Uveitis in Patients Treated with CTLA-4 and PD-1 Checkpoint Blockade Inhibition.

Purpose: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and the 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 (six anterior uveitis, six panuveitis, one posterior uveitis, one 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 two 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.

Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Decrease the Development of Severe Experimental Autoimmune Uveitis in B10.RIII Mice.

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 determine any potential effect on active EAU.

Fundus Autofluorescence Findings in Eyes With Birdshot Chorioretinitis.

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.

Choroidal Findings in Eyes With Birdshot Chorioretinitis Using Enhanced-Depth Optical Coherence Tomography.

PURPOSE: The purposes of this study were to describe choroidal findings observed using optical coherence tomography with enhanced depth imaging (EDI-OCT) in eyes with birdshot chorioretinitis (BSCR) and to test the hypothesis that these findings are related to participant demographics, clinical characteristics, and treatment. METHODS: In a multicenter, cross-sectional study, 172 eyes of 86 individuals with BSCR underwent a standardized clinical evaluation, including defined protocols for EDI-OCT imaging, with macular and peripapillary volume scans. Choroidal findings were compared to demographic information, ophthalmic examination findings, and treatment history, using logistic regression models. EDI-OCT images were evaluated by two independent, masked graders. RESULTS: Median age was 56 years old; 54 participants (62.8%) were female. One or more choroidal lesions (a predefined hyporeflective zone) were identified in 105 eyes (63.6%). Median choroidal thickness was 293 µm. Choroidal lesions were associated with longer disease durations (odds ratio [OR]: 1.08; P = 0.03), increased vitreous haze (>0.5+; OR: 4.43; P = 0.02), presence of macular edema (OR: 3.00; P = 0.02), and thick choroids (OR: 3.89; P = 0.001). Use of immunomodulatory therapy was associated with lower risk of thin choroids (lower 25th percentile, OR: 0.17; P = 0.001) or thick choroids (upper 25th percentile, OR: 0.22; P = 0.002). At least some choroidal lesions did not have corresponding, clinically apparent "birdshot lesions" on fundus examination. CONCLUSIONS: Choroidal abnormalities identified by EDI-OCT imaging are common in the macular and peripapillary regions of eyes with BSCR. Choroidal lesions were associated with clinical signs of inflammation, suggesting that they represent foci of disease activity. EDI-OCT may provide useful information about disease mechanisms and response to treatment in future, longitudinal studies of BSCR.

KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease.

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.

Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush.

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 cell population derived from human pluripotent stem cells displays potent immunomodulatory and therapeutic properties.

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.

Visual migraine aura with or without headache: association with right to left shunt and assessment following transcutaneous closure.

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.

The effect of patent foramen ovale closure on visual aura without headache or typical aura with migraine headache.

OBJECTIVES: The aim of this study was to assess the prevalence of right-to-left (R to L) shunt in patients with visual aura and evaluate the effect of shunt closure on resolution of aura. BACKGROUND: Right-to-left shunting is associated with migraine headache (MH) with aura. Some patients present with visual aura without headaches. It is unclear whether visual aura without headache is a form of migraine or a transient neurologic dysfunction. METHODS: Of patients referred to the University of California, Los Angeles for suspected patent foramen ovale (PFO), 225 had visual aura with or without MH. Patients were assessed for a shunt and evaluated for MH and/or visual aura. They were divided into 3 groups: 1) visual aura associated with MH; 2) visual aura unrelated in time to MH; and 3) visual aura without MH. The frequency of R to L shunt was compared with a control group of 200 patients. Eighty patients underwent PFO closure. Residual shunts, MH, and visual aura were reassessed after 3 and 12 months. RESULTS: The prevalence of R to L shunt in Groups A, B, and C was 96%, 72%, and 67%, respectively, versus 18% in the control group (p < 0.0001). The frequency of shunting was similar in Group B versus Group C, but much higher in all 3 groups compared with control subjects. Twelve months after PFO closure, symptoms of aura were resolved in 52%, 75%, and 80% of patients in Groups A, B, and C, respectively (p = NS). CONCLUSIONS: The similar distribution of R to L shunting in all 3 patient groups and the correlation between PFO closure and improvement of aura suggests a similar pathophysiology between the presence of PFO and the visual aura phenomenon, whether or not headache is present in the symptom complex.

HLA-A29 and birdshot chorioretinopathy.

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.

Killer immunoglobulin-like receptor genes in uveitis.

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 Bw4(T80) 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 pathogenesis of uveitis has been found.

Extraocular manifestations of birdshot chorioretinopathy in 118 French patients.

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 receptor gene-cluster 3DS1-2DL5-2DS1-2DS5 predisposes susceptibility to Vogt-Koyanagi-Harada syndrome in Japanese individuals.

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 KIR 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 KIR 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.

Killer cell immunoglobulin-like receptors in HLA-B27-associated acute anterior uveitis, with and without axial spondyloarthropathy.

PURPOSE: To determine associations between polymorphic genes that encode KIRs and their HLA class I ligands in patients with HLA-B27-associated acute anterior uveitis (AAU), with and without axial spondyloarthropathy (axial SpA). METHODS: Molecular DNA typing methods were used to define the frequencies of variable KIR genes and their relevant HLA class I ligands in HLA-B27(+) (B27(+)) Caucasian subjects with AAU and 429 healthy Caucasian control subjects. The patients were evaluated for axial SpA based on their histories using published criteria. RESULTS: Of 143 Caucasian subjects with AAU, 71 (49.6%) had features of axial SpA. The only difference between cases and controls in KIR gene frequencies was a trend toward fewer activating KIRs in subjects with AAU with axial SpA, which reached statistical significance for 2DS5 (P = 0.025, corrected P [P(c)] = 0.05; odds ratio [OR], 0.48; 95% CI, 0.25-0.90). The 3DL1+Bw4(T80) combination implicated in weak inhibition was more frequent in subjects with AAU than in control subjects (P = 2.73 x 10(-28), P(c) = 8.2 x 10(-27); OR, 13.5; 95% CI, 7.73-23.68). The 2DL1+HLA-C2 combination was decreased in subjects with axial SpA compared with subjects with AAU without axial SpA (P = 0.022; P(c) = NS; OR, 0.43; 95% CI, 0.21-0.88). CONCLUSIONS: Evidence was found of a role for KIR-HLA combinations that trigger weaker inhibition in subjects with AAU. Furthermore, there was a trend toward fewer KIR3DS1, -2DS1, and -2DS5 in AAU patients with axial SpA, which have been implicated in NK cell activation. HLA-B27(+) without KIR2DS3 (and -2DS1 and -3DS1) may fail to trigger an early NK cell response to clear antigenic stimuli, which may in part contribute to disease pathogenesis.