Comparative Analysis of Induced vs. Spontaneous Models of Autoimmune Uveitis Targeting the Interphotoreceptor Retinoid Binding Protein

Falick Y (2013) Comparative Analysis of Induced vs. Spontaneous Models of Autoimmune Uveitis Targeting the Interphotoreceptor Retinoid Binding Protein. PLoS ONE 8(8): e72161. doi:10.1371/journal.pone.0072161 Comparative Analysis of Induced vs. Spontaneous Models of Autoimmune Uveitis Targeting the Interphotoreceptor Retinoid Binding Protein Jun Chen 0 Haohua Qian 0 Reiko Horai 0 Chi-Chao Chan 0 Yishay Falick 0 Rachel R. Caspi 0 James T. Rosenbaum, Oregon Health & Science University, United States of America 0 1 Immunoregulation Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health , Bethesda , Maryland, United States of America , 2 Visual Function Core , National Eye Institute, National Institutes of Health , Bethesda , Maryland, United States of America, 3 Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health , Bethesda, Maryland , United States of America Animal models of autoimmunity to the retina mimic specific features of human uveitis, but no model by itself reproduces the full spectrum of human disease. We compared three mouse models of uveitis that target the interphotoreceptor retinoid binding protein (IRBP): (i) the ''classical'' model of experimental autoimmune uveitis (EAU) induced by immunization with IRBP; (ii) spontaneous uveitis in IRBP T cell receptor transgenic mice (R161H) and (iii) spontaneous uveitis in Autoimmune Regulator (AIRE)2/2 mice. Disease course and severity, pathology and changes in visual function were studied using fundus imaging and histological examinations, optical coherence tomography and electroretinography. All models were on the B10.RIII background. Unlike previously reported, IRBP-induced EAU in B10.RIII mice exhibited two distinct patterns of disease depending on clinical scores developed after onset: severe monophasic with extensive destruction of the retina and rapid loss of visual signal, or lower grade with a prolonged chronic phase culminating after several months in retinal degeneration and loss of vision. R161H and AIRE2/2 mice spontaneously developed chronic progressive inflammation; visual function declined gradually as retinal degeneration developed. Spontaneous uveitis in R161H mice was characterized by persistent cellular infiltrates and lymphoid aggregation, whereas AIRE2/2 mice characteristically developed multi-focal infiltrates and severe choroidal inflammation. These data demonstrate variability and unique distinguishing features in the different models of uveitis, suggesting that each one can represent distinct aspects of uveitis in humans. - Funding: The study was supported by National Institutes of Health (NIH)/National Eye Institute (NEI) Intramural funding, project #EY000184. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Non-infectious uveitis involves a range of clinical pathologies including iritis, cyclitis, choroiditis, retinitis (including retinal vasculitis), and uveoretinitis, and is estimated to underlie 1015% of blindness in the Western world [1,2]. The etiology and pathogenesis are not fully understood and autoimmunity, which may in some cases also involve an autoinflammatory component, is believed to be involved [2,3]. Due to practical and ethical limitations of human studies, the animal model of experimental autoimmune uveitis/uveoretinitis (EAU) [4,5] has been used to study the basic mechanisms of disease. EAU can be induced in mice [6] and in rats [79] by active immunization with retinal antigens that are recognized by lymphocytes of uveitis patients, such as interphotoreceptor retinoid-binding protein (IRBP) and retinal soluble antigen (S-Ag). The main features of EAU in animals are retinal and/or choroidal inflammation, retinal vasculitis, photoreceptor destruction and loss of visional function [10]. As such they reproduce many essential clinico-pathological features of human uveitis [11]. Much of our current understanding of the basic mechanisms involved in uveitis has been derived from this classical EAU model. A limitation of the model is its dependence on use of complete Freunds adjuvant (CFA). CFA contains heat-killed mycobacteria which cause a massive stimulation of the innate immune response, and thereby also affect the adaptive response, in a way that may not be physiological. Therefore, the data should be compared to adjuvant-free models. Our group recently established a spontaneous model of uveitis in IRBP T cell receptor (TCR) transgenic (R161H) mice ([12] and Horai et al., submitted). R161H mice express a transgenic TCR specific to IRBP residues 161-180 (IRBP161-180; amino acid sequence SGIPYIISYLHPGNTILHVD) and spontaneously develop ocular inflammation by 56 weeks of age. In addition to R161H mice, spontaneous autoimmune uveitis develops in mice deficient in the AIRE (AutoImmune Regulator) gene [13]. AIRE controls expression in the thymus of tissuespecific antigens, including IRBP and S-Ag, thus culling the most highly uveitogenic T cells from the repertoire. AIRE2/2 mice develop a multi-organ autoimmune disease that resembles human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which also includes uveoretinitis [13,14]. It is of note that uveitis in AIRE2/2 mice targets the IRBP antigen, as mice deficient in IRBP fail to develop retinal disease [15]. The pathology and clinical characteristics of the classical IRBP-induced EAU has been well characterized in previous studies [4,10,16]. However, the uveitis in R161H and AIRE2/2 mice has not been well characterized. In this study, we applied a series of non-invasive methods including fundoscopy, Micron-II fundus imaging, Bioptigen Envisu R2200 ultra-high resolution optical coherence tomography (OCT) system as well as electroretinography (ERG) to monitor the development and progression of uveitis longitudinally in individual animals. Clinical and histopathological findings as well as functional change of the retina are compared in the three murine models of uveitis. Our findings demonstrate variability and unique distinguishing features in each of the three uveitis models. The results suggest that while no single model represents the full spectrum of clinical and pathological features of human uveitis, each one can reproduce particular aspects of the human disease. Materials and Methods Animals, immunization for EAU and Ethics statement B10.RIII mice were purchased from the Jackson Laboratory (Bar Harbor, Maine). Induction of EAU in B10.RIII mice was by active immunization with 68 mg IRBP emulsified in CFA (Sigma, St. Louis, MO) as described [17]. IRBP TCR transgenic R161H mice on B10RIII background were generated by the NEI Genetic Engineering Core using a TCR constrict cloned in our laboratory from a uveitogenic T cell line [18]. AIRE2/2 mice on (...truncated)