Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals.

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.

Kinetics of Tear Fluid Proteins after Endothelial Keratoplasty and Predictive Factors for Recovery from Corneal Haze.

Endothelial keratoplasty (EK) is less invasive with faster recovery as compared to conventional penetrating keratoplasty, however, it relies on the clarity of the host corneal stroma. Corneal transplantation involves the induction of immune tolerance for allogeneic tissues as well as the corneal wound healing process, in which coordinated interactions between cytokines and growth factors are critical. In this study, we profiled the expression of 51 soluble factors in the tear fluid over the course of EK and have provided evidence of dynamic changes in cytokine expression in the ipsilateral and contralateral eyes. Cluster analyses classified the cytokine expression kinetics into five groups. Group 1 proteins included TGF-b1, IL-1b, and innate proinflammatory cytokines, which bilaterally increased after surgery, despite the use of topical corticosteroid in the transplanted eyes. Local corticosteroids suppressed cytokines involved in adaptive immunity in the transplanted eyes but not in the contralateral eyes. We found tear protein expression at baseline and one week post-surgery to be a potential predictive biomarker of delayed recovery after EK in terms of the corneal haze and visual acuity. Furthermore, Group 1 tear proteins were most associated with persistent corneal haze pre-surgery as well as visual acuity at one month-post transplant.

Apoptosis in perforated cornea of a patient with graft-versus-host disease.

CASE REPORT: Although ocular complications associated with graft-versus-host disease (GVHD) can include corneal dysfunction, corneal perforation is not common. We report the presence of apoptotic cells in a perforated cornea of a patient with GVHD. A 72-year-old man with the angioimmunoblastic type of malignant lymphoma developed chronic GVHD after allogeneic peripheral blood stem cell transplantation. Despite systemic and topical treatment, both corneas perforated, and penetrating keratoplasty with cataract extraction and intraocular lens implantation was performed on both eyes. COMMENTS: The corneal button excised from the right eye was examined histologically and stained for apoptotic cells by TdT-mediated dUTP nick end labeling (TUNEL). This revealed thinning of the epithelial cell layer and stroma, with cells, including lymphocytes, infiltrating to the site of the perforation. Some of the epithelial cells and keratocytes were TUNEL positive. The presence of apoptotic cells in our case suggests that apoptosis may be involved in the perforation of the cornea in patients with GVHD.

Serous retinal detachment in an elderly patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia.

PURPOSE: To describe an elderly woman who presented with a serous retinal detachment (SRD) as the first sign of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). DESIGN: Observational case report. METHODS: A complete ophthalmic and systemic evaluation was performed on a 62-year-old woman because of decreased vision of 20/60 OD and 20/25 OS. RESULTS: Fundus examination revealed a SRD involving the fovea, OU. Fluorescein angiography disclosed multifocal spots of hyperfluorescence in the early phase, and diffuse subretinal accumulation of fluorescein in the late phase. She was diagnosed with Ph(+) ALL because of systemic findings. She underwent systemic chemotherapy and went into complete remission. Visual acuity improved to 20/20 in both eyes with resolution of the bilateral SRD. CONCLUSIONS: Our observations indicate that a sudden appearance of SRD, even in an elderly patient, warrants a thorough systemic screening for underlying leukemia. This is especially important, because prompt systemic chemotherapy can improve the visual acuity and the prognosis.

CXCR2 Expression on neutrophils is upregulated during the relapsing phase of ocular Behcet disease.

PURPOSE: To search for markers of Behcet disease (BD) activity,we measured CXCR1 and CXCR2 levels on the circulating leukocytes of patients suffering from ocular BD. METHODS: Peripheral blood leukocytes were harvested from healthy volunteers (n = 16) and ocular BD patients (n = 35). The patients consisted of 15 individuals in relapsing phase (6 with prednisolone treatment) and 20 individuals in remission phase (9 with prednisolone treatment). Expression of CXC chemokine receptors (CXCRs) on leukocytes (including lymphocytes, monocytes, neutrophils) was measured using flow cytometry. RESULTS: Without prednisolone treatment, CXCR2 expression (on both total leukocytes and neutrophils) in relapsing phase was significantly higher than in remission-phase patients or normal individuals. By contrast, no significant difference was detected in the expression of CXCR1 between any ofthe groups. Importantly, low-dose prednisolone therapy reduced CXCR2 expression on neutrophils. CONCLUSIONS: CXCR2 has a potential role in promot-ing uveitis during ocular attack and might also be a useful marker for disease activity.

A case of Vogt-Koyanagi-Harada disease with good visual acuity in spite of subfoveal fold.

BACKGROUND: Vogt-Koyanagi-Harada (VKH) disease patients with the complication of subretinal pigmented proliferative tissue tend to have a poor visual prognosis. CASE: We herein report a case of VKH with good visual acuity despite a prominent subretinal fold. OBSERVATIONS: A 24-year-old woman, who experienced several recurrent episodes of VKH disease, had bilateral serous retinal detachment with poor vision (RE 20/40 and LE 20/25). After the administration of high doses of systemic corticosteroids and D-mannitol, the subretinal fluid disappeared and the sensory retinas gradually became reattached. During the course of therapy, prominent pigmented subretinal strands were formed in both eyes. Optical coherence tomography disclosed that the strands existed at the retinal pigment epithelium level. Amazingly, we observed a change in the location of the fold in the posterior retina during the course of the disease. The patient finally showed the "sunset glow" fundi and a subretinal fold that was located almost directly beneath both fovea. Fortunately, this patient was able to recover and finally achieve a good visual acuity (RE 20/17 and LE 20/17). CONCLUSION: We reported a VKH disease patient with a good visual acuity despite a remarkable subfoveal fold, which changed its location during the course of the disease.

[Incidence of endogenous uveitis at Kyushu University Hospital].

PURPOSE: We performed a clinical statistical study on recent patients with endogenous uveitis at the clinic of the Department of Ophthalmology, Kyushu University Hospital. SUBJECTS: We studied 616 patients with endogenous uveitis who first visited the clinic of the Department of Ophthalmology, Kyushu University Hospital, between January 1996 and December 2001. RESULTS AND CONCLUSION: The most frequent clinical entity was sarcoidosis (8.6%), followed by Behçet's disease (8.4%), Vogt-Koyanagi-Harada syndrome (6.5%), human T-lymphotropic virus type I (HTLV-1) uveitis (3.9%), and toxoplasmosis (2.6%). Unclassified uveitis comprised 58.1% in our study. Next we classified the subjects into four age groups; adolescent (0-19 years old), young (20-39 years old), middle-aged (40-59 years old), and elderly (60-years old). We also classified the disease into four groups: uveitis pan, anterior, intermediate, and posterior uveitis, according to the site of inflammation. The most frequent clinical entity was Behçet's disease in the young group, and sarcoidosis in the elderly group. The frequency of unclassified uveitis was high in the adolescent and the elderly groups. As to the anatomic diagnosis of uveitis, panuveitis was most frequent, followed by anterior, posterior, and intermediate uveitis. Finally we investigated the frequency of secondary glaucoma. The frequency in all 616 patients was 19.7%. Secondary glaucoma was more frequent in male patients and more frequent in the middle-aged and the elderly groups.

Immunoregulatory role of ocular macrophages: the macrophages produce RANTES to suppress experimental autoimmune uveitis.

Murine experimental autoimmune uveitis (EAU) is a model of human uveitis. Ocular-infiltrating macrophages play a crucial role in the generation of tissue damage in EAU. In fact, several chemokines are actually produced in the inflamed eye. The aim of this study was to elucidate the role of ocular macrophage-derived chemokines in EAU. C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20, and the EAU severity was scored at multiple time points based on microscopic fundus observations (retinal vascular dilatation and exudates) and histological examinations. The peak inflammatory response was observed 1 wk (day 16) after the beginning of macrophage infiltration to the eye (day 9). Ocular-infiltrating cells were enriched or depleted of macrophages by magnetic beads and analyzed by real-time RT-PCR for chemokine mRNA production. We found that only the macrophage-enriched cells from the eye produced RANTES, and thus proposed that macrophage-derived RANTES facilitated the ocular inflammations. In contrast to our postulate, neutralization of RANTES by specific Ab in vivo on days 9 and 13 exacerbated EAU. We also found that the ratio of ocular CD4/CD8 T cells was markedly increased after treatment. As a result, RANTES neutralization might exacerbate EAU by modulating the type of T cell subsets recruited to the eye. In conclusion, our data provide insight into the immunoregulatory role of macrophages and RANTES in the pathogenesis of ocular inflammation. Not all macrophage-derived chemokines cause local inflammation, since RANTES produced by ocular macrophages appears to suppress EAU.