Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3)

Liu, Yi Hsia; Corbett, Clare; Klaska, Izabela P.; Makinen, Kimmo; Nickerson, John M.; Cornall, Richard J.; Kuffová, Lucia; Forrester, John V.

doi:10.1016/j.exer.2018.03.020

Cited by 7 publications

(13 citation statements)

References 60 publications

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“…This also raised the central question of whether the amount of HEL antigen expressed in the retina influences the degree of the inflammatory response it triggers. We have shown that sTg mice, which develop an age-related photoreceptor degeneration with reduced levels of HEL expression (12), become less susceptible to HEL-activated 3A9 CD4+ T cell-induced EAU. The precise role the DN T cells play in this model is not clear.…”

Section: Discussionmentioning

confidence: 91%

“…We report here new data in a previously described model of spontaneous experimental autoimmune uveoretinitis (EAU) generated by cross-breeding IRBP:HEL sTg mice (sTg) with 3A9 TCR mice to produce dTg HEL/TCR (dTg) mice (11). In a companion paper series (12,30), we showed that insertion of the HEL gene in B10.BR wild type mice to create the sTg mice, induces a non-inflammatory, mild to moderate retinal degeneration with photoreceptor shortening. This is associated with a relative reduction in the amount of IRBP in the retina, an essential retina-specific protein for normal photoreceptor health (36).…”

Section: Discussionmentioning

confidence: 99%

“…The generation of dTg mice was previously described (11,12). The procedures adopted conformed to the regulations of the Animal License Act (United Kingdom).…”

Section: Animalsmentioning

confidence: 99%

“…If this were the case, this finding would explain the model's high level of antigen-specificity in EAU induction. We have shown in a companion paper series that the levels of HEL expression decline in sTg mice as retinal degeneration develops with age (12,30). We therefore adoptively transferred 4.5 × 10 6 CD4+ T cells to sTg mice of increasing age.…”

Section: Hel-specific Cd4+ T Cells Induce Eau On Adoptive Transfer Bumentioning

confidence: 99%

“…Both rhodopsin-HEL and IRBP:HEL sTg mice develop a degree of retinal photoreceptor shortening without inflammation, which, in the case of IRBP:HEL sTg mice is associated with reduced levels of IRBP. This retinal degeneration is age-related and has no impact on the development of EAU in dTg mice which has its onset at P21 when the retina is normal and there is abundant retinal HEL expression (12).…”

Section: Introductionmentioning

confidence: 99%

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Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis

et al. 2020

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We specify the clinical features of a spontaneous experimental autoimmune uveitis (EAU) model, in which foreign hen-egg lysozyme (HEL) is expressed in the retina, controlled by the promoter for interphotoreceptor retinol binding protein (IRBP). We previously reported 100% P21 (post-partum day) IRBP:HEL single transgenic (sTg) mice, when crossed to transgenic T cell receptor mice (3A9) generating the double transgenic (dTg) genotype, develop EAU despite profound lymphopenia (thymic HEL-specific T cell deletion). In this work, we characterized the immune component of this model and found conventional dTg CD4+ T cells were less anergic than those from 3A9 controls. Furthermore, prior in vitro HEL-activation of 3A9 anergic T cells (T an) rendered them uveitogenic upon adoptive transfer (Tx) to sTg mice, while antigen-experienced (AgX, dTg), but not naïve (3A9) T cells halted disease in P21 dTg mice. Flow cytometric analysis of the AgX cells elucidated the underlying pathology: FoxP3+CD25 hi CD4+ T regulatory cells (T reg) comprised ∼18%, while FR4+CD73+FoxP3-CD25 lo/− CD4+ T an comprised ∼1.2% of total cells. Further T reg-enrichment (∼80%) of the AgX population indicated FoxP3+CD25 hi CD4+ T reg played a key role in EAU-suppression while FoxP3-CD25 lo/− CD4+ T cells did not. Here we present the novel concept of dual immunological tolerance where spontaneous EAU is due to escape from anergy with consequent failure of T reg induction and subsequent imbalance in the [T reg :T effector ] cell ratio. The reduced numbers of T an , normally sustaining T reg to prevent autoimmunity, are the trigger for disease, while immune homeostasis can be restored by supplementation with AgX, but not naïve, antigen-specific T reg .

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

“…The generation of dTg mice was previously described (11,12). The procedures adopted conformed to the regulations of the Animal License Act (United Kingdom).…”

Section: Animalsmentioning

confidence: 99%

Section: Hel-specific Cd4+ T Cells Induce Eau On Adoptive Transfer Bumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis

et al. 2020

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Transmission Electron Microscopy Data on drusen-like deposits in the retinal degeneration sTg-IRBP: HEL mouse model

et al. 2019

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Histology (H&E) and transmission electron microscopy (TEM) data are provided showing age-related changes in the retinal structure of sTg-IRBP:HEL mice. These include substantial photoreceptor loss, atrophy of the retinal pigment epithelium, Bruch׳s membrane disruption and thickening, along with the presence of drusenoid deposits and changes in basal laminar infoldings. These features resemble some of those key characteristics found in the course of human dry (atrophic) age-related macular degeneration (AMD), particularly with regard to drusen. Hence, we believe the sTg-IRBP:HEL mouse model represents a useful and promising archetype for future study of the mechanism of drusen formation in AMD.

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Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

Mölzer

Liu

Muckersie

et al. 2023

Sci Rep

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Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.

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Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3)

Cited by 7 publications

References 60 publications

Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis

Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis

Transmission Electron Microscopy Data on drusen-like deposits in the retinal degeneration sTg-IRBP: HEL mouse model

Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

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