface protein with significantly upregulated transcripts was assessed immunohistochemically.ResultsCompared with the controls, in the conjunctival epithelium of patients with SJS, 50 transcripts were downregulated by less than one-tenth (analysis of variance (ANOVA) p<0.05). Transcripts MUC7, PIGR, HEPACAM2, ADH1C and SMR3A were downregulated by less than one-fiftieth. 65 transcripts were upregulated more than 10- fold; the difference between patients with SJS and the controls was significant (ANOVA p<0.05). There were 14 transcripts that were upregulated more than 50-fold; they were SERPINB4, KRT1, KRTDAP, S100A7, SBSN, KLK6, SERPINB12, PNLIPRP3, CASP14, ODZ2, CA2, CRCT1, CWH43 and FLG. Quantitative RT-PCR of conjunctival epithelium samples from 11 patients with SJS and 26 controls showed that the gene expression of PIGR, HEPACAM2 and ADH1C was significantly downregulated while the gene expression of ODZ2 (teneurin-2) was significantly upregulated in patients with SJS. We document that teneurin-2 protein can be expressed in human conjunctival epithelium.ConclusionOur results suggest that the downregulation of PIGR, HEPACAM2 and ADH1C and upregulation of teneurin-2 expression contribute to the pathology of the ocular surface in patients with SJS in the chronic stage.

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Mapping of susceptible variants for cold medicine-related Stevens–Johnson syndrome by whole-genome resequencing

et al. 2021

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Stevens–Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10−17), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.

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Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1‐keratin 5–specific transgenic mice

Abstract: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

Cited by 13 publications

References 33 publications

Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Gene expression analysis of conjunctival epithelium of patients with Stevens-Johnson syndrome in the chronic stage

Mapping of susceptible variants for cold medicine-related Stevens–Johnson syndrome by whole-genome resequencing

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