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Zusammenfassung Hintergrund Die Blut-Kammerwasser-Schranke (BKS) grenzt immunprivilegiertes Gewebe des Auges von der Blutzirkulation ab. Die Störung der BKS stellt somit einen Risikofaktor für Abstoßungsreaktionen nach Keratoplastik dar. Ziel der Arbeit Die vorliegende Arbeit bietet eine Übersicht der Arbeiten unserer und anderer Arbeitsgruppen zu BKS-Störungen bei perforierender (PKPL) und posteriorer lamellärer Keratoplastik sowie deren Implikationen für das klinische Ergebnis. Methoden Es erfolgte eine PubMed-Literaturrecherche zur Erstellung einer Übersichtsarbeit. Ergebnis Die Laser-Flare-Photometrie bietet ein objektives und reproduzierbares Verfahren zur Beurteilung der Integrität der BKS. Untersuchungen des Flares nach perforierender und posteriorer lamellärer Keratoplastik belegen eine im postoperativen Verlauf meist rückläufige Störung der BKS, die in Ausmaß und Dauer durch multiple Faktoren beeinflusst wird. Persistierend erhöhte Flare-Werte oder ein Anstieg des Flares nach zunächst postoperativer Regeneration können dabei auf ein erhöhtes Abstoßungsrisiko hinweisen. Diskussion Bei persistierend oder im postoperativen Verlauf rezidivierend erhöhten Flare-Werten nach Keratoplastik ist eine intensivierte (lokale) Immunsuppression möglicherweise sinnvoll. Dies könnte zukünftig, insbesondere beim Monitoring von Patienten nach Hochrisiko-Keratoplastik, Bedeutung erlangen. Ob ein Anstieg des Laser-Flares ein reliabler Frühindikator einer drohenden Immunreaktion nach PKPL oder posteriorer lamellärer Keratoplastik ist, müssen jedoch prospektive Studien zeigen.

ZusammenfassungUveitis ist ein Sammelbegriff für eine Vielzahl unterschiedlicher intraokularer Entzündungen. Dabei variieren die zugrunde liegenden Ätiologien sehr stark in Abhängigkeit vom Subtyp der Uveitis, vor allem vom anatomischen Schwerpunkt. Die Hauptformen der anterioren Uveitis stellen die akute fibrinöse unilaterale Verlaufsform, häufig mit dem HLA-B27-Haplotyp assoziiert, und die granulomatöse Entzündung, typischerweise im Zusammenhang mit einer Sarkoidose oder einer Herpesinfektion, dar. Die intermediäre Uveitis ist meistens idiopathischer Natur, kann jedoch auch mit einer Multiplen Sklerose oder einer Sarkoidose assoziiert sein, während bei Patienten nach dem 45. Lebensjahr auch an ein vitreoretinales Lymphom als Masquerade-Syndrom gedacht werden muss. Die Uveitis posterior wiederum, und ähnlich auch die retinale Vaskulitis und Panuveitis, haben eine sehr breite ätiologische Vielfalt, die aber ebenso befundorientiert eingegrenzt werden kann. So haben Retinitiden häufig eine infektiöse Genese (Toxoplasma und Viren der Herpesgruppe), während es sich bei Chorioiditiden häufig um spezifische, vermutlich autoimmune Entitäten handelt, wobei auch hier Infektionen, z. B. Tuberkulose, zugrunde liegen können. Anamnese und Labordiagnostik sollten bei Patienten mit Uveitis daher maßgeschneidert und orientiert am anatomischen Schwerpunkt der Entzündung (Uveitis anterior, intermedia, posterior oder Panuveitis) und dem klinischen Bild (z. B. granulomatös vs. nicht granulomatös) erfolgen.

Das Corona-Virus-Disease-19 (COVID-19) auslösende Severe-Acute-Respiratory-Syndrome-related Coronavirus‑2 (SARS-CoV-2) führte zu einer weltweiten Pandemie und stellt das Gesundheitssystem insgesamt, aber auch die Augenheilkunde vor große Herausforderungen. Bisherige Studien und Fallberichte deuten darauf hin, dass SARS-CoV‑2 auch die Bindehaut infizieren, eine Bindehautentzündung verursachen und dass infektiöse Viruspartikel in der Tränenflüssigkeit potenzielle Infektionsherde darstellen können. Der Nachweis von SARS-CoV-2-RNA in der Tränenflüssigkeit gelang jedoch bisher selten. Auch wenn eine isolierte Bindehautbeteiligung sehr unwahrscheinlich ist, könnte zum gegenwärtigen Zeitpunkt der COVID-19-Pandemie praktisch jeder Patient, der von einem Augenarzt untersucht wird, mit SARS-CoV‑2 infiziert sein. Daher sollten Schutz- und Hygienemaßnahmen aktuell konsequent eingehalten werden, um das Risiko der Verbreitung des Virus zu minimieren. Aktuell gibt es keinerlei Therapieempfehlungen einer COVID-19-assoziierten Konjunktivitis. Tränenersatzmittel könnten zur Symptomlinderung hilfreich sein, eine Evidenz für eine topische antivirale Therapie liegt nicht vor. Dem Augenarzt könnte in Zukunft eine entscheidende Rolle bei dem Screening von Makulopathien zukommen, die im Rahmen einer COVID-19-Therapie mittels Chloroquin oder Hydroxychloroquin auftreten können.

ZusammenfassungDas Makulaödem ist die häufigste Ursache einer irreversiblen Visusminderung bei Patienten mit Uveitis. Pathogenetisch führen proinflammatorische Zytokine zu einem Zusammenbruch der Blut-Retina-Schranke. Zur Diagnostik des entzündlichen Makulaödems wird heutzutage überwiegend die optische Kohärenztomografie eingesetzt, welche die Fluoreszenzangiografie jedoch nicht immer zu ersetzen vermag. Die Therapie erfolgt überwiegend mittels intravitreal applizierter Kortikosteroide sowie systemischer immunmodulierender Substanzen und sollte so früh wie möglich einsetzen, um einer Chronifizierung des Makulaödems vorzubeugen.

Since the beginning of 2020, SARS-CoV-2, the pathogen of COVID-19, has led to a global pandemic that also affects ophthalmology. Ophthalmologists can be confronted at any time with potentially COVID-19 associated ocular symptoms or manifestations in patients and also become infected through close patient contact. Even without systemic infection, the ocular surface can come into direct contact with aerosols or liquids containing SARS-CoV-2 particles. A smear infection through hand-to-eye contact is also possible. A purely isolated ocular infection has not yet been shown. Rather, it seems that ocular complications occur in the context of a systemic infection. However, ocular symptoms can also be the first symptom of COVID-19. The most common ocular complication of COVID-19 is mild follicular conjunctivitis. Haemorrhagic conjunctivitis, dry eye disease, episcleritis, or retinal involvement can also occur less frequently. There are currently no evidence-based therapy recommendations for COVID-19 associated diseases of the ocular surface. Artificial tears might be helpful for symptom relief. There is no evidence for antiviral, antibiotic, or anti-inflammatory therapies, but these medications might be used in individual cases. Potential intraocular complications include retinal artery occlusions and haemorrhages, as well as cotton wool spots caused by complement-mediated thrombotic angiopathy. Neuro-ophthalmological complications including Miller-Fisher syndrome or infarct-related central blindness can also occur in very rare cases. Knowledge of potential transmission routes and personal protective equipment is just as essential for each ophthalmologist as a basic knowledge of potential ocular symptoms and complications.SARS-CoV-2, der Erreger von COVID-19, führt seit Anfang 2020 zu einer weltweiten Pandemie, von der auch die Augenheilkunde betroffen ist. Dabei kann ein Ophthalmologe aktuell jederzeit mit potenziell COVID-19-assoziierten okulären Symptomen oder Manifestationen bei Patienten konfrontiert werden und sich aber auch selber durch engen Patientenkontakt anstecken. Auch ohne systemische Infektion kann die Augenoberfläche direkt mit Aerosolen und Flüssigkeiten, die SARS-CoV-2-Partikel enthalten, in Kontakt kommen. Auch eine Schmierinfektion durch Hand-zu-Augen-Kontakt ist möglich. Eine rein isolierte okuläre Infektion ist bisher nicht nachgewiesen. Vielmehr scheint es so, dass okuläre Komplikationen im Rahmen einer systemischen Infektion auftreten können, wobei okuläre Symptome auch Erstsymptom sein können. Die häufigste okuläre Komplikation einer COVID-19-Infektion ist die milde follikuläre Konjunktivitis. Seltener können auch hämorrhagische Konjunktivitiden, eine Keratoconjunctivitis sicca, eine Episkleritis sowie retinale Beteiligungen auftreten. Aktuell gibt es keinerlei evidenzbasierte Therapieempfehlungen für COVID-19-assoziierte Erkrankungen der Augenoberfläche. Tränenersatzmittel könnten zur Symptomlinderung hilfreich sein, eine Evidenz für antivirale, antibakterielle oder antientzündliche Therapien liegt nicht vor, sie können im Einzelfall aber angewendet werden. Zu den potenziellen intraokulären Komplikationen gehören Arterienverschlüsse und retinale Hämorrhagien sowie Cotton-Wool-Spots, verursacht durch eine komplementvermittelte thrombotische Angiopathie. Sehr selten können auch neuroophthalmologische Komplikationen wie das Miller-Fisher-Syndrom oder infarktbedingte zentrale Erblindungen auftreten. Das Wissen um potenzielle Übertragungswege und über die persönliche Schutzausrüstung ist für den Ophthalmologen genauso unerlässlich wie ein Grundwissen über potenzielle okuläre Symptome und Komplikationen.

Objectives The aims of this study were to evaluate the isolated prevalence of real-time reverse transcriptase-polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 on the ocular surface without systemic infection in hospitalized asymptomatic patients and to determine the risk for ophthalmologists and medical staff to be infected by prescreened asymptomatic patients in a tertiary eye care center. Methods In this prospective, observational study, bilateral swaps of the conjunctiva in the lower fornices as well as nasopharyngeal swaps were collected in 1145 hospitalized asymptomatic patients of a tertiary eye care center. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed for each swap to evaluate the prevalence of SARS-CoV-2. Demographic data and potential risk factors for an isolated infection of the ocular surface were noted. Results Two thousand two hundred eighty-eight (99.9%) of all 2290 tested eyes had negative results in the RT-PCR analysis of the conjunctival swabs. One patient had bilateral false-positive results in the conjunctival swabs. None of the 1145 patients had any positive RT-PCR-confirmed result in the nasopharyngeal swabs. Conclusions The risk for an isolated conjunctival viral activity in patients with a negative nasopharyngeal swab-based RT-PCR seems to be absent or extremely low, suggesting no need to perform additional conjunctival swabs in patients with negative nasopharyngeal swabs. Furthermore, the risk of a work-related SARS-CoV-2 infection due to direct contact with preselected asymptomatic patients in an eye care center is very low, especially when additional hygiene standards and safe distances are respected carefully. This might reassure medical staff and reduce the fear of SARS-CoV-2 infection.

PURPOSE The purpose of this study was to investigate the impact of transient elevations in postoperative intraocular pressure (IOP) on the clinical outcome of Descemet membrane endothelial keratoplasty (DMEK) surgery in non-glaucoma patients. METHODS Retrospective analysis from a prospective database of eyes without preexisting glaucoma that underwent DMEK with 90% anterior chamber and 20% sulfur hexafluoride endotamponade. Group A included eyes without postoperative IOP increase (IOP

Macular oedema is the most common cause of irreversible visual loss in patients with uveitis. The pathogenesis is caused by pro-inflammatory cytokines that lead to the breakdown of the blood-retina barrier. For the diagnosis of inflammatory macular oedema, optical coherence tomography is now mainly used, but cannot always replace fluorescein angiography. The therapy is mainly performed with intravitreally applied corticosteroids as well as systemic immunomodulators and should start as early as possible to prevent chronification of macular oedema.Das Makulaödem ist die häufigste Ursache einer irreversiblen Visusminderung bei Patienten mit Uveitis. Pathogenetisch führen proinflammatorische Zytokine zu einem Zusammenbruch der Blut-Retina-Schranke. Zur Diagnostik des entzündlichen Makulaödems wird heutzutage überwiegend die optische Kohärenztomografie eingesetzt, welche die Fluoreszenzangiografie jedoch nicht immer zu ersetzen vermag. Die Therapie erfolgt überwiegend mittels intravitreal applizierter Kortikosteroide sowie systemischer immunmodulierender Substanzen und sollte so früh wie möglich einsetzen, um einer Chronifizierung des Makulaödems vorzubeugen.

ZusammenfassungTopische Kortikosteroide sind effektive entzündungshemmende Medikamente in der Therapie der anterioren Uveitis. Die intraokulare Effektivität der topischen Steroide ist überwiegend durch ihre Penetrationsfähigkeit ins Auge limitiert. Lipophile Präparate wie Dexamethason oder Prednisolonacetat penetrieren besser in die Vorderkammer als hydrophile. Prednisolonacetat 1% ist das Mittel der Wahl in der Behandlung von Patienten mit anteriorer Uveitis. Loteprednol und Fluorometholon besitzen eine schwächere antientzündliche Wirkung, beeinflussen aber weniger den Augeninnendruck und sind deswegen hilfreich bei Patienten mit Steroidresponse. Die antientzündliche Therapie mit lokalen Steroiden muss individuell angepasst werden in Abhängigkeit von Verlauf und Schweregrad der Uveitis. Die häufigsten unerwünschten Wirkungen der lokalen Kortisontherapie sind das steroidinduzierte Glaukom und die Katarakt. Nicht steroidale Antiphlogistika hemmen das Enzym Zyklooxygenase, das für die Bildung proinflammatorischer Prostaglandine zuständig ist. Sie haben eine ergänzende Rolle bei der Behandlung und Vorbeugung postoperativer Reizzustände nach Kataraktoperation. Eine therapeutische Rolle in der Behandlung der Uveitis und des zystoiden Makulaödems sekundär nach Uveitis konnte bisher nicht etabliert werden.

Background HLA-B27 positive acute anterior uveitis is the most common type of uveitis, and it is an autoimmune disease that can be triggered by infections. The precise mechanism of the interaction between involved microbes (mostly gram negative bacteria) and the host immune system is not clear. The disease probably results from an imbalance between pro- and anti-inflammatory components. Project description This article gives a compact overview about the current knowledge of the clinic and the etiopathogenesis of acute anterior uveitis as a basis for future research approaches. The goal of the current research is to classify the cellular and molecular pathogenetic factors in acute anterior uveitis. In this regard, a project on uveitis within the clinical research unit FOR 2240 "(Lymph)Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye", examines the hypothesis that dysregulation of regulatory cell populations and anti-inflammatory cytokines, such as interleukin-10 (IL-10), might contribute to the development of ocular autoimmunity following infections. The goal is to establish new markers for individual susceptibility in the risk group of the HLA-B27 positive population, because only about 1% of the HLA-B27 positive population will eventually develop acute anterior uveitis. Conclusions Translational research approaches to identify predisposed risk groups from the HLA-B27 population could improve patient care both on a prophylactic and a therapeutic level.

Hintergrund Die Augenheilkunde ist ein sehr erfolgreicher Teilbereich der Medizin. Dennoch gibt es Erkrankungen mit fehlendem Krankheitsverstandnis und unzureichender Therapie. Hier kann translationale Forschung helfen. Methoden Die Fordermoglichkeiten fur translationale Forschung unter anderem durch die Deutsche Forschungsgemeinschaft (DFG) werden am Beispiel der Forschergruppe 2240 an der Universitatsaugenklinik in Koln dargestellt. Ergebnisse Das Forderinstrument der Forschergruppe erlaubt es mehreren Arbeitsgruppen an verschiedenen Standorten an einer Kernthematik zusammenzuarbeiten. Des Weiteren kann der wissenschaftliche Nachwuchs durch Rotationsstellen und Anschubfinanzierung erheblich unterstutzt werden. Eine Forschergruppe kann ebenfalls zur Strukturbildung an einer medizinischen Fakultat mit besonderer Starkung z. B. der Augenheilkunde beitragen. Schlussfolgerung Das Instrument einer DFG-Forschergruppe ist in hervorragendem Mase geeignet, translationale Forschung z. B. in der Augenheilkunde voranzutreiben, den wissenschaftlichen Nachwuchs nachhaltig zu fordern und den Stellenwert einer medizinischen Teildisziplin, wie z. B. der Augenheilkunde, im arztlichen Facherkanon zu unterstutzen.

Objectives To evaluate ocular symptoms in European non-hospitalized patients with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and to investigate associations with the demographic data as well as nasal and general physical symptoms. Methods In this prospective, observational study, 108 non-hospitalized patients with polymerase chain reaction (PCR) confirmed SARS-CoV-2 infection not requiring intensive care were asked using a standardized questionnaire regarding disease associated ocular symptoms, demographic data, as well as general physical and nasal symptoms. Total ocular symptom score (TOSS) was evaluated during and retrospectively prior to coronavirus disease 19 (COVID-19) infection. Associations between TOSS and demographic data as well as general and nasal symptoms were evaluated. Results 75 out of the 108 COVID-19 patients (69.4 %) suffered from at least one ocular symptom during COVID-19. The most common symptoms included burning sensations in 36.1% (n=39), epiphora in 34.3% (n=37), and redness in 25.9% (n=28), compatible with conjunctivitis. These symptoms occurred 1.96 ± 3.17 days after the beginning of COVID-19 and were rather mild. TOSS was significantly higher during COVID-19 (1.27±1.85) than prior to the infection (0.33±1.04; p

Inflammatorische Prozesse des Auges gehören zu den häufigsten Entitäten in der Augenheilkunde. Die Anwendung antientzündlicher Substanzen ist daher für den Behandler eine zentrale therapeutische Option. Hierbei kommen zumeist aufgrund der guten Zugänglichkeit des Auges topische Applikationen zur Anwendung. Substanzgruppen wie Antiallergika, nichtsteroidale Antirheumatika, Glukokortikoide, Calcineurininhibitoren, Serumaugentropfen sowie neuere, noch in der Entwicklung befindliche Substanzen werden spezifisch sowohl in schmalen als auch in breiten Indikationsspektren eingesetzt, weshalb die Kenntnis der Wirkmechanismen und der potenziellen Nebenwirkungen von großer Bedeutung ist. Dieser Artikel soll einen Überblick über die derzeitig verfügbaren antiinflammatorisch wirksamen Substanzen geben, die topisch verabreicht werden können. Hierbei wird auf eine detaillierte Anwendungsbeschreibung (Dosis, Applikationshäufigkeit, Dauer usw.) in Bezug auf die einzelnen Krankheitsbilder bewusst verzichtet. Ziel ist es, dem Leser pharmakologisches Basiswissen mit direktem ophthalmologischen Bezug zu vermitteln.

The metastatic spread of carcinoma cells is not fully understood. Here, we compare the peripheral blood mononuclear cells (PBMC) and intraocular metastatic cells in parotid gland carcinoma with the PBMCs of healthy donors by immunohistochemistry and flow cytometry. We found Ber-EP4 tumor marker–positive carcinoma cells in the aqueous humor of the patient's right eye and a CD45 and Ber-EP4–expressing PBMC population in his blood. These Ber-EP4–expressing cells exhibited a monocytic-myeloid phenotype with coexpression of CD11b, CD115, and the macrophage marker CD172a (SIRP-α). Uptake of pHrodogreen revealed their phagocytic activity. Our findings suggest that the tumor cells in the anterior chamber originally derived from cell fusions between tumor cells and myeloid cells in the peripheral blood. Thus, metastases of a solid malignancy could use monocytes–macrophages as the Trojan horse to enter the eye. Cancer Immunol Res; 4(2); 92–94. ©2015 AACR.

Prostaglandin analogs are first line therapy in the treatment of glaucoma, but also display side effects during ocular inflammation. In this context, the potential side effects of prostaglandin analogs on the normally avascular cornea, the main application route for eye drops, are so far not fully defined. Therefore, the aim of this study was to evaluate the vascular effects of the prostaglandin analog tafluprost on the healthy and inflamed cornea.For in vitro studies, blood and lymphatic endothelial cells were treated with tafluprost; cell proliferation was assessed after 48 h. For long-term in vivo studies under healthy conditions, naïve corneas of BALB/c mice were treated with tafluprost eye drops for 4 weeks. For short-term in vivo studies under inflammatory conditions, corneal inflammation was induced by suture placement; mice then received tafluprost eye drops for 1 week. Afterwards, corneas were stained with CD31 as panendothelial and LYVE-1 as lymphendothelial (and macrophage) marker.In vitro, tafluprost did not alter blood or lymphatic endothelial cell proliferation. In vivo, there was no change in limbal blood or lymphatic vessel anatomy after long-term treatment with tafluprost. Short-term treatment with tafluprost under inflammatory conditions did not influence the recruitment of LYVE-1 positive macrophages into the cornea. Moreover, treatment of inflamed corneas with tafluprost did not significantly influence corneal hem- and lymphangiogenesis.Tafluprost does not affect blood and lymphatic vessel growth, neither under resting nor under inflammatory conditions. These findings suggest a safe vascular profile of tafluprost eye drops at the inflammatory neovascularized cornea.

A 22-year-old white man presented with photopsia of 3-year duration despite a corrected distance visual acuity of 20/20 in both eyes. Ophthalmic examination revealed multiple irregularly shaped white cortical opacifications of the lens in both eyes but no other significant ocular findings. One year after the photopsia onset, the patient experienced an episode of seizures with generalized tonic-clonic movements. Neurological follow-up examination demonstrated extensive brain calcification in the basal ganglia and frontal lobes, leading to a diagnosis of pseudohypoparathyroidism. Pseudohypoparathyroidism is a rare condition, and there are few reports of ocular findings with this underlying pathology. Our findings clearly demonstrate that even relatively unremarkable ocular signs can lead to diagnosis of severe systemic diseases. Therefore, the cataract surgeon should be aware of these conditions before removing the lens. Financial Disclosure None of the authors has a financial or proprietary interest in any material or method mentioned.

To assess the risk of pseudophakic cystoid macular edema (PCME) following cataract surgery in patients with allergies and/or atopic disorders. Medical records of 3,850 consecutive eyes that underwent cataract surgery were retrospectively reviewed for prevalence of allergies and atopic status and development of PCME. Patients with any known risk factors for PCME were excluded. Macular examination was performed using spectral-domain optical coherence tomography (SD-OCT) before and at 4, 8, 12, 16, 24, and 36 weeks after surgery. If both eyes in one patient underwent cataract surgery, one eye was randomly selected. Odds ratios and confidence intervals were estimated. Out of 240 patients enrolled in this series, 65 patients (27.1 %) showed positive allergic status, 19 patients (7.9 %) suffered from atopic syndromes, and 11 (4.6 %) showed both (allergies and atopic diseases). PCME occurred in eight patients (12.3 %) of the allergy cohort, whereas no patient (0 %) of the atopy cohort developed PCME. The risk of PCME was comparable in patients with allergies or atopic diseases to patients without allergies or atopy (allergy: p = 0.635; odds ratio (OR) 1.303, 95 % confidence interval (CI) 0.461–3.398; atopy: p = 0.234; OR 0.000, 95 % CI 0–1.815). Positive status of allergy or atopy does not seem to increase the risk of PCME. Therefore, postoperative treatment after cataract surgery does not have to be modified in allergic or atopic patients.

Purpose: Management of uveitic cataract in patients with juvenile idiopathic arthritis (JIA) is challenging, and intraocular lens (IOL) implantation is controversial. This study investigated the outcome after minimally invasive surgery with IOL implantation. Methods: Retrospective analysis after phacoemulsification with in-the-bag IOL implantation was performed in 16 patients (17 operations) with ANA-positive JIA-associated chronic uveitis. In these patients, 25 G capsulectomy and anterior vitrectomy was performed and they received an intravitreal triamcinolone (TA) injection. Results: Mean age at uveitis onset was 5 ± 2 years, and surgery was performed at a mean age of 11 ± 2.2 years. Preoperatively, uveitis was inactive in all patients, and visual acuity was logMAR 0.8 ± 0.44; additional uveitis complications were present in all patients, and 15 patients were receiving systemic immunosuppression/biologicals. After surgery (mean follow-up 26.5 ± 11.7 months), presence of cystoid macular oedema, papilloedema, ocular hypertension/glaucoma and hypotony did not increase compared with baseline. There was no significant worsening of AC inflammation (by cell numbers and laser flare values). IOL deposits persisted in four patients, and synechiae developed in eight. The visual acuity was improved (≥2 lines) in all patients (mean logMAR 0.3 ± 0.24). Retrolental membrane formation was not noted. Secondary capsular opacification was observed in seven patients, requiring Nd:YAG capsulotomy in five of them. Conclusions: Phacoemulsification and in-the-bag IOL implantation may improve visual outcome in JIA-associated uveitis with minimally invasive surgical technique and intravitreal TA injection. Well-controlled uveitis with appropriate use of topical steroids and systemic immunosuppression or biologicals appears as a perioperative requirement.

Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D3) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4+ T cells without inhibiting Th17 lineage commitment, as reflected by unaltered RORγt, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both RORγt and IL-17 in CD4+ T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-α, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4+ T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4+ T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17.

Experimental autoimmune uveitis (EAU) induced by immunization of animals with retinal Ags is a model for human uveitis. The immunosuppressive cytokine IL-10 regulates EAU susceptibility and may be a factor in genetic resistance to EAU. To further elucidate the regulatory role of endogenous IL-10 in the mouse model of EAU, we examined transgenic (Tg) mice expressing IL-10 either in activated T cells (inducible) or in macrophages (constitutive). These IL-10-Tg mice and non-Tg wild-type controls were immunized with a uveitogenic regimen of the retinal Ag interphotoreceptor retinoid-binding protein. Constitutive expression of IL-10 in macrophages abrogated disease and reduced Ag-specific immunological responses. These mice had detectable levels of IL-10 in sera and in ocular extracts. In contrast, expression of IL-10 in activated T cells only partially protected from EAU and marginally reduced Ag-specific responses. All IL-10-Tg lines showed suppression of Ag-specific effector cytokines. APC from Tg mice constitutively expressing IL-10 in macrophages exhibited decreased ability to prime naive T cells, however, Ag presentation to already primed T cells was not compromised. Importantly, IL-10-Tg mice that received interphotoreceptor retinoid-binding protein-specific uveitogenic T cells from wild-type donors were protected from EAU. We suggest that constitutively produced endogenous IL-10 ameliorates the development of EAU by suppressing de novo priming of Ag-specific T cells and inhibiting the recruitment and/or function of inflammatory leukocytes, rather than by inhibiting local Ag presentation within the eye.

Inflammatorische Prozesse des Auges gehören zu den häufigsten Entitäten in der Augenheilkunde. Die Anwendung antientzündlicher Substanzen ist daher für den Behandler eine zentrale therapeutische Option. Hierbei kommen zumeist aufgrund der guten Zugänglichkeit des Auges topische Applikationen zur Anwendung. Substanzgruppen wie Antiallergika, nichtsteroidale Antirheumatika, Glukokortikoide, Calcineurininhibitoren, Serumaugentropfen sowie neuere, noch in der Entwicklung befindliche Substanzen werden spezifisch sowohl in schmalen als auch in breiten Indikationsspektren eingesetzt, weshalb die Kenntnis der Wirkmechanismen und der potenziellen Nebenwirkungen von großer Bedeutung ist. Dieser Artikel soll einen Überblick über die derzeitig verfügbaren antiinflammatorisch wirksamen Substanzen geben, die topisch verabreicht werden können. Hierbei wird auf eine detaillierte Anwendungsbeschreibung (Dosis, Applikationshäufigkeit, Dauer usw.) in Bezug auf die einzelnen Krankheitsbilder bewusst verzichtet. Ziel ist es, dem Leser pharmakologisches Basiswissen mit direktem ophthalmologischen Bezug zu vermitteln.

Purpose The inappropriate immune response to harmless foreign and self-antigens is a common feature of allergy, atopy and autoimmune disease. The influence of environmental factors in the initiation of autoimmunity is not well understood. It is conceivable that immune responses to allergens may also serve as a trigger of bystander immune reactions, including autoimmunity such as uveitis. Therefore, we wanted to investigate the prevalence of allergies and atopy in patients with different types of uveitis in comparison to a control cohort. Methods In total, 530 consecutive patients with new-onset anterior, intermediate, posterior and panuveitis were compared to a non-uveitis control cohort consisting of 1.060 consecutive new-referral patients who attended our specialized outpatient clinics for other reasons than uveitis. Allergy and atopy status as well as demographic data (age, gender and ethnicity) were obtained by standardized interviewer-assisted questionnaires. Results Uveitis case cohort and control cohort did not differ significantly in the allergy status (p = 0.910), such as the history of pollen allergy (p = 0.671), history of drug allergy (p = 0.920), history of food allergy (p = 0.941), history of house dust mite allergy (p = 0.197) or history of other allergens (p = 0.593), nor in the atopy status (p = 0.802), such as the history of atopic dermatitis (p = 0.365), history of asthma (p = 0.430) or history of allergic rhinitis (p = 0.115). Conclusions Our results argue against a substantial influence of allergies and atopy on the onset of uveitis.

The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 μg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8+ cells, IL-10, or TGF-β. In contrast, depletion of CD25+ cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4+CD25high T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3+CD4+CD25+ regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.

PurposeTo analyze the macular structure in a large series of consecutive patients with different types of uveitis using spectral-domain optical coherence tomography (SD-OCT).Patients and methodsFive hundred eyes of 500 consecutive patients with anterior, intermediate, posterior, and panuveitis underwent standardized macular examination using SD-OCT. Central retinal thickness (CRT), macular volume (MV), and presence of cystoid macular edema (CME), diffuse macular edema (DME), serous retinal detachment (SRD), epiretinal membrane with (ERM+) and without (ERM-) retinal surface wrinkling were determined.ResultsThe anatomic location of inflammation affected significantly CRT and MV (P

Susceptibility to experimental autoimmune uveitis (EAU), a model for human uveitis induced in mice with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP), is controlled by “natural” CD4+CD25+ regulatory T (T reg) cells. To examine whether endogenous expression of IRBP is necessary to generate these T reg cells, we studied responses of IRBP knockout (KO) versus wild-type (WT) mice. Unexpectedly, not only WT but also IRBP KO mice immunized with a uveitogenic regimen of IRBP in complete Freund's adjuvant (CFA) exhibited CD25+ regulatory cells that could be depleted by PC61 treatment, which suppressed development of uveitogenic effector T cells and decreased immunological responses to IRBP. These EAU-relevant T reg cells were not IRBP specific, as their activity was not present in IRBP KO mice immunized with IRBP in incomplete Freund's adjuvant (IFA), lacking mycobacteria (whereas the same mice exhibited normal T reg cell activity to retinal arrestin in IFA). We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific. Our data also provide the first evidence that generation of specific T reg cells to a native autoantigen in a mouse with a diverse T cell repertoire requires a cognate interaction.

Induction of tissue-specific experimental autoimmune diseases involves an obligatory adjuvant effect to trigger an innate response of a type that will drive a Th1-biased adaptive response. This is achieved by use of CFA containing mycobacteria (Mycobacterium tuberculosis), whose recognition by cells of the innate immune system depends on TLRs that signal through the adaptor molecule MyD88. We examined the role of selected components of the MyD88 pathway in promoting experimental autoimmune uveitis (EAU). Mice deficient in MyD88, TLR2, TLR4, or TLR9 were immunized with the retinal Ag interphotoreceptor retinoid-binding protein in CFA, and their EAU scores and associated immunological responses were examined. MyD88−/− mice were completely resistant to EAU and had a profound defect in Th1, but not Th2, responses to autoantigen challenge. Surprisingly, TLR2−/−, TLR4−/−, and TLR9−/− mice were fully susceptible to EAU and had unaltered adaptive responses to interphotoreceptor retinoid-binding protein. Examination of IL-1R family members, which share the common adaptor MyD88 with the TLR family, revealed that IL-1R-deficient mice, but not IL-18-deficient mice, are resistant to EAU and have profoundly reduced Th1 and Th2 responses. These data are compatible with the interpretation that TLR9, TLR4, and TLR2 signaling is either not needed, or, more likely, redundant in the adjuvant effect needed to induce EAU. In contrast, signaling through the IL-1R plays a necessary and nonredundant role in EAU and can by itself account for the lack of EAU development in MyD88 mice.

Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.

Purpose: To report an unusual case of fulminant anterior uveitis, confirmed as endogenous Listeria monocytogenes infection. Subject: A 67-year-old man with multiple comorbidities acutely developed a severe endogenous anterior uveitis. Results: L. monocytogenes, a ubiquitous Gram-positive bacillus, was directly indicated by culture and PCR. Early and aggressive treatment with intravenous antibiotics likely prevented the endophthalmitis which most cases on record experienced. Our patient regained satisfactory visual acuity. Conclusions: Prompt antimicrobial therapy is paramount when severe endogenous uveitis develops in a patient with comorbidities, especially with systemic immunosuppression. Treatment solely with corticosteroids should be avoided.

PURPOSE To investigate whether the normal adult human sclera contains lymphatic vessels and to study their relation to immune cells and blood vessel anatomy. METHODS Scleral tissue probes from 35 adult human donor bulbi were analyzed by immunohistochemistry and confocal microscopy for blood vessels (CD31+), lymphatic vessels (lymphatic vessel endothelial hyaluronan receptor 1 [LYVE1]+, podoplanin+), and macrophages (CD68+) at 12 locations (anterior, equatorial, and posterior at 3, 6, 9, and 12 o'clock positions of the eye) in all three scleral layers (episclera, stroma, and lamina fusca). Approval for scientific examination was obtained. RESULTS CD31+ blood vessels were detectable in the human sclera, where the percentage area covered by CD31+ blood vessels was highest in the anterior episclera, followed by equatorial and posterior episclera, and was lowest in the scleral stroma (regardless of location). LYVE1+ podoplanin+ lymphatic vessels were not detectable in any location investigated, although there was a high number of LYVE1+ CD68+ macrophages. These macrophages were concentrated around blood vessels. In contrast, in the episclera, the number of detected LYVE1+ CD68+ macrophages was comparable in all locations; within the stroma, their number increased toward the posterior part of the eye. CONCLUSIONS The adult sclera contains blood vessels but lacks, as revealed by immunohistochemistry and confocal microscopy, true lymphatic vessels. LYVE1+ CD68+ macrophages are located adjacent to the longitudinal axis of blood vessels. The function of these cells needs further investigation, but could be a next step toward a better understanding of pathological disorders such as inflammation, tumor, trauma, or glaucoma.

To analyze the incidence and spectrum of ocular disease in patients with metastatic cutaneous melanoma.One hundred and eight consecutive patients with metastatic cutaneous melanoma were screened for ocular diseases using standardized eye examination, including measurement of visual acuity and intraocular pressure, slit-lamp examination, funduscopy in mydriasis, and spectral-domain optical coherence tomography (SDOCT) of the retina. Selected cases with atypical findings underwent electrophysiological studies. One patient was examined for hypercortisolism by a dexamethasone suppression test.Ocular diseases were found in 65 out of 108 patients (60 %) with metastatic cutaneous melanoma, significantly more often in older patients (p = 0.004). Cataract was present in 27 patients (25 %), pseudophakia in 22 patients (20 %), macular disease in 29 patients (28 %), diabetic retinopathy in ten patients (9 %), hypertensive retinal disease in 14 patients (13 %), retinal venous and arterial occlusive disease in three patients (3 %), optic neuropathy in four patients (4 %), and uveitis in one patient (1 %). Eight patients (8 %) had choroidal or iridal nevi, one patient (1 %) choroidal hemangioma, and one patient (1 %) choroidal metastasis. No patient had periocular neoplastic lesions. Paraneoplastic retinopathy manifesting as acute exudative polymorphous vitelliform maculopathy (AEPVM)-like disease was diagnosed in two patients (2 %) with multifocal central serous chorioretinopathy and development of vitelliform or fibrin-like subretinal deposits in one patient.Patients with metastatic cutaneous melanoma reveal ocular diseases with a spectrum similar to the normal population of this age range. Very rarely, uveal metastasis as well as paraneoplastic retinopathy can occur.

Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine known to participate in intraocular inflammatory disease. This study investigated whether treatment with intravitreal antisense-oligonucleotides (ASON) targeting TNF-α mRNA affects the progression of herpes simplex virus 1 (HSV-1) retinitis in mice. The in vivo uptake of the oligonucleotid after intravitreal injection was determined with FITC-labeled TNF-α ASON. HSV-retinitis was induced on day 0 by the injection of HSV-1 (KOS strain) into the anterior chamber (AC) of the right eyes of BALB/c mice (von Szily model). The left contralateral eyes were injected intravitreally on day 7 with TNF-α ASON, sequence-unspecific control ASON (CON), or buffer. The clinical course of retinitis, ocular inflammatory cell-infiltration, TNF-α expression in the eye by ELISA, delayed-type hypersensitivity (DTH) reaction, virus-neutralizing antibody titers in the serum, uptake of [3H]thymidine from regional lymph node (rln) cells, and viral content in the eyes were determined. In vivo, strong fluorescence of FITC- TNF-α ASON was detected in the choroid and retina up to 3 days after intravitreal injection, but none in the rln. After treatment of eyes with ASON, decreased expression of TNF-α in the eye, and reduced incidence and severity of retinitis on day 10 after infection (P

Endogenous uveitis is a sight-threatening disease. In addition to corticosteroids, immunosuppressive agents are commonly used to treat patients with severe course. Immunosuppressive drugs act nonspecifically, rather than providing a specific interaction with the critical pathogenetic pathways of uveitis. Better knowledge of the basic mechanisms underlying uveitis and of the molecules that are important for regulating inflammation has helped to create new and more specific treatment approaches. Biological therapy for inflammatory diseases employs substances that interfere with specific molecules or pathways induced in the body during the inflammatory process. This review gives an overview on molecules that play a critical role in the pathogenetic process of uveitis, as has been observed in patients or the respective animal models, and summarizes the current experience with biologicals for the treatment of uveitis refractive to conventional immunosuppressives.

Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with α-C-GalCer, which induces a strong IFN-γ but only a weak IL-4 production by iNKT cells, in contrast to the ligands α-GalCer (both IFN-γ and IL-4) and OCH (primarily IL-4). The protective effect of α-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-γ and IL-17 production and was negated by systemic neutralization of IFN-γ. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-γ and a consequent dampening of the Th1 as well as the Th17 effector responses.