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Purpose To determine classification criteria for multifocal choroiditis with panuveitis (MFCPU) DESIGN: : Machine learning of cases with MFCPU and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the posterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 138 cases of MFCPU, were evaluated by machine learning. Key criteria for MFCPU included: 1) multifocal choroiditis with the predominant lesions size >125 µm in diameter; 2) lesions outside the posterior pole (with or without posterior involvement); and either 3) punched-out atrophic chorioretinal scars or 4) more than minimal mild anterior chamber and/or vitreous inflammation. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for MFCPU were 15% in the training set and 0% in the validation set. Conclusions The criteria for MFCPU had a reasonably low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for birdshot chorioretinitis. Design Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with: 1) the characteristic appearance a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots ("birdshot" spots); 2) absent to mild anterior chamber inflammation; and 3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either: 1) classic "birdshot spots" or 2) characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set. Conclusions The criteria for birdshot chorioretinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

PURPOSE: To determine classification criteria for serpiginous choroiditis. DESIGN: Machine learning of cases with serpiginous choroiditis and 8 other posterior uveitides. METHODS: Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand sixty-eight cases of posterior uveitides, including 122 cases of serpiginous choroiditis, were evaluated by machine learning. Key criteria for serpiginous choroiditis included (1) choroiditis with an ameboid or serpentine shape; (2) characteristic imaging on fluorescein angiography or fundus autofluorescence; (3) absent to mild anterior chamber and vitreous inflammation; and (4) the exclusion of tuberculosis. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for serpiginous choroiditis were 0% in both the training set and the validation set. CONCLUSIONS: The criteria for serpiginous choroiditis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Design Machine learning of cases with APMPPE and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 82 cases of APMPPE, were evaluated by machine learning. Key criteria for APMPPE included: 1) choroidal lesions with a plaque-like or placoid appearance and 2) characteristic imaging on fluorescein angiography (lesions "block early and stain late diffusely"). Overall accuracy for posterior uveitides was 92.7% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for APMPPE were 5% in the training set and 0% in the validation set. Conclusions The criteria for APMPPE had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

PURPOSE: To determine classification criteria for multiple evanescent white dot syndrome (MEWDS).DESIGN: Machine learning of cases with MEWDS and 8 other posterior uveitides.METHODS: Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set.RESULTS: One thousand sixty-eight cases of posterior uveitides, including 51 cases of MEWDS, were evaluated by machine learning. Key criteria for MEWDS included: 1) multifocal gray white chorioretinal spots with foveal granularity; 2) characteristic imaging on fluorescein angiography ("wreath-like" hyperfluorescent lesions) and/or optical coherence tomography (hyper-reflective lesions extending from retinal pigment epithelium through ellipsoid zone into the retinal outer nuclear layer); and 3) absent to mild anterior chamber and vitreous inflammation. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for MEWDS were 7% in the training set and 0% in the validation set.CONCLUSIONS: The criteria for MEWDS had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose: We investigated the effect of exogenously administered human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) in experimental autoimmune uveitis (EAU) in B10.RIII mice, a murine model of severe uveitis.Methods: B10.RIII mice were immunized with an uveitogenic peptide, and intraperitoneal injections of 5 million hESC-MSCs per animal were given on the same day. Behavioral light sensitivity assays, histological evaluation, cytokine production, and regulatory T cells were analyzed at the peak of the disease.Results: Histological and behavioral evidence demonstrated that early systemic treatment with hESC-MSCs decreases the development of severe EAU in B10.RIII mice. hESC-MSCs suppress Th17 and upregulate Th1 and Th2 responses as well as IL-2 and GM-CSF in splenocytes from hESC-MSC-treated mice.Conclusions: MSCs that originate from hESC decrease the development of severe EAU in B10.RIII mice, likely through systemic immune modulation. Further investigation is needed to determi...

PURPOSE: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and development of noninfectious uveitis. METHODS: A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab. RESULTS: Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (6 anterior uveitis, 6 panuveitis, 1 posterior uveitis, 1 anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although 2 patients had permanent loss of vision. CONCLUSIONS: Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.

To describe fluocinolone acetonide implant dissociations in the Multicenter Uveitis Steroid Treatment (MUST) Trial.Randomized clinical trial with extended follow-up.Review of data collected on the first implant in the eye(s) of participants. Dissociation was defined as the drug pellet no longer being affixed to the strut and categorized as spontaneous or surgically related.A total of 250 eyes (146 patients) had at least 1 implant placed. Median follow-up time after implant placement was 6 years (range 0.5-9.2 years). Thirty-four dissociations were reported in 30 participants. There were 22 spontaneous events in 22 participants; 6-year cumulative risk of a spontaneous dissociation was 4.8% (95% confidence interval [CI]: 2.4%-9.1%). The earliest event occurred 4.8 years after placement. Nine of 22 eyes with data had a decline in visual acuity ≥5 letters temporally related to the dissociation. Thirty-nine implant removal surgeries were performed, 33 with replacement. Twelve dissociations were noted during implant removal surgeries in 10 participants (26%, 95% CI 15%-48%); 5 of these eyes had a decline in visual acuity ≥5 letters after surgery. The time from implant placement to removal surgery was longer for the surgeries at which dissociated implants were identified than for those without one (5.7 vs 3.7 years, P.001). Overall, visual acuity declined 15 or more letters from pre-implant values in 22% of affected eyes; declines were frequently associated with complications of uveitis or its treatment.There is an increasing risk of dissociation of Retisert implants during follow-up; the risk is greater with removal/exchange surgeries, but the risk of both spontaneous and surgically related events increases with longevity of the implants. In 22% of affected eyes visual acuity declined by 15 letters. In the context of eyes with moderate to severe uveitis for years, this rate is not unexpected.

Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury.

Mesenchymal stem cells (MSCs) are being tested in a wide range of human diseases; however, loss of potency and inconsistent quality severely limit their use. To overcome these issues, we have utilized a developmental precursor called the hemangioblast as an intermediate cell type in the derivation of a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs). This method circumvents the need for labor-intensive hand-picking, scraping, and sorting that other hESC-MSC derivation methods require. Moreover, unlike previous reports on hESC-MSCs, we have systematically evaluated their immunomodulatory properties and in vivo potency. As expected, they dynamically secrete a range of bioactive factors, display enzymatic activity, and suppress T-cell proliferation that is induced by either allogeneic cells or mitogenic stimuli. However, they also display unique immunophenotypic properties, as well as a smaller size and >30,000-fold proliferative capacity than bone marrow-derived MSCs. In addition, this is the first report which demonstrates that hESC-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2). This is also the first report which shows that hESC-MSCs have therapeutic efficacy in two different autoimmune disorder models, including a marked increase in survival of lupus-prone mice and a reduction of symptoms in an autoimmune model of uveitis. Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt-Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher's exact probabilities. The incidence of Bx-KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral-infection that may trigger VKH pathogenesis in genetically susceptible individuals, such as HLA-DR4 carriers.

Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA-A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA-A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease.

Accounting for approximately 10% of blindness in the USA, uveitis refers to a group of heterogeneous diseases that share the features of intraocular inflammation but whose etiologies include idiopathic autoimmune disease, infections, rheumatologic diseases and masquerade syndromes. Correct diagnosis with timely and appropriate therapy is key to reducing disease-associated morbidity. The multitude of possible causes can create diagnostic challenges, but a successful approach includes a targeted history of the illness and associated symptoms, detailed ocular evaluation and specific laboratory investigations. The purpose of this article is to aid in the initial evaluation and decision-making strategy for uveitis according to the Standardization of Uveitis Nomenclature Working Group classification scheme and to provide a brief look at the anticipated future for diagnostic tools.

Tubulointerstitial nephritis and uveitis (TINU) is the association of acute interstitial nephritis (AIN) with uveitis, although the two do not need to occur at the same time. There should be no other systemic inflammatory disease (either putative autoimmune or infectious processes) to explain the concurrence of uveitis and interstitial nephritis.

Ocular inflammatory disease comprises of a diverse group of clinical entities that may result from autoimmune processes, infections, or both. While many individual ocular inflammatory diseases are quite rare, ocular inflammation is one of the more common causes of visual disability, including blindness, in the developed world. Better understanding of ocular inflammatory disease is an important step in designing more sophisticated therapies that may help prevent loss of visual function for these patients.

Purpose To describe baseline clinical characteristics of a cohort of 80 patients with birdshot chorioretinopathy in anticipation of a longitudinal study, and to identify relationships between visual acuity, symptoms, and ophthalmic findings. Design Single-center cross-sectional study. Methods A standardized examination was performed in the same order on a single day for each patient. A grading system for birdshot lesions was established prospectively to evaluate the following lesion characteristics: quantity, distribution, morphology, and pigmentation. Relationships between clinical features of disease were sought in multivariate analyses that adjusted for age, duration of uveitis, and treatment. Results Mean age at baseline examination was 55.6 years. Median best-corrected visual acuity (BCVA) was 0.8 (range, counting fingers to 1.2). There were no relationships between BCVA and any birdshot lesion characteristic. The most common cause of BCVA ≤0.4 was macular edema. Visual symptoms were present in 78 patients (97.5%), including 17 (94.4%) of 18 patients with BCVA ≥1.0 in both eyes. Blurred vision was associated with decreased BCVA ( P = .02) and macular edema ( P = .022). Increased lesion pigmentation was associated with complaints of blurred vision ( P = .030), vibrating vision ( P = .011), and nyctalopia ( P = .056). Conclusions Symptoms are common in patients with birdshot chorioretinopathy, even among those with good BCVA. Lesion pigmentation may be a marker of decreased visual function that is not reflected in central visual acuity. These findings highlight the limitation of using visual acuity measurements for monitoring patients with birdshot chorioretinopathy and as an outcome measure for studies of this disease.

To adapt a standardized technique for assessment of visual fields to the study of patients with birdshot chorioretinopathy and to describe visual field patterns and changes over time for affected individuals.A retrospective chart review was performed of patients with a diagnosis of birdshot chorioretinopathy who had undergone at least two automated visual field studies. A masked evaluation of each visual field was performed using standardized criteria. Subjective symptoms and visual acuity measurements were compared to visual field data from the same examination dates. Serial visual field studies were evaluated for changes in the findings over time.Six patients met inclusion criteria. A total of 104 visual field studies (ranging from 2-19 studies per eye) were evaluated. Visual field abnormalities occurred in all tested eyes and were observed even in eyes with a Snellen visual acuity of 20/15. Discordant patterns were observed in the two eyes of some individual patients. On serial testing, multiple patterns of visual field abnormality were observed in the same eye over time.A standardized protocol for systematic evaluation of visual field measurements can be used to characterize disturbances of vision in patients with birdshot chorioretinopathy. Abnormalities of visual fields may occur even when central visual acuity is preserved.

Birdshot chorioretinopathy is a well-known, yet poorly understood, form of posterior uveitis, characterized by multiple, distinctive, hypopigmented choroidal lesions, and strongly associated with human leukocyte antigen (HLA)-A29. We reviewed all English language publications regarding birdshot chorioretinopathy and performed analyses of combined patient data taken from these articles. The mean age at presentation was 53 years, with a slight female predominance (54.1%). At least 95.7% of reported patients have been HLA-A29-positive. Blurring of vision and floaters are the most prevalent presenting complaints, even in patients with visual acuity of 20/20 or better in both eyes. Birdshot chorioretinopathy is a slowly progressive disease with profound dysfunction of vision that may not be reflected in Snellen visual acuity. Two or more lines of Snellen visual acuity were lost in approximately 20% of eyes over a median follow-up of 3.5 years; macular edema was the most common cause of reduced visual acuity. Overall, patients had a slow decline in visual acuity, despite the fact that nearly all were treated with anti-inflammatory therapies. Final visual acuity in the better eye was 20/40 or better in 75.1% of patients and 20/200 or worse in 9.8% of patients. Oral corticosteroids and cyclosporine were the most commonly used medications. Using a regression model, patients in the literature that have been treated with cyclosporine alone had better final visual acuity than patients treated with oral corticosteroids alone. Further study is needed to determine the optimal methods for treating and monitoring patients with birdshot chorioretinopathy.

We evaluated peptides demonstrated to be immunogenic in studies of HLA-DRB1*0405-restricted T cells from patients with Vogt–Koyanagi–Harada (VKH) disease for likelihood of binding to HLA-DRB1*0405 using internet-accessible algorithms. Immunogenic peptides were more likely to overlap with fragments predicted to have a high likelihood of binding to HLA-DRB1*0405 and were more likely to bind to HLA-DRB1*0405 than the negative control, HLA-DRB1*0701. We also determined the likelihood of binding to other HLA molecules associated with VKH disease. The peptide immunogenic in the most patients was predicted to bind to HLA-DRB1*0101, 0404, and 0405, but not to the negative control, HLA-DRB1*0701. In silico methods hold promise for high-throughput evaluation of putative auto-antigens, for testing and generating hypotheses, and suggest a correlation between HLA binding and immunogenicity.

Objective Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects ∼40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation—AAU—of a multisystem, inflammatory, genetically complex disease, AS. Methods Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA–B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. Results As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA–B). Strong linkage was seen at a region on chromosome 9p21–9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23–1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. Conclusion This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21–9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

Purpose: To compare the changes in visual acuity and the development of posterior capsule opacification (PCO) with AcrySof® acrylic intraocular lenses (IOLs) (Alcon Laboratories) and second-generation PhacoFlex® silicone IOLs (Allergan ). Setting: Eye Associates of New Mexico and Southwest Colorado, Albuquerque, New Mexico, USA. Methods: Medical charts of patients having cataract extraction with implantation of an AcrySof MA30BA or MA60BM (MA30/60) or PhacoFlex SI-30NB or SI-40NB (SI-30/40) IOL between January 1995 and June 1997 were abstracted. Analyzed were the changes in visual acuity and development of PCO 1 month postoperatively and at the last available ophthalmologist visit or the visit before neodymium:YAG (Nd:YAG) capsulotomy. Results: Patients with MA30/60 acrylic IOLs were significantly older, had a worse preoperative best corrected visual acuity (BCVA), and had more concomitant ocular diseases than those with SI-30/40 silicone IOLs. The change in BCVA from preoperatively to 1 month postoperatively was equivalent in the 2 lens groups. The BCVA declined from 1 month postoperatively to the last recorded or pre-Nd:YAG visit. This decline was greater in eyes with SI-30/40 silicone IOLs than in those with MA30/60 acrylic IOLs. Although the decrease in BCVA between IOL types was not significantly different, eyes with a SI-30/40 silicone IOL were significantly more likely to develop PCO and have Nd:YAG capsulotomy. Eyes developing PCO had a statistically significant decline in BCVA from 1 month postoperatively to the last/pre-Nd:YAG visit. Conclusions: The MA30/60 acrylic lenses were associated with lower PCO and Nd:YAG capsulotomy rates than second-generation SI-30/40 silicone IOLs. Patients with MA30/60 IOLs also tended to have less of a decrease in visual acuity than patients with SI-30/40 silicone lenses, probably as a result of the difference in PCO rates between groups.

Purpose The purpose of this study was to describe fundus autofluorescence (FAF) findings in eyes with birdshot chorioretinitis (BSCR) and to compare findings to demographic, medical, and clinical characteristics. Methods In this multicenter, prospective, cross-sectional study, 172 eyes (86 patients) with BSCR were investigated. Participants underwent a standardized evaluation including collection of demographic data, ophthalmic and treatment history, and ophthalmologic examination. Using a standardized protocol, hypo- and hyperautofluorescence in macular and extramacular regions and specific patterns of abnormal FAF could be scored for 167 eyes. Images were scored by two independent, masked graders. Measures of visual function included best-corrected visual acuity (BCVA), contrast sensitivity (CS), color vision, and Humphrey visual field mean deviation (HVF-MD). Results Any abnormal FAF finding was observed in 132 eyes (79.0%); macular abnormalities were observed in 84 eyes (49.1%). The most common findings were peripapillary confluent hypoautofluorescence (122 eyes [73.1%]); extramacular granular hypoautofluorescence (100 eyes [59.9%]); and macular granular hypoautofluorescence (67 eyes [40.1%]). Confluent hypoautofluorescence was related to longer median disease duration (8.7 years) than granular hypoautofluorescence (7.9 years) or hyperautofluorescence (5.6 years). Macular confluent hypoautofluorescence was associated with BCVA ≤20/25 (odds ratio [OR] = 7.83, P = 0.007), BCVA ≤20/50 (OR = 4.94, P = 0.002), and abnormal CS (OR = 4.56, P = 0.009). Presence of macular or extramacular hypoautofluorescence was related to HVF-MD ≤-3 dB (OR = 2.43, P = 0.01 and OR = 2.89, P = 0.003, respectively). Conclusions In this large cohort, various FAF abnormalities were found, indicating that disorders of the retinal pigment epithelium are features of BSCR. Abnormal FAF is a marker of visual dysfunction in the disease.

Objective To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. Methods Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. Results Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. Conclusion TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

Tubulointerstitial nephritis and uveitis (TINU) generally occurs at young age and has a female preponderance. Renal biopsy reveals interstitial infiltration of inflammatory cells and edema, and the associated intraocular inflammation typically consists of an anterior, bilateral uveitis. The pathogenesis of TINU likely involves both humoral and cellular immunity and is mediated by medications, infectious agents, or other unknown causes. A previous report detected a renal antigen recognized by the serum of a TINU patient. In this report the authors extend these observations to document seroreactivity against a retinal antigen of similar size.

e recently reported that 73.8%of subjects diagnosed withVogt–Koyanaga–Harada (VKH) dis-ease experienced recurrences (Erreraet al. 2011). Based on our experience,we believed that finding an exudativeretinal detachment (ERD) thatresponded to corticosteroids or othermedical treatment more than 1 yearafter onset is low. To better evaluatelate posterior recurrences, we reviewedthe records of a large series of 45patients with VKH disease from fourtertiary centres. The median follow-upduration was 34 months since initialpresentation.Late posterior segment relapses weredefined as posterior segment manifes-tations of inflammation occurring laterthan 52 weeks after first presentationof VKH (Garcia-Valenzuela et al.2000; Sachdev et al. 2008; Dolz-Marcoet al. 2011). The study adhered to thetenets of the Declaration of Helsinki.Relapsing ERDs were noted within10 months after presentation in 16(84%) of 19 subjects who experiencedsuch reactivation, with only four expe-riencing late ERDs, one of whom alsohad early relapses. Report of foursubjects with late ERDs relapses at amedian of 19 months (16–25 months).By examination and optical coher-ence tomography (OCT), subretinalfluid was limited localized areas ofsubmacular ERDs in all late posteriorsegment relapses (Fig. 1).Intravenous pulse therapy was usedwithin the first month for three of thefour subjects who experienced a lateposterior reactivation. In the fourthsubject, the diagnosis of VKH diseasewas made 3 months after the firstinflammatory signs, which caused adelay in the initiation of the correcttreatment. This latter subject had treat-ment with corticosteroids for only1 month, while the other three subjectsreceived an initial duration of systemiccorticosteroids for at least 6 months.In all four subjects, immunosuppres-sive therapy (infliximab, cyclosporin orinterferon) was initiated after the firstrelapse because response to therapywith corticosteroid at acceptable long-term doses was insufficient.All four subjects had been on immu-nomodulatory agents (cyclophospha-mide, infliximab and azathioprine),but these agents had been stopped 5to 13 months prior to the relapse.In one subject, the relapse occurredwhile he was taking 25 mg/day ofprednisone. He had responded to rein-troduction of high-dose corticotherapyfor an episode 6 months previously,and he was on tapering of therapy. Thesecond subject was receiving bothprednisone and cyclophosphamide.The third was on infliximab and low-dose oral corticosteroids at the time ofrelapse.In the experience at our institutionsthere were 4 late relapses (ERDs) of 45subjects with an incidence rate of 12cases per 1000 VKH affected person-years. Late relapses as ERDs occurredin patients receiving early intravenouspulse corticosteroids, and all four hadbeen on other corticosteroid-sparingimmunomodulatory therapy at somepoint. One possible explanation is thatthe need for more aggressive treatmentin our patients with late relapses ofVKH may be a marker of more severedisease. Early corticosteroid-sparingimmunomodulatory therapy might beuseful as first-line therapy to reduce thedevelopment of complications (AbuEl-Asrar et al. 2013). Although it is

Purpose To describe the clinical features of a disorder characterized by chronic multifocal retinal infiltrates and uveitis in individuals with human immunodeficiency virus (HIV) disease. Methods We reviewed the medical records of HIV-infected patients with multifocal retinal infiltrates of unknown cause seen by investigators at four institutions. The following data were collected: demographic characteristics, presenting signs and symptoms, laboratory test results, and course of disease. Results We identified 26 HIV-infected patients (50 involved eyes) with this syndrome. Median CD4 + T-lymphocyte count at presentation was 272 per μl (range, 7 to 2,118 per μl). The most common presenting symptom was floaters. Median visual acuity of involved eyes at presentation was 20/20 (range, 20/15 to 20/100) and remained stable (median, 20/20; range, 20/15 to 20/70) after a median follow-up period of 9 months (range, 0 to 110 months). Typical retinal lesions were gray-white or yellow, irregular in shape, and less than 200 (Am in greatest dimension. All were located in the midperiphery or anterior retina and enlarged slowly or remained static in size. Mild to moderate anterior chamber or vitreous humor inflammatory cells were present in 47 of 50 eyes (26 of 26 patients). Retinal lesions possibly responded to zidovudine but not to acyclovir or ganciclovir. Anterior chamber and vitreous humor inflammatory reactions responded to topical or periocular injections of corticosteroid. Conclusions Uveitis with chronic multifocal retinal infiltrates is a distinct clinical entity of unknown cause that occurs in HIV-infected patients. Retinal lesions may respond to antiretroviral therapy. Visual prognosis is good.

Purpose A previous dose-ranging study of foscarnet maintenance therapy for cytomegalovirus retinopathy showed a positive relationship between dose and survival but could not confirm a relationship between dose and time to first progression. This retrospective analysis of data from that study was undertaken to determine whether there was a relationship between dose and progression rates, which reflects the amount of retina destroyed when progression occurs. Methods Patients were randomly given one of two foscarnet maintenance therapy doses (90 mg/kg of body weight/day [FOS-90 group] or 120 mg/kg of body weight/day [FOS-120 group] after induction therapy. Using baseline and follow-up photographs and pre-established definitions and methodology in a masked analysis, posterior progression rates and foveal proximity rates for individual lesions, selected by prospectively defined criteria, were calculated in each patient. Rates were compared between groups. Results The following median rates were greater for the FOS-90 group (N = 8) than for the FOS-120 group (N = 10): greatest maximum rate at which lesions enlarged in a posterior direction (43.5 vs 12.5 μm/day; P=.002); posterior progression rate for lesions closest to the fovea (42.8 vs 5.5 μm/day; P=.010); and maximum foveal proximity rate for either eye (32.3 vs 3.4 μm/day; P=.031). Conclusion Patients receiving higher doses of foscarnet have slower rates of progression and therefore less retinal tissue damage during maintenance therapy. A foscarnet maintenance therapy dose of 120 mg/kg of body weight/day instead of 90 mg/kg of body weight/day may help to preserve vision in patients with cytomegalovirus retinopathy.

Purpose HLA class I-specific killer cell immunoglobulin-like receptors (KIR) gene and HLA gene combinations have been associated with autoimmune uveitis (e.g., birdshot chorioretinopathy (BCR) and Vogt-Koyanagi-Harada syndrome (VKH)). In oligoarticular juvenile idiopathic arthritis (JIA), uveitis is one of the most serious complications, affecting approximately 20% of patients. Multiple studies suggest there are HLA Class II associations with chronic anterior uveitis in JIA; however, there is a paucity of evidence demonstrating Class I associations. Given the importance of HLA Class I and KIR gene combinations in other forms of autoimmune uveitis, we hypothesized that an interplay between these genes may contribute to the pathogenesis of uveitis in JIA. To test this hypothesis, we are: 1) determining HLA Class I and KIR gene associations in children with JIA with and without uveitis and comparing them with healthy controls, and 2) determining associations between clinical course and HLA Class I KIR gene associations.

Video abstract Video, Background Right to left shunting, usually caused by a patent foramen ovale (PFO), is associated with migraine and visual aura. It is unknown if patients who present with visual aura without headache behave similarly to those experiencing typical migraine headache with aura. The purpose of this study was to assess the prevalence of right to left shunting in patients who present with migraine aura without headache and evaluate the response to PFO closure. Methods The records of patients referred to the Interventional Cardiology program at the University of California at Los Angeles for suspected intracardiac right to left shunt were reviewed. Individuals with visual auras with or without migraine headaches were divided into three groups: group A (aura + migraine), migraine aura during or within 60 minutes of headache; group B (migraine aura unrelated to headache), migraine aura and headache temporally unrelated; and group C (migraine aura only), isolated migraine visual aura without a history of headaches. The presence of right to left shunt was assessed using transcranial Doppler with an agitated saline test. PFO closure was performed in 80 patients. Residual headache and migraine visual aura were assessed 3 and 12 months after the procedure. The control group consisted of 200 patients referred for diagnostic cardiac catheterization. Results Of 590 referred patients, 225 had migraine visual aura with or without headache. The prevalence of right to left shunt was similar (P = 0.66) in groups B (21/29, 72%) and C (14/21, 67%). Group A patients had a higher prevalence of right to left shunt (168/175, 96%) due to selection bias. The prevalence of right to left shunt in the control group was significantly (P < 0.0001) lower (36/200, 18%) than in groups A, B, and C. At 12 months after PFO closure, visual aura was resolved in 52%, 75%, and 80% of patients in groups A, B, and C, respectively (difference not statistically significant). Conclusion There is an increased prevalence of PFO among patients with migraine aura without headache. The closure of PFO correlates with improvement of the visual aura, suggesting a causative association between the presence of PFO and both visual aura and migraine headaches. Ophthalmologists should be aware of the association of right to left shunts with visual aura.

To identify factors associated with best-corrected visual acuity (BCVA) presentation and 2-year outcome in 479 intermediate, posterior, and panuveitic eyes.Cohort study using randomized controlled trial data.Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and at 2 years follow-up used gold-standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and 2-year change in BCVA.Baseline factors significantly associated with reduced BCVA included age ≥50 vs50 years; posterior vs intermediate uveitis; uveitis duration10 vs6 years; anterior chamber (AC) flaregrade 0; cataract; macular thickening; and exudative retinal detachment. Over 2 years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter (P = .52) and 10 letters (P.001), respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, resolution of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6-10 or10 vs6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening.Intermediate, posterior, and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.

Purpose: to review the function and genetics of killer immunoglobulin-like receptors (KIRs) and studies of KIR genetic associations with uveitis.Methods: Review of published studies.Results: KIRs are receptors on NK and some T cells. They may inhibit or activate cellular function, such as cytotoxicity and cytokine production. Studies have been published examining KIR gene associations with birdshot chorioretinopathy (BCR), Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27-associated acute anterior uveitis (AAU) and axial spondyloarthropathy. Evidence for increased activating and/or less inhibitory KIR and HLA gene combinations was found for BCR and VKH disease. In HLA-B27-associated disease, a trend toward decreased activation and stronger inhibition was found, except for the weakly inhibitory 3DL1 and Bw4T80 combination. This latter combination was also found to confer risk in BCR.Conclusions: KIR genetics are complex, as are the functions of KIR-bearing cells. Nonetheless, evidence for KIRs in the pathoge...

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN).Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18).The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p0.0001; RR 14.3 (6.9-29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8-9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant).The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Summary Introduction Published studies on birdshot chorioretinopathy (BCR) did not provide definitive information on possibly associated extraocular manifestations. Methods Single-center cross-sectional analysis of extraocular manifestations in a cohort of patients with BCR. Results Since 2002, 118 patients (45 men, 73 women) were enrolled. Their mean age was 51.5 years at diagnosis. The most common features of their medical histories were: hypertension (32 patients), drug allergy (19), sinusitis (17), thyroid disease (12), otitis media (11), asthma (11); diabetes (10); cancer (8); psoriasis (5); monoclonal gammopathies (3). At the time of disease onset, arthralgias were noted in 23, ENT manifestations in 26, Raynaud's phenomenon in 6, headaches in 10, psoriasis in 3 others. Between diagnosis and cross-sectional evaluation visits, only the frequency of hypertension has increased significantly (11 additional patients). Discussion and conclusions No predominant extraocular manifestation of BCR was identified in our patients. Their ongoing follow-up may yet discern whether BCR is definitively eye-restricted.

Killer cell immunoglobulin-like receptors (KIR) control the effector function of natural killer (NK) cells and subsets of T cell, and the genes encoding KIRs are substantially variable among individuals. A majority (58.4%) of Japanese individuals were found to be homozygous for group A K IR haplotypes that encode only a single activating KIR2DS4. Contrarily, most of Japanese patients with Vogt–Koyanagi–Harada (VKH) disease (69.2%), a panuveitis carry Bx genotypes that encode 2–5 activating KIR receptors. Particularly, individuals carrying three activating KIR genes 3DS1 , 2DS1 , and 2DS5 are more frequent in patient group compared with the controls (42.2% vs 21.4%, p = 0.02). In addition, the inhibitory K IR gene 3DL1 was significantly decreased in patients compared with controls (76.9% vs 98.8%, p = 0.00006). These data suggest that the genotypes encoding a dominant activating KIR receptor repertoire predispose susceptibility to VKH disease.

Programmed death-1 (PD-1) ligation downregulates active lymphocyte responses. The authors tested whether PD-1 or its ligands are expressed in the posterior segment during active intraocular inflammation.Experimental autoimmune uveitis (EAU) was induced using interphotoreceptor retinoid-binding protein (IRBP 161-180). Ocular inflammation was evaluated by histology and expression of PD-1 ligand tested by immunohistochemistry. PD-1 expression was evaluated by immunohistochemistry, RT-PCR, and Western immunoblotting.Using immunohistochemistry, PD-1, but not its ligands, was constitutively expressed in retinal neurons of naive mouse retina. Both PD-1 and its ligands were observed, as expected, in sites of active inflammation.PD-1 and its ligands were expressed in sites of active inflammation, in accordance with many other models of inflammatory disease. Surprisingly, PD-1, not previously described outside the immune system, was constitutively expressed in retinal neurons, raising the possibility that PD-1 signaling may be important for neuronal function in the absence of an inflammatory insult.

Purpose Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis but there is reason to believe that this syndrome is underdiagnosed and renal manifestation may not be treated. Gold standard for diagnosisng TINU is invasive renal biopsy. Here, we show that performing beta-2 microglobulin analysis in urine and HLA typing is helpful to find otherwise undiagnosed TINU cases with subclinical forms of nephritis. Methods Beginning January 2006 we prospectively obtained Ub2MG levels in all children with AU attending our pediatric uveitis clinic for the first time. Mandeville criteria were used to grade certainty of diagnosis. We compared with a healthy control group of children. HLA typing on patients with AU but no nephritis (n =28) by a Luminex-based PCR-SSO typing method was performed in another study. We compared frequencies to normal published controls and a published TINU cohort (n=20). Results The simple screening method of determining urinary Beta-2-Mikroglobulin showed in up to 2/3 of children with new-onset AU subclinical renal manifestation. HLA Typing showed the TINU associated HLA DRB1*0102 in 12.5% of patients with AU with normal renal function opposed to 0.6% in healthy controls (p

Crystallins are major lens structural proteins expressed in the vertebrate eye that contribute to the transparency and refractive properties of the lens. In addition to its structural role, a variety of crystallin proteins are expressed in extralenticular locations. The best characterized are the α-crystallins, which are widely expressed throughout the body in tissues as diverse as the heart, skeletal muscle, and brain. These proteins act as intracellular molecular chaperones and heat shock proteins (HSP).1 In addition, α-crystallin may act to inhibit apoptotic cell death and is implicated in neuroprotection.2 Several investigators have suggested a role for α-crystallin protein in the pathophysiology of glaucomatous optic atrophy, multiple sclerosis, Alzheimer disease, and neuro-Behcet disease.3–5 Pathogenesis of noninfectious uveitis is thought to involve genetic predisposition, environmental exposures, and a T-lymphocyte–mediated, antigen-specific response.6 Complications of anterior uveitis include cataract, secondary glaucoma, and cystoid macular edema; the pathophysiology of which, in the context of inflammation, is not fully understood.7 Several autoimmune diseases, such as inflammatory bowel disease, diabetes, and Wegener’s granulomatosis, are associated with marker antibodies that may be used for diagnostic purposes, to identify clinically meaningful subgroups, and to determine the potential for disease complications.8,9 Identification of uveitis-associated marker antibodies may provide clues for understanding the specific pathogenesis of either the primary disease target or the secondary complications of the disease and may ultimately suggest tools for the modulation of specific self-destructive inflammatory responses. Our previous work identified βB1-crystallin as a candidate uveitis-associated antigen and demonstrated its extralenticular expression in the ciliary body.10 βB1-crystallin is also identified in drusen.11 Purified crystallin proteins are immunogenetic in the Lewis rat, causing autoimmune ocular inflammation in preliminary studies in our laboratory (Chen L, Gordon LK, unpublished data, 2004). It has been reported that antibodies against lens proteins may be observed in patients with uveitis and in some patients with senile cataract.12,13 In the present study we hypothesize that crystallin may be an important autoantigen in human anterior uveitis and demonstrate that reactivity against specific crystallin proteins may be associated, either with the active intraocular inflammation or with secondary cataract pathogenesis.

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

Aim Vogt–Koyanagi–Harada (VKH) is an uncommon autoimmune disease characterized by chronic, bilateral, diffuse, granulomatous uveitis with accompanying dermatologic, neurologic and auditory involvement. There is a higher rate of VKH in people of Asian, Mestizo, and Mediterranean descent. Our preliminary studies of small cohorts of Japanese and Mestizo reported higher incidence of activating KIRs, which corroborates the autoimmune nature of VKH. Herein, we extended our pilot study with Japanese to a larger cohort. Methods We characterized 196 patients with VKH and 209 healthy controls from Yokohama City University School of Medicine, Japan for KIR and HLA class I genes using Luminex rSSO. Results Differences between controls and patients in the distribution of KIR genotypes, HLA allotypes, and KIR–HLA pairs were tested by two-tailed Fisher’s exact probabilities (Table 1). In contrast to previous findings, Bx KIR genotypes occurred at a lower frequency in patients with VKH compared to controls (39.3% vs. 52.6%, p = 0.007). The Bx decrease was due to the differences at the centromeric half of the KIR gene complex, and consequently all variable B haplotype KIR genes at the centromeric half (2DS2, 2DL2, 2DS3, 2DL5) were reduced in patients. Compared to controls, certain HLA allotypes were significantly increased (B54, B56, Cw1) or decreased (A33, B7, B44, B46, B52, Cw12, and A2-B46-Cw1 combination) in VKH. Among all known HLA class I ligands, only Bw4 showed a significant decrease in patients (42.4% vs. 55.5%, p = 0.0097). The decrease in 2DL2 and in Bw4 was associated with a reduction in 2DL2+C1/C2 and 3DL1+Bw4 combinations in VKH. Conclusions Decreased inhibitory KIR–HLA gene combinations in patients with VKH suggest the possibility of impaired class I mediated licensing, thus generating hyporesponsive NK cells. Absence of activating KIRs 2DS2 and 2DS3 further support the notion of a poorly responding NK cells in VKH. NK cell hyporesponsiveness to certain infections might trigger an autoimmune response and pathogenesis of VKH. Download : Download full-size image