Aniki Rothova

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Serum autoantibody profiling of patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy

Purpose Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling. Methods An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively. Results Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis (p = 0.015 and p = 0.018, respectively). The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients. Conclusions Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients.

Diagnostic Value of Serum-Soluble Interleukin 2 Receptor Levels vs Angiotensin-Converting Enzyme in Patients With Sarcoidosis-Associated Uveitis

Importance New and improved diagnostic tests for sarcoidosis-associated uveitis are needed because the currently available laboratory diagnostic biomarkers (eg, lysozyme and angiotensin-converting enzyme [ACE]) are lacking in high sensitivity and specificity. Objective To compare the value of soluble interleukin 2 receptor (sIL-2R) with ACE as diagnostic biomarkers of sarcoidosis in patients with uveitis. Design, Setting, and Participants A cross-sectional retrospective study was conducted using data collected from 249 consecutive patients with uveitis at the Erasmus University Medical Center uveitis outpatient clinic, Rotterdam, the Netherlands, from April 3, 2013, through November 25, 2015. Measurements of sIL-2R and ACE in serum samples and data extraction from patient files were conducted from December 2016 through February 2017, and analysis from April to May 2017. Main Outcomes and Measures Serum levels of sIL-2R and ACE and chest radiographic findings were assessed. Receiver operating characteristics analysis was used to determine the probability that individual tests correctly identified patients with sarcoidosis. The Youden Index was used to determine the optimal cutoff points for serum sIL-2R and ACE levels to define sarcoidosis in patients with uveitis. Results Data were analyzed from 249 patients with uveitis who had their serum sIL-2R and ACE levels determined and underwent chest radiography. Mean (SD) age at the time of sampling was 51 (16) years, 161 patients (64.7%) were women, and 191 (76.7%) were white. Although patients with sarcoidosis-associated uveitis had the highest mean (SD) serum sIL-2R (6047 [2533] pg/mL) and ACE (61 [38] U/L) levels, elevated serum sIL-2R levels were also found in patients with HLA-B27–associated (4460 [2465] pg/mL) and varicella-zoster virus–associated (5386 [1778] pg/mL) uveitis. Serum sIL-2R and ACE levels were significantly correlated (Pearson correlation coefficient, 0.205; Pu2009=u2009.001, 2-sided), but no association was found between uveitis activity and sIL-2R (Spearman rank correlation coefficient [&rgr;], 0.070, Pu2009=u2009.27) nor uveitis activity and ACE (&rgr;, −0.071; Pu2009=u2009.27). The highest Youden index for sIL-2R alone was 0.45, corresponding to an optimal cutoff of 4000 pg/mL and providing 81% (95% CI, 74%-89%) sensitivity and 64% (95% CI, 56%-72%) specificity alone but combined with chest radiography yielded 92% sensitivity and 58% specificity. Chest radiography combined with sIL-2R at a cutoff of 6000 pg/mL resulted in 77% sensitivity and 73% specificity. Combined chest radiography and serum ACE levels at the standard cutoff of 68 U/L resulted in 70% sensitivity and 79% specificity. Conclusions and Relevance This cross-sectional study demonstrates that sIL-2R is a useful marker for diagnosing sarcoidosis in patients with uveitis and has slightly better diagnostic value than ACE.

Antiretinal antibodies in central serous chorioretinopathy: prevalence and clinical implications

To investigate the possible role of autoimmune reactions directed against retinal tissue in central serous chorioretinopathy (CSC), by analysing the presence of serum antiretinal antibodies (ARAs) and establishing their clinical relevance.

Three-dimensional tubule formation assay as therapeutic screening model for ocular microvascular disorders

PurposeThis study is aimed to adapt a three-dimensional (3-D) in vitro angiogenesis model to the ophthalmology field using retinal endothelial cells (REC). This system is applied to assess the angiogenic capacity of aqueous humor (AH) from patients with ocular disorders, and to test the effect of VEGF inhibitor (aflibercept) on induced angiogenesis.MethodsHuman REC and umbilical vein endothelial cells (HUVEC) and pericytes were co-cultured in a gel matrix with 25–200u2009ng/ml pro-angiogenic growth factors (GF). AH from patients with cataract, glaucoma or proliferative diabetic retinopathy (PDR) was tested in the REC-pericyte co-culture. Aflibercept was then introduced to the co-culture containing PDR AH. The surface area and total tubule length were measured using Image J.ResultsOptimal GF concentrations at 200u2009ng/ml induced angiogenesis by REC as well as HUVEC, while vessel formation by both cell types was strongly reduced using 25–50u2009ng/ml GF. Addition of AH from the PDR patient triggered tubule formation by REC at low GF concentration. Aflibercept, however, significantly inhibited angiogenesis induced by PDR AH, but showed no significant influence on other conditions.ConclusionREC can be applied efficiently in the 3-D in vitro angiogenesis model as a diagnostic tool to assess the AH angiogenic status and to validate new anti-angiogenic therapeutic compounds prior to clinical trial.

Autoantibody profiling in intraocular fluid of patients with uveitis

&NA; A high prevalence of serum antiretinal antibodies (ARAs) in patients with uveitis has been previously described, though their clinical role remains elusive. Assessment of intraocular ARAs may provide further insight into the pathogenesis of diverse uveitis entities. In this study we investigate the prevalence of multiple specific anti‐ocular antibodies (AOcAs), including ARAs, in intraocular fluid of patients with uveitis. Autoantibody profiling with 188 different ocular antigens was performed by a multiplex immunoassay with intraocular fluid samples of 76 patients with uveitis. Clinical data from uveitis patients were collected and statistical analyses were executed to evaluate associations between intraocular AOcAs and clinical characteristics. Controls consisted of 19 intraocular fluid samples from cataract patients. A spectrum of 22 different AOcAs was present in higher levels in patients with uveitis than in controls (p < 0.05), but in moderately elevated titers (<2x). High elevations of intraocular AOcAs in uveitis (>5x compared to cataract) were observed in varicella zoster virus‐induced uveitis, multiple sclerosis‐associated uveitis and patients with unexplained uveitis but positive quantiferon test. Presence of macular edema was associated with increased intraocular levels of tyrosinase antibodies. Our results show that patients with uveitis are characterized by the presence of a broad spectrum of moderately elevated levels of intraocular AOcAs, and high intraocular AOcA levels were found in several specific uveitis entities. This study favors secondary production of AOcAs and not their inciting role. HighlightsUveitis is associated with a broad spectrum of intraocular autoantibodies.Specific uveitis entities exhibit heterogeneous intraocular autoantibody profiles.Macular edema is associated with increased intraocular levels of anti‐tyrosinase.

Antinuclear and antiretinal antibodies in uveitis associated with active and latent tuberculosis

The patients included who were not referred to ophthalmic evaluation were followed up by a questionnaire to detect possible misdiagnosis. This study was made according to the guidelines of the Helsinki Declaration, and relevant approvals have been achieved. To our knowledge, this is the first study to report objective ocular signs found in an ER without access to specialized ophthalmologic instrumentation. Twenty-four patients were included; 83% were men, 29% of the injuries were work related, and mean age was 36 years. Traumas with a history of hammering stone or metal comprised 37.5%, blunt traumas 25%, traumas with sharp objects 25% and 16% were projectile traumas. Eighteen patients (75%) were admitted to an acute ophthalmological evaluation. Six patients (25%) were not referred, all having a history of hammering metal or stone. Objective signs among the group of patients referred to further examination (n = 18) were as follows: decreased VA (n = 14); irregular pupil (n = 4); no pupillary reaction to light (n = 4); hyphaema (n = 3); open injury visual to the naked eye (n = 2); and subconjunctival haemorrhage (n = 2) (Fig. 1). Patients not referred presented the following: subconjunctival haemorrhage (n = 1), injection of eye (n = 4) and fluorescein stain (n = 1) (Fig. 1). During a 5-year period, there was not detected any misdiagnosis of patients with mechanical ocular trauma in a Danish ER without ophthalmic assistance. Our study shows that patients with a history of hammering stone or metal are only referred to an ophthalmological examination if there are obvious signs of eye injury. Hammering, as in previous studies, has been found to be the most common mechanism in ocular traumas with an IOFB (Imrie et al. 2008; Nicoara et al. 2015). Therefore, we recommend that all patients with a history of hammering stone or metal undergo an ophthalmologic examination to decrease the risk ofmisdiagnosis. References

Reduced number of relapses of human leucocyte antigen-B27-associated uveitis during pregnancy

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