Language：Japanese   Publisher：(公財)日本眼科学会  

分子生物学的手法や検査機器の開発といった技術革新により,ポリメラーゼ連鎖反応法を用いた眼内液中の網羅的病原体遺伝子解析,ゲノム解析による発症や進行予測など,診断・活動性評価法の発展が目覚ましい.また,抗tumor necrosis factor(TNF)α阻害薬や抗vascular endothelial growth factor(VEGF)薬療法に代表される生物学的製剤の登場により治療のパラダイムシフトが生じ,有効な治療法がなく,光覚を維持することすら難しかった難治性眼疾患患者に,文字どおり光を与えることが可能になってきている.しかし,これらの診断,治療法の進歩にもかかわらず依然として課題が残されている.近年,個人の臨床情報の蓄積と,ゲノム情報,遺伝子発現(トランスクリプトーム),蛋白質発現(プロテオーム)などの網羅的な解析技術の発展により,効果的な薬剤選択,再発・予後予測など,個別化医療あるいは精密医療の実現が近づきつつある.我々の研究グループでは,(1)ぶどう膜炎の視力障害の原因第1位である黄斑浮腫,(2)ウイルスが原因となるぶどう膜炎の代表的眼疾患である急性網膜壊死(ARN)とhuman T-cell lymphotropicvirus type 1(HTLV-1)関連ぶどう膜炎(HAU),(3)眼疾患のなかで最も生命予後不良な硝子体網膜リンパ腫(VRL)の3疾患を,眼炎症,感染症疾患における臨床的重要課題と位置づけている.本稿では,これら3疾患を中心に,基礎研究ではヒト眼内液を用いた遺伝子や蛋白質などの網羅的解析,臨床研究では臨床データを用いた統計学的解析による視力予後予測などを中心に,その研究成果について報告する.I.ぶどう膜炎黄斑浮腫(UME)に対する新規治療標的の探索についてUMEは,当初は副腎皮質ステロイド治療に反応していても長期的には副腎皮質ステロイド治療抵抗性や副作用により難治性となる.抗TNF阻害薬療法に対し治療効果のない症例もあり,新規治療法の開発が求められている.我々はぶどう膜炎患者由来眼内液中のサイトカイン・ケモカインなどの催炎症因子を網羅的に解析し,UMEの新規標的因子を探索した.サルコイドーシス・Behcet病に伴う黄斑浮腫では,B-cell activating factor belonging to the TNF family(BAFF)の硝子体液中の濃度が高値であることを見出した.分子生物学的手法を用いたBAFFの機能解析結果から,BAFFのUMEへの関連について報告する.II.ARNに対する視力予後とHAUの病態解明ARNはその激烈な転帰のため視力予後が不良となる代表的な眼疾患である.今回,九州大学病院眼科の臨床データを用いて,ARNの初診時臨床所見から視力予後予測を行った.さらに視力予後予測式の構築の試みについて報告する.また,HAUの病態はCD4陽性T細胞が主体であるとされているが,CD8陽性T細胞でもHAUと類似した病態が生じる可能性について報告する.III.VRLの病態制御機構の解明と遺伝子パネルによる診断について近年,罹患数が増加しているVRLは発症後高率に中枢神経系(CNS)へ浸潤し,生命予後が不良とされている.CNS浸潤予防目的のメトトレキサートを基盤とする化学療法は予後改善に有効との報告はあるが,我々の4年以上の長期経過観察が可能であった症例の全生存解析の結果から,化学療法を施行しても短期間でCNSに浸潤し予後不良な症例があることを見出した.また,我々はVRL由来硝子体液中の催炎症因子の網羅的解析により,早期死亡例で制御性T細胞(Treg)の分化・増殖に関連するサイトカインであるインターロイキン(IL)-35の濃度上昇を見出した.さらに眼内液の遺伝子パネルを用いたVRL診断,治療薬の候補の提示についての試みを報告する.(著者抄録)

researchmap

Language：English   Publisher：Cell Stem Cell  

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome. Human NGFR+ basal cells are identified as bipotent conjunctiva stem cells. Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), human adenovirus 8 (hAdV8), and SARS-CoV-2. HSV1 infection was reversed by acyclovir addition, whereas hAdV8 infection, which lacks an approved drug therapy, was inhibited by cidofovir. We document transcriptional programs induced by HSV1 and hAdV8. Finally, conjunctival organoids can be transplanted. Together, human conjunctiva organoid cultures enable the study of conjunctival (patho)-physiology.

DOI： 10.1016/j.stem.2023.12.008

Web of Science

Scopus

PubMed

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Mucosal-associated invariant T (MAIT) cells are a unique subset of T cells that recognizes metabolites derived from the vitamin B2 biosynthetic pathway. Since the identification of cognate antigens for MAIT cells, knowledge of the functions of MAIT cells in cancer, autoimmunity, and infectious diseases has been rapidly expanding. Recently, MAIT cells have been found to contribute to visual protection against autoimmunity in the eye. The protective functions of MAIT cells are induced by T-cell receptor (TCR)-mediated activation. However, the underlying mechanisms remain unclear. Thus, this mini-review aims to discuss our findings and the complexity of MAIT cell-mediated immune regulation in the eye.

DOI： 10.3389/fimmu.2024.1341180

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ocular Immunology and Inflammation  

PURPOSE: This study aimed to assess the clinical features of pediatric uveitis at a tertiary referral center in Western Japan. METHODS: One hundred forty eyes of 80 patients aged <20 years at the time of uveitis onset, who visited Kyushu University Hospital between January 2010 and December 2019 were included in this study. Clinical records were retrospectively reviewed. Demographics, clinical findings, treatments, and visual prognoses were compared between the disease groups. RESULTS: Of 80 patients, 32 were males and 48 were females. The average age of onset was 12.5 ± 4.8 (0-19) years. Tubulointerstitial nephritis and uveitis (TINU) and juvenile idiopathic arthritis (JIA) were the most frequent causes, accounting for 11.3% and 10% of cases, respectively, followed by sarcoidosis (5%), Behçet's disease, acute anterior uveitis, Vogt-Koyanagi-Harada disease, and juvenile chronic iridocyclitis (3.8% each). Infectious uveitis accounted for 7.6% of the cases: cytomegalovirus was the most frequent agent. Of these cases, 43.8% were unclassified. Systemic therapies were administered to 87.5% of the patients with JIA, 33.3% of those with TINU, and 28.6% of the other diagnostic groups. In the unclassified group, 80% of the patients were followed up with only topical corticosteroids. LogMAR visual acuity of 0 or less accounted for more than 80% in the final examination. CONCLUSION: TINU and JIA were the most common causes of pediatric uveitis. Although each required systemic therapy, most unclassified cases of pediatric uveitis were managed by topical corticosteroids alone with good visual prognosis. Accurate diagnosis is important for pediatric uveitis management.

DOI： 10.1080/09273948.2023.2273363

Web of Science

Scopus

PubMed

researchmap

Web of Science

Web of Science

Publisher：金原出版  

DOI： 10.18888/ga.0000003125

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Ophthalmology  

OBJECTIVES: To evaluate long-term outcomes of infliximab (IFX) treatment in patients with Behçet's disease (BD)-associated uveitis. PATIENTS AND METHODS: We retrospectively analyzed the cases of patients with BD-associated uveitis treated with IFX for > 5 years. We compared the numbers of ocular inflammatory attacks, ocular disease activities, and visual acuity before and after the initiation of IFX treatment. RESULTS: The 24 patients were 20 men and 4 women. Their mean age at the initiation of IFX treatment was 37.3 ± 9.2 years. The mean term from the initiation of IFX treatment was 10.3 ± 2.4 years. The average number of ocular inflammatory attacks was 5.4 ± 2.1 per 12 months before the IFX treatment and significantly lower at 0.83 ± 0.96 per 12 months after the initiation of IFX treatment (p < 0.05). We used a scoring system for BD-associated uveitis named the Behçet's disease ocular attack score 24 (BOS24) to estimate the changes in ocular disease activities between before and after initiation of IFX treatment. The average score decreased significantly from 7.58 ± 2.77 to 2.55 ± 2.74 after the initiation of IFX treatment (p < 0.05). Even after > 5 years of the treatment, both the number of ocular attacks and the BOS24 score kept decreasing. The visual acuity in 42 of 48 eyes (24 patients) was improved or maintained. CONCLUSIONS: IFX was effective for controlling ocular inflammatory attacks and diminishing ocular disease activities in patients with BD-associated uveitis, and it maintained the patients' visual acuity.

DOI： 10.1007/s10792-022-02495-z

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(公財)日本眼科学会  

researchmap

Publisher：金原出版  

DOI： 10.18888/ga.0000003028

CiNii Research

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

In the published article, there were errors. In the original article, there was an error in the description of the Reverse primer sequence in Materials and methods. A correction has been made to Materials and methods, “Deep amplicon sequencing of CMV-UL40 genomic DNA”. This sentence previously stated: “The following forward and reverse primers were used:Forward, 5′-TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGCAACAGTCGGCAGAATGAAC-3′ and Reverse, 5′-GTCTCGTGGGCTCGGAGATGTGTATAAGAGACA GCTGGAACACGACGCATA-3’.”The corrected sentence appears below: “The following forward and reverse primers were used: Forward, 5′-TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGCAACAGTCGGCAGAATGAAC-3′ and Reverse, 5′-GTCTCGTGGGCTCGGAGATGTGTATAAGAGAC AGCTGGAACACGAGCGGACATA-3’.”In the original article, there was another error in the description of the concentration of the anti-HLA-E antibody in Materials and methods. A correction has been made to Materials and methods, “Immunohistochemistry analysis”. This sentence previously stated: “After antigen retrieval with boiling citrate buffer (pH 6.0), the sections were incubated with 5% skim milk for 1 h at room temperature to prevent nonspecific binding and stained with 10 mL/mL anti-HLA-E antibody [MEM-E/02] (Abcam; Cambridge, UK) or IgG from mouse serum (Sigma-Aldrich) overnight at 4°C.” The corrected sentence appears below: “After antigen retrieval with boiling citrate buffer (pH 6.0), the sections were incubated with 5% skim milk for 1 h at room temperature to prevent nonspecific binding and stained with 10 mg/mL anti-HLA-E antibody [MEM-E/02] (Abcam; Cambridge, UK) or IgG from mouse serum (Sigma-Aldrich) overnight at 4°C.” The authors apologize for these errors and state that these do not change the scientific conclusions of the article in any way. The original article has been updated.

DOI： 10.3389/fimmu.2022.1124440

Web of Science

Scopus

PubMed

researchmap

CiNii Research

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD8+T cell responses. Variations in UL40 sequences have been studied mainly in the peripheral blood of CMV-viremia cases. In this study, we sought to investigate how ocular CMV disease develops from CMV infections. CMV gene sequences were compared between the intraocular fluids and peripheral blood of 77 clinical cases. UL40 signal peptide sequences were more diverse, and multiple sequences were typically present in CMV-viremia blood compared to intraocular fluid. Significantly stronger NK cell suppression was induced by UL40-derived peptides from intraocular HCMV compared to those identified only in peripheral blood. HCMV present in intraocular fluids were limited to those carrying a UL40 peptide sequence corresponding to the leader peptide sequence of the host's HLA class I, while UL40-derived peptides from HCMV found only in the peripheral blood were disparate from any HLA class I allotype. Overall, our analyses of CMV-retinitis inferred that specific HCMV strains with UL40 signal sequences matching the host's HLA signal peptide sequences were those that crossed the blood-ocular barrier to enter the intraocular space. UL40 peptide repertoires were the same in the intraocular fluids of all ocular CMV diseases, regardless of host immune status, implying that virus type is likely to be a common determinant in ocular CMV disease development. We thus propose a mechanism for ocular CMV disease development, in which particular HCMV types in the blood exploit peripheral and central HLA-E-mediated tolerance mechanisms and, thus, escape the antivirus responses of both innate and adaptive immunity.

DOI： 10.3389/fimmu.2022.1008220

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：American Journal of Ophthalmology Case Reports  

PURPOSE: This article presents a case of panuveitis that occurred after unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a patient with lymphoma-type human T-cell leukemia virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL). OBSERVATIONS: A 45-year-old man developed unilateral panuveitis 18 months after undergoing allo-HSCT. He underwent vitrectomy, and depositions of grey-white granules localized on the retinal artery were observed in the eye. Cytological examination of the vitreous aspirates showed that the atypical lymphoid cells stained positive for CD3 and CD8, but negative for CD4, B-cell markers, and cytomegalovirus antigen. Interphase fluorescence in situ hybridization using X- and Y-chromosome probes revealed complete donor chimerism in CD8+ T cells in the vitreous aspirates. CONCLUSIONS AND IMPORTANCE: Donor-derived CD8+ T lymphocytes can induce panuveitis like HTLV-1-assiciated uveitis after allo-HSCT in patients with ATL. Pathological diagnosis of vitreous infiltration by vitrectomy is helpful in patients with ATL. Donor-derived CD8+ T lymphocytes-induced panuveitis is recurrent but susceptible to regional corticosteroid treatment.

DOI： 10.1016/j.ajoc.2022.101673

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Medicine  

AIM: To investigate the causes of low prevalence of Fuchs' uveitis syndrome (FUS) in Japan. METHODS: Medical records of 160 patients diagnosed with FUS at 14 uveitis specialty facilities in Japan were reviewed retrospectively. RESULTS: In 160 FUS patients, mean follow-up period before referral to our uveitis facilities was 31.6 ± 50.9 months. The most common reason for referral was idiopathic uveitis (61.9%), followed by cataract (25.0%), high intraocular pressure (IOP) including glaucoma (16.3%), and FUS (14.4%). Unilateral involvement was 96.9%. The most frequent ocular finding of FUS was anterior inflammation (91.9%), followed by stellate-shaped keratic precipitates (88.1%), cataract/pseudophakia (88.1%), diffuse iris atrophy (84.4%), vitreous opacity (62.5%), heterochromia (53.1%) and high IOP including glaucoma (36.3%). As treatments of these ocular findings, cataract surgery was performed in 52.5%, glaucoma surgery in 10.6%, and vitrectomy in 13.8%. Mean logMAR VA was 0.28 ± 0.59 at the initial visit, and decreased significantly to 0.04 ± 0.32 at the last visit. Proportions of FUS patients with BCVA <0.1 and 0.1 to <0.5 decreased, while that of ≥0.5 increased at the last visit compared with the initial visit. CONCLUSIONS: Ocular findings of FUS in Japanese FUS patients were consistent with the characteristic features. The low prevalence of FUS in Japan may be a result of being overlooked and misdiagnosed as mild idiopathic uveitis, cataract, and/or glaucoma.

DOI： 10.3389/fmed.2022.999804

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology  

PURPOSE: Uveitis accounts for 10-15% of all cases of blindness in the developed world. Uveitic macular edema (UME) is a primary cause of permanent visual impairment in patients with uveitis. Because proinflammatory mediators elicit inflammation and lead to UME, we determined the profiles of proinflammatory mediators associated with complications, such as ME, in the vitreous humor of patients with panuveitis related to Behçet's disease (BD) and sarcoidosis. METHODS: In this retrospective study, we enrolled 21 patients with uveitis, including 6 with BD and 15 with sarcoidosis, and 15 patients with idiopathic epiretinal membrane (iERM) at the Department of Ophthalmology, Kyushu University Hospital, between January 2008 and April 2016. Vitreous concentrations of 32 proinflammatory mediators, including cytokines and soluble receptors of tumor necrosis factor (TNF) and interleukin (IL)-6 families, were assessed using a bead-based multiplex assay and their association with clinical data was examined. RESULTS: The levels of proinflammatory mediators, including a proliferation-inducing ligand (APRIL), B cell activating factor belonging to the TNF family (BAFF), soluble cluster of differentiation 30 (sCD30), soluble TNF receptor-1 (sTNFR1), sTNFR2, TNF-α, IL-6, and soluble IL-6 receptor-α (sIL-6Rα), were significantly higher in patients with uveitis. With regard to clinical parameters in patients with uveitis, vitreous levels of BAFF and sIL-6Rα were prominently elevated in patients with UME compared to in those without UME (P < 0.01, respectively). CONCLUSIONS: Our results suggest that elevated vitreous levels of BAFF and sIL-6Rα are associated with the pathogenesis of UME in patients with panuveitis related to BD and sarcoidosis.

DOI： 10.1007/s00417-022-05600-1

Web of Science

Scopus

PubMed

researchmap

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Methods in Molecular Biology  

This chapter is intended to serve as a practical guide for establishing a workflow using sequence-specific polymorphism PCR (SSP-PCR) for killer cell immunoglobulin-like receptor (KIR) genotyping in a clinical setting, especially in allogeneic hematopoietic stem cell transplantation (HSCT). As clinical evidence accumulates on the application of KIR and HLA genetics to guide donor selection in HSCT, there is an increasing need for KIR genotyping in clinical settings, and thus medical institutes may need to build this capability. Among the various KIR genotyping approaches now available, SSP-PCR methods are well-established and are the most cost-effective and will likely be the method of choice especially when expenses will be passed on to the patient. The protocol described in this chapter developed by Vilches et al. features small amplicon PCR and is suitable for KIR genotyping using FFPE-derived DNA as well as DNA extracted from blood samples. Setting up a laboratory workflow for in-house KIR genotyping is relatively straightforward; in this chapter, considerations for KIR genotyping to guide clinical decisions are discussed.In HSCT, a main objective of KIR genotyping is to apply the genetic analysis to predict donor and recipient combinations that have the most potential to produce NK cell alloresponses either through the missing-self mechanism or by action associated with activating KIR. The desired effects are reduction in acute GVHD and relapse rates and enhancement of overall survival. The information herein may also be useful to clinical laboratories considering the application of KIR genotyping in areas such as solid organ transplantation, NK cell-based treatment in other forms of cancer and autoimmune diseases, humanized antibody treatment, regenerative medicine, and reproductive medicine. Some background knowledge on KIR genetics will be necessary in managing a KIR genotyping platform. This chapter aims to address the main difficulties often encountered by physicians in understanding the KIR system, such as basic aspects of the nomenclature of KIR genes and haplotypes, genotypes, and determining presence/absence of KIR ligands in the patient and donor from the extensively diversified HLA class I allotypes. In describing the workflow, emphasis has been placed on the processes after genotype PCR and gel image acquisition: haplotype inference, generating B content scores, deduction of KIR ligands from HLA typing results, and the emerging algorithms for donor selection based on KIR and HLA genetics.

DOI： 10.1007/978-1-0716-2160-8_20

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cell Genomics  

The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (nreference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (ntotal = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10-4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.

DOI： 10.1016/j.xgen.2022.100101

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Methods in Molecular Biology  

Natural killer (NK) cells play a critical role in defending against virus infections.Investigating human NK cell antiviral functions is of prime importance; however, there are challenges such as the human-specific nature of many viruses and differences in NK cell surface markers between humans and rodents. Research on the antivirus response of human NK cells must therefore be carefully planned around species tropism of the viruses of interest and the specific biological questions to be answered. The initial site of many virus infections is a mucosal/epithelial surface. In this context, a clinical virus infection at the ocular surface enables direct analyses on the mechanisms and consequences of infection and immune reactions in situ over the course of disease. For example, the site of infection of a clinical infection in the conjunctiva and cornea can be directly observed in real-time, utilizing split-lamp microscopy, and specimens are readily accessed with minimally invasive techniques.In this chapter, we describe protocols for investigating NK cell responses using clinically isolated viruses in co-culture assays. We also describe procedures for ex vivo analysis of conjunctiva-derived NK cells in adenovirus infection.

DOI： 10.1007/978-1-0716-2160-8_15

Scopus

PubMed

researchmap

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mucosal Immunology  

Autoimmune uveitis is a sight-threatening disease induced by pathogenic T cells that recognize retinal antigens; it is observed in disorders including Vogt-Koyanagi-Harada disease (VKH). The roles of specific T cell subsets and their therapeutic potential against autoimmune uveitis are not fully understood. Here we conducted multi-parametric single-cell protein quantification which shows that the frequency of CD161highTRAV1-2+ mucosal-associated invariant T (MAIT) cells that recognize vitamin B2 metabolite-based antigens is decreased in relapsing VKH patients compared to individuals without active ocular inflammation. An experimental autoimmune uveitis (EAU) mouse model revealed that genetic depletion of MAIT cells reduced the expression of interleukin (Il) 22 and exacerbated retinal pathology. Reduced IL-22 levels were commonly observed in patients with relapsing VKH compared to individuals without active ocular inflammation. Both mouse and human MAIT cells produced IL-22 upon stimulation with their antigenic metabolite in vitro. An intravitreal administration of the antigenic metabolite into EAU mice induced retinal MAIT cell expansion and enhanced the expressions of Il22, as well as its downstream genes related to anti-inflammatory and neuroprotective effects, leading to an improvement in both retinal pathology and visual function. Taken together, we demonstrate that a metabolite-driven approach targeting MAIT cells has therapeutic potential against autoimmune uveitis.

DOI： 10.1038/s41385-021-00469-5

Web of Science

Scopus

PubMed

Language：Others   Publishing type：Research paper (scientific journal)  

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.

DOI： 10.3390/ijms22073623

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Adenoviral epidemic keratoconjunctivitis (EKC) is a major cause of ocular morbidity worldwide and specific antiviral therapies are not available. EKC is primarily caused by Human adenovirus D (HAdV-D) types 8, 37, 53, 54, 56 and 64. Considering the genomic variation in HAdV-D, we hypothesized that clinical signs could be differentiated by virus type. The hypothesis was retrospectively tested with clinical signs recorded from 250 patients with ocular infections visiting an ophthalmological clinic in southern Japan between 2011 and 2014. The results showed that conjunctival opacity, corneal epithelial disorders and pre-auricular lymphadenopathy, were more frequently associated with EKC than other ocular infections. Furthermore, HAdV types 8, 37 and 54, caused corneal complications and longer infections significantly more frequently than infections by types 53 and 56 (P < 0.05). Our descriptive results supported that symptoms severity vary with the infecting type, however, further research is needed to improve diagnosis of EKC.

DOI： 10.1016/j.diagmicrobio.2019.114885

Language：English   Publishing type：Research paper (scientific journal)  

Uveitis, which is a major cause of blindness worldwide, is defined as intraocular inflammation that affects the iris, ciliary body, vitreous, retina and choroid. Tumor necrosis factor-alpha (TNF-α) is a key cytokine involved in the pathogenesis of many inflammatory diseases including uveitis. Corticosteroids and immunosuppressive agents are the conventional therapy to treat non-infectious uveitis. In cases that are resistant to these therapies, anti-TNF agents are added. An anti-TNF-α agent, adalimumab, was recently approved for the treatment of refractory non-infectious uveitis. In this review, we provide an introduction to uveitis and summarize the effectiveness and safety of adalimumab in the treatment of non-infectious uveitis.

DOI： 10.1080/25785826.2019.1642080

Language：English   Publishing type：Research paper (scientific journal)  

Adenoviral epidemic keratoconjunctivitis (EKC) presents as severe conjunctival inflammations involving the cornea that can lead to the development of corneal opacities and blurred vision, which can persist for months. EKC is highly contagious and responsible for outbreaks worldwide, therefore accurate diagnosis and rapid containment are imperative. EKC is caused by a number of types within Human adenovirus species D (HAdV-D): 8, 37 and 64 (formerly known as 19a) and these types were considered the major causes of EKC for over fifty years. Nonetheless, recent improved molecular typing methodologies have identified recombinant HAdV-D types 53, 54 and 56, as newly emerging etiologic agents of EKC infections worldwide. EKC cases due to these recombinant types have potentially been underdiagnosed and underestimated as a source of new EKC outbreaks. Recombination events among circulating HAdV-D types represent a source of new infectious disease threats. Also, the growing number of adenoviral types enabled genomic and phenotypic comparisons to determine pathological properties related to EKC. This review covers the clinical features of EKC, current challenges in clinical practice and recent progress in EKC-related HAdV research, which focuses on the development of novel diagnostic and therapeutic approaches.

DOI： 10.1016/j.jcv.2019.01.004

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The aim of this study was to test the antiviral effectivity of potassium peroxymonosulfate (RUBYSTA^®, KYORIN) against five epidemic keratoconjunctivitis-related types of Human adenovirus D in vitro. Methods: Five types of Human adenovirus D (8, 37, 53, 54 and 56) were incubated with 1% potassium peroxymonosulfate, 0.1% sodium hypochlorite (NaClO) or alcohol-based disinfectant for 30 s or 1 min. These solutions were subjected to measurements of viral titres by infection assays in A549 cells. At day 6 post-infection, both, supernatants and cells, were collected and the viral genome was assessed by real-time polymerase chain reaction analysis. Results: Treatments with 1% potassium peroxymonosulfate led to significant reduction in all tested Human adenovirus D types comparable to disinfecting effects by 0.1% NaClO. Overall, potassium peroxymonosulfate demonstrated sufficient inactivation of the major epidemic keratoconjunctivitis-causing Human adenovirus D to be considered for disinfection and prevention purposes in ophthalmological clinics and hospitals. Conclusion: This study demonstrated that potassium peroxymonosulfate is a promising disinfectant for the prevention of epidemic keratoconjunctivitis nosocomial infections in ophthalmological clinics.

DOI： 10.1177/1120672119891408

Language：English   Publishing type：Research paper (scientific journal)  

The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B, and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2 ⁺ HLA-C. The relatively high frequency of C2 ⁺ HLA-C in the Nama and the Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

DOI： 10.4049/jimmunol.1701780

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The primary aim of this study is to isolate cytokines specific for active Graves’ orbitopathy (GO) in the tears of affected patients. The secondary aim is to identify other cytokines of interest and to look at the profile of their levels over time. Methods: This is a prospective pilot study conducted at the Singapore National Eye Centre. A total of 10 patients with active GO and 10 patients from each of 3 control groups were recruited. The 3 control groups were the following: age-matched normal female patients, patients with GO who were clinically inactive and patients with bilateral viral conjunctivitis. Tears from patients from the control groups were collected on a single visit. For patients with active GO, tears were collected on presentation, at 6 months, 12 months and 18 months. Results: Of all the cytokines examined, only IL-7 yielded a difference when the concentration in patients with active GO was compared with concentrations in all the control groups. This difference was most significant at the 18-month follow-up visit. Conclusions: Low concentrations of IL-7 in tears exhibit specificity for active GO in patients nearly 2 years from the clinical onset of activity. Although using IL-7 in tears as a biomarker for disease activity may be limited due to its late manifestation, targeting immune restitution using IL-7 may have disease modifying effects.

DOI： 10.1007/s12020-017-1467-2

Language：English   Publishing type：Research paper (scientific journal)  

HLA haplotype-homozygous (HLA-homo) induced pluripotent stem cells (iPSCs) are being prepared to be used for allogeneic transplantation of regenerated tissue into recipients carrying an identical haplotype in one of the alleles (HLA-hetero). However, it remains unaddressed whether natural killer (NK) cells respond to these regenerated cells. HLA-C allotypes, known to serve as major ligands for inhibitory receptors of NK cells, can be classified into group 1 (C1) and group 2 (C2), based on their binding specificities. We found that the T cells and vascular endothelial cells regenerated from HLA-homo-C1/C1 iPSCs were killed by specific NK cell subsets from a putative HLA-hetero-C1/C2 recipient. Such cytotoxicity was canceled when target cells were regenerated from iPSCs transduced with the C2 gene identical to the recipient. These results clarify that NK cells can kill regenerated cells by sensing the lack of HLA-C expression and further provide the basis for an approach to prevent such NK cell-mediated rejection responses.

DOI： 10.1016/j.stemcr.2017.07.020

Language：English   Publishing type：Research paper (scientific journal)  

The most severe form of virus-induced inflammation at the ocular surface is epidemic keratoconjunctivitis (EKC), often caused by group D human adenoviruses (HAdVs). We investigated the dynamics and mechanisms of changes in natural killer (NK) cell types in the human ocular mucosal surface in situ over the course of infection. In the acute phase of infection, the mature CD56 dim NK cells that comprise a major subpopulation in the normal human conjunctiva are replaced by CD56 bright NK cells recruited to the ocular surface by chemokines produced by the infected epithelium, and NKG2A-expressing CD56 dim and CD56 bright NK cells become the major subpopulations in severe inflammation. These NK cells attracted to the mucosal surface are however incapable of mounting a strong antiviral response because of upregulation of the inhibitory ligand human leukocyte antigen-E (HLA-E) on infected epithelium. Furthermore, group D HAdVs downregulate ligands for activating NK cell receptors, thus rendering even the mature NKG2A - NK cells unresponsive, an immune-escape mechanism distinct from other adenoviruses. Our findings imply that the EKC-causing group D HAdVs utilize these multiple pathways to inhibit antiviral NK cell responses in the initial stages of the infection.

DOI： 10.1038/mi.2015.47

Language：English   Publishing type：Research paper (scientific journal)  

Purpose The aim of the study was to determine the prevalence of human papillomavirus (HPV) in primary and recurrent pterygia samples collected from different ethnic groups in the equatorial Malay Peninsula. Methods DNA was extracted from 45 specimens of freshly obtained primary and recurrent pterygia from patients and from 11 normal conjunctival swabs from volunteers with no ocular surface lesion as control. The presence of HPV DNA was detected by nested PCR. PCR-positive samples were subjected to DNA sequencing to determine the HPV genotypes. Real-time PCR with HPV16 and HPV18 type-specific TaqMan probes was employed to determine the viral DNA copy number. Results Of 45 pterygia samples with acceptable DNA quality, 29 (64.4%) were positive for HPV DNA, whereas all the normal conjunctiva swabs were HPV negative. Type 18 was the most prevalent (41.4% of positive samples) genotype followed by type 16 (27.6%). There was one case each of the less common HPV58 and HPV59. Seven of the samples harboured mixed infections of both HPV16 and HPV18. All the four known recurrent pterygia samples were HPV-positive, whereas the sole early-stage pterygium sample in the study was HPV-negative. There was no significant association between HPV-positive status with gender or age. A high proportion of patients from the Indian ethnic group (five of six) were HPV-positive, whereas the Malay patients were found to have higher HPV positivity than the Chinese. The viral load of HPV18 samples ranged between 2 × 10² and 3 × 10⁴ copies per μg, whereas the viral load of HPV16 specimen was 4 × 10¹ to 10² copies per μg. Conclusion This report describes for the first time the quantitative measurement of HPV viral DNA for pterygium samples. The high prevalence of oncogenic HPVs in our samples suggests a possible role for HPV in the pathogenesis of pterygia. Moreover, the relatively low HPV viral load is concordant with the premalignant nature of this ocular condition.

DOI： 10.1111/aos.12427

Language：English   Publishing type：Research paper (scientific journal)  

Clinical studies have suggested the importance of the NK cell response against dengue virus (DenV), an arboviral infection that afflicts >50 million individuals each year. However, a comprehensive understanding of the NK cell response against dengueinfected cells is lacking. To characterize cell-contact mechanisms and soluble factors that contribute to the antidengue response, primary human NK cells were cocultured with autologous DenV-infected monocyte-derived dendritic cells (DC). NK cells responded by cytokine production and the lysis of target cells. Notably, in the absence of significant monokine production by DenV-infected DC, it was the combination of type I IFNs and TNF-α produced by DenV-infected DC that was important for stimulating the IFN-γ and cytotoxic responses of NK cells. Cell-bound factors enhanced NK cell IFN-γ production. In particular, reduced HLA class I expression was observed on DenV-infected DC, and IFN-γ production was enhanced in licensed/educated NK cell subsets. NK-DC cell contact was also identified as a requirement for a cytotoxic response, and there was evidence for both perforin/granzyme as well as Fas/Fas ligand-dependent pathways of killing by NK cells. In summary, our results have uncovered a previously unappreciated role for the combined effect of type I IFNs, TNF-α, and cell surface receptor-ligand interactions in triggering the antidengue response of primary human NK cells.

DOI： 10.4049/jimmunol.1302240

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1128/JVI.02875-12

Language：English   Publishing type：Research paper (scientific journal)  

Comparison of mutant killer cell Ig-like receptor (KIR) 3DL1*015 substituted at natural positions of variation showed that tryptophan/leucine dimorphism at position 283 uniquely changes receptor conformation and can strongly influence binding of the A24nef tetramer. Dimorphic motifs at positions 2, 47, and 54 in D0 and 182 and 283 in D1+D2 distinguish the two 3DL1 lineages, typified by 3DL1*005 and 3DL1*015. The interlineage recombinant, KIR3DL1*001, combines D0 of 3DL1*005 with D1+D2 of 3DL1*015 and binds A24nef more strongly than either parent. In contrast, the reciprocal recombinant with D0 from 3DL1*015 and D1+D2 from 3DL1*005 cannot bind A24nef. Thus, D0 polymorphism directly affects the avidity of the KIR3DL1 ligand binding site. From these observations, multiple sequence alignment, and homology modeling, we constructed structural models for KIR3DL1 and its complex with A24nef. In these models, D0, D1, and D2 come together to form a binding surface for A24nef, which is contacted by all three Ig-like domains. A central pocket binds arginine 83, the only Bw4 motif residue essential for KIR3DL1 interaction, similar to the binding of lysine 80 in HLA-C by KIR2DL1. Central to this interaction is a salt bridge between arginine 83 of Bw4 and glutamate 282 of 3DL1, which juxtaposes the functionally influential dimorphism at position 283. Further 3DL1 mutants were tested and shown to have A24nef-binding properties consistent with the models. A24nef was not bound by KIR3DS1, the activating counterpart of KIR3DL1. Moreover, introducing any one of three residues specific to KIR3DS1, serine 163, arginine 166, or leucine 199, into 3DL1*015, abrogated A24nef binding.

DOI： 10.4049/jimmunol.0901734

Language：English   Publishing type：Research paper (scientific journal)  

Variegated expression of 6 inhibitory HLA class I-specific receptors on primary NK cells was studied using high-dimension flow cytometry in 58 humans to understand the structure and function of NK-cell repertoires. Sixty-four subsets expressing all possible receptor combinations were present in each repertoire, and the frequency of receptor-null cells varied among the donors. Enhancement in missing-self response between NK subsets varied substantially where subset responses were defined by donor KIR/HLA allotypes, reflecting the differences in interaction between inhibitory receptors and their ligands. This contrasted to the enhancement conferred by NKG2A, which was constant and of intermediate strength. We infer a mechanism that modulates frequencies of the NK subsets displaying diverse levels of missing-self response, a system that reduces the presence of KIR-expressing subsets that display either too strong or too weak a response and effectively replaces them with NKG2A-expressing cells in the repertoire. Through this high-resolution analysis of inhibitory receptor expression, 5 types of NK-cell repertoire were defined by their content of NKG2A ⁺/NKG2A ^- cells, frequency of receptor-null cells, and degree of KIR receptor coexpression. The analyses provide new perspective on how personalized human NK-cell repertoires are structured.

DOI： 10.1182/blood-2008-03-143727

Language：English   Publishing type：Research paper (scientific journal)  

Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the "cross-reactions" were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor's interactions with HLA-C.

DOI： 10.4049/jimmunol.180.6.3969

Language：English   Publishing type：Research paper (scientific journal)  

Although it is clear that KIR3DL1 recognizes Bw4⁺ HLA-B, the role of Bw4⁺ HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4⁺ HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4⁺ tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLAA*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4⁺ ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.

DOI： 10.4049/jimmunol.178.1.33

Language：English   Publishing type：Research paper (scientific journal)  

Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand-receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR-HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population. JEM

DOI： 10.1084/jem.20051884

Language：English   Publishing type：Research paper (scientific journal)  

Natural killer (NK) cells activate quickly in response to pathogens, tumors, and allogeneic hematopoietic cell transplants. Modulating the NK cell response are clonally distributed NK cell receptors that survey cells for change in the expression of major histocompatibility complex (MHC) class I and structurally related ligands. Here the enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine staining (ICS), and short-term culture were used to quantify the response of bulk NK cell populations from human donors to HLA class I-deficient 221 cells and to 221 cells transfected with single HLA class I allotypes. NK cells in cultures containing interleukin-2 (IL-2) or IL-12 exhibited specificities of HLA class I-mediated inhibition that correlated well with those previously defined using NK cell clones in long-term culture and with the frequencies of cells expressing particular inhibitory HLA class I receptors. Culture with IL-12, but not IL-2, gave an increased frequency of cells expressing CD94: NKG2A but no change in killer immunoglobulin-like receptor (KIR) expression. For some heterozygote combinations of KIR3DL1 alleles, ICS can be used to compare the functional properties of the 2 allotypes. Thus, both the low-expressing KIR3DL1*005 and the high-expressing KIR3DL1*002 gave similar inhibitory response on challenge with an HLA-B*5801 ligand. The single-cell assays developed here should facilitate future population study and clinical analysis of human NK cell regulation by MHC class I.

DOI： 10.1182/blood-2004-08-3174

Language：English   Publishing type：Research paper (scientific journal)  

The killer cell immunoglobulin-like receptors (KIR) form a family of highly homologous immune receptors that regulate the response of natural killer (NK) cells and some T cells. The genetics of the human KIR family is reviewed in this article. In human populations, diversity in KIR genotype arises from variations in gene content and allelic polymorphism. Comparisons of 81 human KIR sequences reveal past events of gene duplication and recombination, and indicate that individual KIR genes have diversified from the influence of natural selection. Comparison and compilation of population studies reveal extensive KIR genotype variability within human populations and among them. Genomic analysis shows the KIR genes to be close to each other and separated by homologous sequences that promote haplotype diversification through assymetric recombination. In contrast, homologous recombination appears favored at a unique sequence in the center of the KIR locus, and much haplotypic diversity can be explained by recombination between a limited number of gene-content motifs in the centromeric and telomeric halves of the locus. The importance of NK cells for early defenses against infection suggests that human KIR genotype diversity is the accumulated consequence of a history of numerous and successive selective episodes by different pathogens on human NK-cell responses.

Language：English   Publishing type：Research paper (scientific journal)  

Genomic DNA from a panel of 41 healthy unrelated Japanese individuals was typed for the presence or absence of 16 KIR genes and pseudogenes. Only eight different KIR genotypes were found. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 56% of the panel. The frequency of A haplotypes in the Japanese is higher than that observed in other populations. Flow cytometric comparison of KIR expression in 19 panel members showed considerable diversity in NK cell repertoire, which was also seen within the group of individuals having two A haplotypes. This diversity is likely due to allelic polymorphism in expressed genes of the A haplotype. In comparison to other populations, the Japanese appear less heterogeneous in KIR genotype as assessed by gene content.

DOI： 10.1007/s00251-002-0497-x

Language：English   Publishing type：Research paper (scientific journal)  

Aims - To evaluate glucose tolerance of patients with Vogt-Koyanagi-Harada (VKH) disease before systemic corticosteroid therapy, and to assess changes brought on by treatment. Methods - 20 VKH patients with acute bilateral panuveitis were studied. 20 healthy adults and 11 Behcet's disease patients with active uveoretinitis served as controls. A 75 g oral glucose tolerance test (OGTT) was given in the acute stage of ocular inflammation before systemic corticosteroid therapy. The OGTT was repeated in the convalescent stage of VKH disease in the patients with glucose intolerance before treatment. Insulin response was examined at the same time as the OGTT when possible. Results - 55% of VKH patients (11/20) showed glucose intolerance but no apparent insulin secretion deficiency was detected. Four of seven patients in the convalescent stage showed improvement of glucose tolerance. None of the normal controls or disease controls showed glucose intolerance. Conclusion - A high incidence of glucose intolerance was found in the acute stage of VKH disease. However, glucose intolerance improved in most cases after systemic corticosteroid therapy. It is possible that glucose intolerance seen in VKH patients may be related to the autoimmune inflammatory process of this disease.

DOI： 10.1136/bjo.83.1.39

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese  

Language：English  

Language：Japanese  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：(一社)日本臨床免疫学会  

researchmap

Language：Japanese   Publisher：(株)先端医学社  

高度免疫能低下で起こる古典的サイトメガロウイルス(CMV)網膜炎の臨床像は近年変化している。また、眼内液網羅的PCR検査の普及によりCMV感染は古典的網膜炎に加え、ホストの免疫状態によって多様な眼炎症像を呈することが明らかになってきた。軽～中等度免疫抑制状態で発症し、広範な網膜血管閉塞を特徴とするCMV網膜炎は慢性網膜壊死として近年注視されている。多様なCMV関連眼疾患の病態は感染免疫・加齢研究など多分野において重要な知見となることが期待される。(著者抄録)

Language：Japanese   Publisher：(株)メディカル葵出版