Infectious uveitis. New developments in etiology and pathogenesis

Abstract

Uveitis is an inflammation of the inner-eye and is initiated by various infectious and noninfectious causes. In a large portion of patients the etiology is unknown and might be associated with until now undiagnosed infections.The identification of infectious uveitis is of crucial importance since its treatment and visual prognosis differ entirely from noninfectious inflammations. For the definitive diagnosis of infectious uveitis analysis of intraocular fluid, aqueous humor or vitreous fluid, is essential. The aim of this thesis was to discover novel causes of infectious uveitis by analysis of intraocular fluids using real-time PCR and the detection of intraocular antibody production and to gain more insight into the (immuno)-pathogenesis of infectious uveitis. Analysis of intraocular fluids from patients with idiopathic anterior uveitis demonstrated that Rubella virus (RV) is associated with anterior uveitis and causes a distinct clinical spectrum of ocular symptoms known as the Fuchs heterochromic uveitis syndrome (FHUS). Furthermore, we studied the clinical appearance of retinal abnormalities in patients with RV-associated uveitis and compared those with retinal lesions caused by Toxoplasma gondii, however no RV-specific features could be identified. Furthermore, we described a diagnostic assay for the detection of ocular toxocariasis, by detection of intraocular antibody production against Toxocara canis. With this assay four patients were diagnosed with ocular toxocariasis, despite very low or negative T. canis serum titers, underlining the importance of intraocular fluid analysis. In an ongoing project to identify novel causes for infectious uveitis by intraocular fluid analysis, we found positive PCR results for Human herpesvirus 6 and Human parechovirus and intraocular antibody production against Parvovirus B19 and Cytomegalovirus in patients with anterior uveitis of unknown etiology. These studies revealed novel viral associations with infectious uveitis, however, causal relationships have to be established yet. To learn more about the immunopathogenesis of various infectious uveitis entities, cytokine and chemokine profiles were determined in the ocular fluids of patients with RV-associated FHUS, ocular toxoplasmosis (OT) and acute retinal necrosis (ARN) by multiplex immunoassay. RV-FHUS and OT revealed remarkably similar patterns of mediator production, clearly distinct from those of ARN. In the ARN samples more cytokines were detected and the expression levels were higher, with the exception of IL-12, which in contrast to the RV-FHUS and OT samples, was not detected. In addition, comparison of the vascular endothelial growth factor (VEGF) levels between patients with ARN and patients with OT lead us to conclude that the high intraocular VEGF levels in patients with ARN are associated with extensive retinitis and poor visual prognosis. Finally, Surface enhanced laser desorption/ionization time-of-flight (Seldi-tof) technology was employed to determine protein profiles in the vitreous fluid of patients with acute postoperative endophthalmitis and in the aqueous humor of patients with herpetic anterior uveitis and ocular toxoplasmosis in order to identify disease-specific biomarkers. Preliminary results showed similar protein profiles in the vitreous of patients with endophthalmitis distinct from those of the controls. Also, the aqueous humors of patients with Toxoplasma gondii revealed a specific peak. Further studies are required to establish the clinical relevance of these data. The implementation of new diagnostic assays and intraocular fluid analysis enhanced the detection of infectious causes of uveitis and will improve our knowledge on these blinding but treatable intraocular infections.