Current Molecular Medicine - Volume 15, Issue 6, 2015

The “classical” EAU model induced by immunization of mice with the retinal protein IRBP or its peptides has been very useful to study basic mechanisms of ocular inflammation, but is inadequate for some types of studies due to the need for active immunization in the context of strong bacterial adjuvants. We generated transgenic (Tg) mice on the B10.RIII background that express a T cell receptor (TCR) specific for IRBP161-180. Three strains of TCR Tg mice were established. Spontaneous uveitis developed in two of the three strains by 2-3 months of age. Susceptibility correlated with a higher copy number of the transgenic TCR and a higher proportion of TCR Tg T cells in the peripheral repertoire. Even in mice with uveitis, peripheral IRBP-specific CD4+ T cells displayed mostly a naïve phenotype. In contrast, T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells. These mice thus provide a new and distinct model of uveitis from the “classical” EAU, and may represent some types of uveitis more faithfully. Importantly, this new transgenic model of uveitis can serve as a template for therapeutic manipulations, and as a source of naïve retina-specific T cells for a variety of basic and pre-clinical studies. Several examples of such studies will be discussed.

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases of infectious or autoimmune etiology and accounts for more than 10% of severe visual handicaps in the United States. Pathology derives from the presence of inflammatory cells in the optical axis and sustained production of cytotoxic cytokines and other immuneregulatory proteins in the eye. The main therapeutic goals are to down-regulate the immune response, preserve the integrity of the ocular architecture and eventually eliminate the inciting uveitogenic stimuli. Current therapy is based on topical or systemic corticosteroid with or without second line agents and serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. This review summarizes the pathophysiology of uveitis, molecular mechanisms that regulate the initiation and progression of uveitis and concludes with emerging strategies for the treatment of this group of potentially blinding diseases.

Vogt-Koyanagi-Harada (VKH) disease is considered to be an autoimmune disease possibly triggered by an abnormal response to infection. Activation of TLRs signaling pathways by microbial products can drive inflammatory responses and adaptive immunity. In the present study, we investigated the role of TLRs in the pathogenesis of VKH disease. We showed that the expression of TLR3 and TLR4, but not TLR2, was significantly increased in monocyte-derived macrophages (MDMs) from VKH patients with active uveitis compared to controls. VKH patients with active uveitis showed an elevated level of IL-1β, IL-6, IL-8, TNF-α and reactive oxygen species (ROS) in MDMs. IL-1β, IL-6, IL-8 and TNF-α production could be significantly upregulated and downregulated by a ROS activator or inhibitor, respectively. Downregulation of the NLRP3 inflammasome significantly inhibited the production of IL-1β but not IL-6, IL-8 and TNF-α. The phosphorylation levels of p38 and ERK1/2 were significantly higher in MDMs from active VKH patients compared to controls. Inhibition of p38 or ERK1/2 significantly decreased IL-1β, IL-6, IL-8 and TNF-α expression. These results suggest that the increased expression of TLR3/4 in MDMs may be involved in the pathogenesis of VKH disease by the induction of inflammatory cytokines which is mediated by enhanced production of ROS.

Purpose: To evaluate cytokine expression profile in aqueous humor and sera in patients with HLAB27 associated acute anterior uveitis (AAU) and idiopathic AAU. Methods: Twenty patients with AAU and 17 controls were recruited from August 2012 to March 2013. Study subjects with uveitis were divided into two groups: 9 patients with idiopathic AAU and 11 patients with HLA-B27 associated AAU. Complete ophthalmological examinations were performed and clinical features of each group were clearly documented. Aqueous humor and sera were collected and the concentration of 15 immune mediators (IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, TNF-α, IFN-γ, sCD40L) were measured in both aqueous humor and sera simultaneously by multiplex immunoassay. Results: There were significantly higher levels of multiple cytokines in aqueous humor in patients with uveitis compared to controls, including IL-1β, IL-6, IL-10, IL-17a, IL-17f, IL-21, IL-25, IL-31, IFN-γ, TNF-α, and sCD40L. The levels of IL-17a in aqueous humor correlated significantly with disease activity in patients with idiopathic AAU, while the level of IFN-γ in aqueous humor correlated significantly with disease activity in patients with HLA-B27 associated AAU. There was no significant difference in serum cytokine expression between uveitis patients and controls except IL-6, elevated in patients with both idiopathic and HLA-B27 associated AAU. Conclusion: Cytokine expression pattern in the aqueous humor, in contrast to that in serum, may reflect intraocular immune reactions during active inflammation in patients with AAU. Both Th1 and Th17 are involved in immunopathogenesis of HLA-B27 associated and idiopathic AAU, but a different cytokine pattern was identified in these two clinical entities. A predominant Th17-driven immune response may play an important role in the immunopathogenesis of idiopathic AAU, while Th1 dominant immune response may be responsible for the inflammation in HLA-B27 associated AAU.

Mouse models of experimental autoimmune uveitis (EAU) mimic unique features of human uveitis, and serve as a template for preclinical study. The “classical” EAU model is induced by active immunization of mice with the retinal protein IRBP in adjuvant, and has proved to be a useful tool to study basic mechanisms and novel therapy in human uveitis. Several spontaneous models of uveitis induced by autoreactive T cells targeting on IRBP have been recently developed in IRBP specific TCR transgenic mice (R161H) and in AIRE-/- mice. The “classical” immunizationinduced EAU exhibits acute ocular inflammation with two distinct patterns: (i) severe monophasic form with extensive destruction of the retina and rapid loss of visual function, and (ii) lower grade form with an acute onset followed by a prolonged chronic phase of disease. The spontaneous models of uveitis in R161H and AIRE-/- mice have a gradual onset and develop chronic ocular inflammation that ultimately leads to retinal degeneration, along with a progressive decline of visual signal. The adjuvant-dependent model and adjuvantfree spontaneous models represent distinct aspects and/or various forms of human uveitis. This review will discuss and compare clinical manifestations, pathology as well as visual function of the retina in the different models of uveitis, as measured by fundus imaging and histology, optical coherence tomography (OCT) and electroretinography (ERG).

Uveitis refers to a group of ocular inflammatory diseases that can lead to blindness. For years, researchers have been trying to decipher the underlying mechanisms and develop therapeutic strategies using the model of experimental autoimmune uveitis (EAU). Recently, αA-crystallin has been found to be upregulated in EAU and can even ameliorate its severity through different mechanisms, suggesting its use as a potent therapeutic factor against uveitis. Here we review the protective role of αA-crystallin and discuss its functional mechanisms in EAU.

Uveitis represents a spectrum of diseases characterized by ocular inflammation that leads to significant visual loss if left untreated. Adequate, long-term control of inflammation with minimal systemic and local adverse effects is the preferred strategy for treating patients with uveitis. Pharmacotherapy for uveitis consists mainly of corticosteroids in various formulations such as topical, local, intraocular and systemic. However, monotherapy with corticosteroids is often unacceptable due to serious adverse effects on various organ systems. There exist limitations with the use of steroid-sparing systemic immunosuppressive agents, as these medications may have significant adverse events and a narrow therapeutic window. Thus, newer molecular targets that act on various steps of the inflammatory pathway appear to be promising emerging strategies for treating uveitis. Specially designed monoclonal antibodies in development can potentially halt the inflammatory processes resulting in remission of the disease. In the index review, novel molecular agents and biological therapies that have shown promising efficacy and safety data in preclinical and clinical studies have been summarized. In addition, new drug delivery systems that may ensure high intraocular therapeutic levels of pharmacologic agents have been highlighted.

Purpose: To evaluate the thicknesses of individual retinal layers, and the correlation between structural changes and functional loss using spectral domain optical coherence tomography (SD-OCT) scans and electroretinograms (ERG), in eyes with autoimmune retinopathy (AIR). Methods: SD-OCT raster scans of 12 eyes from 6 patients serologically diagnosed with AIR were evaluated. Retinal layers were segmented along a 5 mm horizontal scan passing through the fovea. Retinal layers analyzed include full retinal thickness (FRT), retinal pigment epithelium and Bruch’s membrane complex (RPE+BM complex), photoreceptor layer (PRL), inner nuclear layer (INL), combined ganglion cell and inner plexiform layers (GCL+), nerve fiber layer (NFL), and combined GCL+ and NFL layers (GCL+/NFL). Changes in the thicknesses of the layers were assessed in 0.5 mm increments along the B-scan in the central, nasal, and temporal regions. These recorded values were compared to corresponding values of 51 eyes from 51 subjects with no known ocular pathology. Full-field ERGs were obtained at corresponding visits and were interpreted by a grader masked to the diagnoses and OCT findings. Results: The mean age of the patients was 59.5 years (range, 33-83), with 4 males (66.6%). Within the control population of 51 subjects, mean age was 51.5 years (range, 40-75), with 25 males (49%). Eyes with AIR showed a loss of retinal tissue compared to eyes with no known ocular pathology at the fovea. Specifically, the FRT, RPE+BM complex, and PRL exhibited thinning of statistically significance. ERG findings demonstrated a functional deficit which showed a good correlation with structural loss. Fifty (50) percent of eyes experienced central photoreceptor (rod and cone) dysfunction and 75% of eyes displayed peripheral photoreceptor (rod and cone) dysfunction. Conclusions: Eyes with AIR show a loss of retinal tissue compared to eyes with no known ocular pathology. The greatest loss appears to occur in the RPE and PRL. ERG findings correlate strongly with the loss of tissue seen in these layers. Thus, therapeutic options may be targeted to preserve these regions of the retina.