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Comparative analysis of induced vs. spontaneous models of autoimmune uveitis targeting the interphotoreceptor retinoid binding protein.

Chen J, Qian H, Horai R, Chan CC, Falick Y, Caspi RR - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunoregulation Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
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)(-/-) 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 AIRE(-/-) 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 AIRE(-/-) 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.

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Comparison of retinal images obtained by fundus photography, OCT, and histology in B10.RIII mouse.A, Normal retinal layers in a healthy eye assessed by cross-sectional OCT in comparison with histology. Note the appearance of the ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer nuclear layer (ONL), IS/OS of photoreceptor layer (PRL), retinal pigment epithelium (RPE) and choroid (CH) in the respective images. Blood vessels are indicated by arrows. B, Comparison of fundus appearance by Micron II imaging with OCT volume scan images in multiple retinal layers of normal eye.
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pone-0072161-g001: Comparison of retinal images obtained by fundus photography, OCT, and histology in B10.RIII mouse.A, Normal retinal layers in a healthy eye assessed by cross-sectional OCT in comparison with histology. Note the appearance of the ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer nuclear layer (ONL), IS/OS of photoreceptor layer (PRL), retinal pigment epithelium (RPE) and choroid (CH) in the respective images. Blood vessels are indicated by arrows. B, Comparison of fundus appearance by Micron II imaging with OCT volume scan images in multiple retinal layers of normal eye.

Mentions: The appearance of healthy ocular tissues visualized by the methodologies used in this study is shown in Figure 1 and serves as comparison for all subsequent Figures. Disease severity and course were evaluated and compared between three models of uveitis, the “classical” immunization-induced EAU model, spontaneous uveitis developing in R161H IRBP TCR transgenic mice, and spontaneous uveitis developing in AIRE−/− mice (Figure 2). A common platform for comparison is present because all 3 models were on the B10.RIII background and in all 3 models IRBP is the target antigen. In the immunization-induced model, EAU onset occurred 11–13 days post immunization (p.i.) and peaked on day 14. In contrast to the generally held belief that EAU in B10.RIII mice is strictly an acute monophasic inflammatory disease, two distinct patterns of EAU progression were observed: monophasic and chronic. The progression pattern of individual animals depended on the severity of the initial acute phase of retinal inflammation (depicted in Figure 2A). (i) In the monophasic EAU pattern, mice that developed disease with clinical scores of EAU greater than 2 in the acute phase of inflammation during weeks 2–3 p.i., manifested a rapid resolution of active inflammation (consisting of perivascular exudates, subretinal hemorrhage and retinal folds, etc.) after week 3, as well as thinning of the retina. Active inflammation disappeared around 4–5 weeks p.i., and was followed rapidly by retinal atrophy that marked the end of clinical scoring for EAU. (ii) In the chronic EAU pattern, following the initial phase of acute retinal inflammation 2–3 weeks p.i., mice that had developed clinical disease scores of 2 or less during the acute phase exhibited chronic ocular inflammation manifested as persistent white granulomatous like lesions and perivascular cuffing that continued for 5–6 months until retinal degeneration and atrophy occurred. In the current study, using 6–8 µg IRBP161-180/mouse immunization dose, about ¾ of mice developed monophasic disease, and ¼ developed chronic disease.


Comparative analysis of induced vs. spontaneous models of autoimmune uveitis targeting the interphotoreceptor retinoid binding protein.

Chen J, Qian H, Horai R, Chan CC, Falick Y, Caspi RR - PLoS ONE (2013)

Comparison of retinal images obtained by fundus photography, OCT, and histology in B10.RIII mouse.A, Normal retinal layers in a healthy eye assessed by cross-sectional OCT in comparison with histology. Note the appearance of the ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer nuclear layer (ONL), IS/OS of photoreceptor layer (PRL), retinal pigment epithelium (RPE) and choroid (CH) in the respective images. Blood vessels are indicated by arrows. B, Comparison of fundus appearance by Micron II imaging with OCT volume scan images in multiple retinal layers of normal eye.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756070&req=5

pone-0072161-g001: Comparison of retinal images obtained by fundus photography, OCT, and histology in B10.RIII mouse.A, Normal retinal layers in a healthy eye assessed by cross-sectional OCT in comparison with histology. Note the appearance of the ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer nuclear layer (ONL), IS/OS of photoreceptor layer (PRL), retinal pigment epithelium (RPE) and choroid (CH) in the respective images. Blood vessels are indicated by arrows. B, Comparison of fundus appearance by Micron II imaging with OCT volume scan images in multiple retinal layers of normal eye.
Mentions: The appearance of healthy ocular tissues visualized by the methodologies used in this study is shown in Figure 1 and serves as comparison for all subsequent Figures. Disease severity and course were evaluated and compared between three models of uveitis, the “classical” immunization-induced EAU model, spontaneous uveitis developing in R161H IRBP TCR transgenic mice, and spontaneous uveitis developing in AIRE−/− mice (Figure 2). A common platform for comparison is present because all 3 models were on the B10.RIII background and in all 3 models IRBP is the target antigen. In the immunization-induced model, EAU onset occurred 11–13 days post immunization (p.i.) and peaked on day 14. In contrast to the generally held belief that EAU in B10.RIII mice is strictly an acute monophasic inflammatory disease, two distinct patterns of EAU progression were observed: monophasic and chronic. The progression pattern of individual animals depended on the severity of the initial acute phase of retinal inflammation (depicted in Figure 2A). (i) In the monophasic EAU pattern, mice that developed disease with clinical scores of EAU greater than 2 in the acute phase of inflammation during weeks 2–3 p.i., manifested a rapid resolution of active inflammation (consisting of perivascular exudates, subretinal hemorrhage and retinal folds, etc.) after week 3, as well as thinning of the retina. Active inflammation disappeared around 4–5 weeks p.i., and was followed rapidly by retinal atrophy that marked the end of clinical scoring for EAU. (ii) In the chronic EAU pattern, following the initial phase of acute retinal inflammation 2–3 weeks p.i., mice that had developed clinical disease scores of 2 or less during the acute phase exhibited chronic ocular inflammation manifested as persistent white granulomatous like lesions and perivascular cuffing that continued for 5–6 months until retinal degeneration and atrophy occurred. In the current study, using 6–8 µg IRBP161-180/mouse immunization dose, about ¾ of mice developed monophasic disease, and ¼ developed chronic disease.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunoregulation Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
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)(-/-) 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 AIRE(-/-) 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 AIRE(-/-) 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.

Show MeSH
Related in: MedlinePlus