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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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Histopathology of induced and spontaneous uveitis models.A–D, Mice were immunized with IRBP in adjuvant and eyes were collected at the indicated days after immunization. Note severe ocular inflammation including vitritis, retinal swelling and destruction, retinal folds and infiltrates, subretinal hemorrhage, and choroidal inflammation at the peak of inflammation on day 14 p.i. (A–B, low and high magnification). During the acute phase of EAU, 18–21 days after immunization, eye histology showed well developed retinal lesions and infiltrating cells in the choroid, vitreous, as well as subretinal hemorrhage (arrow) (B and C). Retinal folds were seen in mice that developed the chronic form of EAU (D). E–H, Histology of R161H mice at different ages. Note cellular infiltrates and exudates in the vitreous and in the retina (E–F, low and high magnification), lymphoid aggregation in the retina (G, asterisk), photoreceptor layer destruction (H) and choroidal inflammation (G–H). I–P, Histology of AIRE−/− mice at different ages. Note severe choroiditis (I–J, low magnification; N, high magnification), granuloma-like lesions in the retina (K, low magnification; M–N, high magnification), photoreceptor layer destruction and retinal degeneration (O–P, high magnification). Fourteen B10RIII mice with EAU (10 for monophasic form, 4 for chronic form), 12 R161H and 13 AIRE−/− mice were included in the histological examination. Eyes of 2–3 mice were harvested at each time point.
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pone-0072161-g005: Histopathology of induced and spontaneous uveitis models.A–D, Mice were immunized with IRBP in adjuvant and eyes were collected at the indicated days after immunization. Note severe ocular inflammation including vitritis, retinal swelling and destruction, retinal folds and infiltrates, subretinal hemorrhage, and choroidal inflammation at the peak of inflammation on day 14 p.i. (A–B, low and high magnification). During the acute phase of EAU, 18–21 days after immunization, eye histology showed well developed retinal lesions and infiltrating cells in the choroid, vitreous, as well as subretinal hemorrhage (arrow) (B and C). Retinal folds were seen in mice that developed the chronic form of EAU (D). E–H, Histology of R161H mice at different ages. Note cellular infiltrates and exudates in the vitreous and in the retina (E–F, low and high magnification), lymphoid aggregation in the retina (G, asterisk), photoreceptor layer destruction (H) and choroidal inflammation (G–H). I–P, Histology of AIRE−/− mice at different ages. Note severe choroiditis (I–J, low magnification; N, high magnification), granuloma-like lesions in the retina (K, low magnification; M–N, high magnification), photoreceptor layer destruction and retinal degeneration (O–P, high magnification). Fourteen B10RIII mice with EAU (10 for monophasic form, 4 for chronic form), 12 R161H and 13 AIRE−/− mice were included in the histological examination. Eyes of 2–3 mice were harvested at each time point.

Mentions: We next compared the histopathology of the eyes in the induced and spontaneous models of uveitis (Figure 5). At the peak of IRBP-induced monophasic EAU, on day 14 after immunization (Figure 5A–B), ocular histology showed severe subacute inflammatory cellular infiltration into the vitreous and choroid, along with iridocyclitis, retinal edema, folds and infiltrates. Shortly after that retinal edema diminished, but discrete retinitis, vitreal and subretinal hemorrhage, retinal folds, as well as choroiditis were prominent on days 18–21 after immunization (Figure 5C). Later the retina became diffusely degenerative and atrophic (see Figure 3A). In mice that developed the chronic form of EAU retinal folds were also frequently observed 18–21 days after immunization (Figure 5D) but atrophy at that point was focal at most, and did not set in until 6–7 months.


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)

Histopathology of induced and spontaneous uveitis models.A–D, Mice were immunized with IRBP in adjuvant and eyes were collected at the indicated days after immunization. Note severe ocular inflammation including vitritis, retinal swelling and destruction, retinal folds and infiltrates, subretinal hemorrhage, and choroidal inflammation at the peak of inflammation on day 14 p.i. (A–B, low and high magnification). During the acute phase of EAU, 18–21 days after immunization, eye histology showed well developed retinal lesions and infiltrating cells in the choroid, vitreous, as well as subretinal hemorrhage (arrow) (B and C). Retinal folds were seen in mice that developed the chronic form of EAU (D). E–H, Histology of R161H mice at different ages. Note cellular infiltrates and exudates in the vitreous and in the retina (E–F, low and high magnification), lymphoid aggregation in the retina (G, asterisk), photoreceptor layer destruction (H) and choroidal inflammation (G–H). I–P, Histology of AIRE−/− mice at different ages. Note severe choroiditis (I–J, low magnification; N, high magnification), granuloma-like lesions in the retina (K, low magnification; M–N, high magnification), photoreceptor layer destruction and retinal degeneration (O–P, high magnification). Fourteen B10RIII mice with EAU (10 for monophasic form, 4 for chronic form), 12 R161H and 13 AIRE−/− mice were included in the histological examination. Eyes of 2–3 mice were harvested at each time point.
© Copyright Policy
Related In: Results  -  Collection

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pone-0072161-g005: Histopathology of induced and spontaneous uveitis models.A–D, Mice were immunized with IRBP in adjuvant and eyes were collected at the indicated days after immunization. Note severe ocular inflammation including vitritis, retinal swelling and destruction, retinal folds and infiltrates, subretinal hemorrhage, and choroidal inflammation at the peak of inflammation on day 14 p.i. (A–B, low and high magnification). During the acute phase of EAU, 18–21 days after immunization, eye histology showed well developed retinal lesions and infiltrating cells in the choroid, vitreous, as well as subretinal hemorrhage (arrow) (B and C). Retinal folds were seen in mice that developed the chronic form of EAU (D). E–H, Histology of R161H mice at different ages. Note cellular infiltrates and exudates in the vitreous and in the retina (E–F, low and high magnification), lymphoid aggregation in the retina (G, asterisk), photoreceptor layer destruction (H) and choroidal inflammation (G–H). I–P, Histology of AIRE−/− mice at different ages. Note severe choroiditis (I–J, low magnification; N, high magnification), granuloma-like lesions in the retina (K, low magnification; M–N, high magnification), photoreceptor layer destruction and retinal degeneration (O–P, high magnification). Fourteen B10RIII mice with EAU (10 for monophasic form, 4 for chronic form), 12 R161H and 13 AIRE−/− mice were included in the histological examination. Eyes of 2–3 mice were harvested at each time point.
Mentions: We next compared the histopathology of the eyes in the induced and spontaneous models of uveitis (Figure 5). At the peak of IRBP-induced monophasic EAU, on day 14 after immunization (Figure 5A–B), ocular histology showed severe subacute inflammatory cellular infiltration into the vitreous and choroid, along with iridocyclitis, retinal edema, folds and infiltrates. Shortly after that retinal edema diminished, but discrete retinitis, vitreal and subretinal hemorrhage, retinal folds, as well as choroiditis were prominent on days 18–21 after immunization (Figure 5C). Later the retina became diffusely degenerative and atrophic (see Figure 3A). In mice that developed the chronic form of EAU retinal folds were also frequently observed 18–21 days after immunization (Figure 5D) but atrophy at that point was focal at most, and did not set in until 6–7 months.

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