Mouse Models of Experimental Autoimmune Uveitis: Comparative Analysis of Adjuvant-Induced vs Spontaneous Models of Uveitis

Abstract

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" immunization-induced 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 adjuvant-free 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).

Fig. (1).

Comparison of disease severity and course in induced and spontaneous uveitis models. EAU was induced in B10R.III mice by immunization with IRBP161–180 in adjuvant. R161H and AIRE^−/− mice spontaneously developed uveitis. A, Retinal images obtained by fundus photography at different phase of disease in three models of uveitis. Fundus photographs shown is the chronic form of induced EAU. B, Clinical scores evaluated using an adapted fundus microscope at different stage of disease. EAU induced by immunization with IRBP in adjuvant (a, n=17); spontaneous uveitis seen in R161H (b, n=16) and AIRE^−/− mice (c, n=21). Data are presented as mean ± SEM. Figure modified from reference [14].

Fig. (2).

Comparison of retinal thickness in induced and spontaneous models of uveitis. B-scan OCT of the retina was evaluated at the indicated time points using a Bioptigen SD-OCT imaging system, and retinal thickness was measured and averaged from OCT images of the retina. EAU induced by immunization with IRBP in adjuvant (A-B); spontaneous uveitis seen in R161H (C) and AIRE^−/− mice (D). Data are presented as mean ± SEM of 17 mice from two individual experiments (A-B) and 16–21 mice from two to three individual experiments (C-D). Figure reprinted from reference [14].

Fig. (3).

Semi-quantitative evaluation of cellular infiltrates in the vitreous of mice with induced and spontaneous models of uveitis. Volume-scan of OCT images was captured in the vitreous at the indicated time points using a Bioptigen SD-OCT imaging system. All images were digitally processed in the same way using Photoshop to equalize background contrast levels. Signal intensity of OCT volume scan was then measured and analyzed using ImageJ analysis. EAU induced by immunization with IRBP in adjuvant (A, n=8); spontaneous uveitis seen in R161H (B, n=8) and AIRE^−/− mice (C, n=6). Data are presented as mean ± SEM of percent increase of OCT intensity to normal or WT mice. Figure modified from reference [14].

Fig. (4).

Histopathology of induced and spontaneous uveitis models. a-c, 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 folding and cell infiltrates, subretinal hemorrhage, and choroidal inflammation at the peak of inflammation on day 14 p.i. (a, low magnification). During the acute phase of EAU, 18–21 days after immunization, eye histology showed extensive retinal lesions and infiltrating cells in the choroid, vitreous, as well as subretinal hemorrhage (b, high magnification). Retinal folding was seen in mice that developed the chronic form of EAU (c, high magnification). d-f, Eye histology of R161H mice at different ages. Note cell infiltrates and exudates in the vitreous and in the retina (d-e, low and high magnification), lymphoid aggregation in the retina (f, asterisk), and choroidal inflammation (e-f). g-i, Eye histology of AIRE^−/− mice at different ages. Note severe choroiditis (g, low magnification; i, high magnification), granuloma-like lesions in the retina (h-i, low magnification). Figure modified from reference [14].

Fig. (5).

Kinetics of light-adapted ERG response in induced and spontaneous uveitis models. Mice that developed induced and spontaneous EAU were monitored and followed up at the indicative time points by ERG. Amplitude of light-adapted ERG was recorded and analyzed in mice developed adjuvant-induced EAU (A) and in R161H (B) and AIRE^−/− (C) mice that developed spontaneous uveitis. Data represent the mean ± SEM of 17 mice from two individual experiments (A) and 16–21 mice from two to three individual experiments (B, C). Figure modified from reference [14].