A clinical grading system for retinal inflammation in the chronic model of experimental autoimmune uveoretinitis using digital fundus images

Xu, Heping; Koch, Philippe; Chen, Mei; Lau, Angela Wong; Reid, Delyth M.; Forrester, John V.

doi:10.1016/j.exer.2008.06.012

Cited by 117 publications

(143 citation statements)

References 17 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…Images of the retinal fundus were acquired using an endoscopic imaging system described previously 51. Mice were anaesthetized with an intraperitoneal injection of a mixture of 20 mg/ml Ketaset (Fort Dodge Animal Health LDT, Overland Park, KS) and 1 mg/ml Domitor (Orion Pharma, Espoo, Finland) diluted in PBS.…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

Self Cite

View full text Add to dashboard Cite

SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

show abstract

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mice simultaneously received 0.3 μg Bordetella pertussis toxin. Clinical disease was scored by fundoscopy (31) and histological analysis (32), as detailed in SI Materials and Methods. Tissue sections were also examined using a multiphoton laser-scanning confocal microscope with fluorescence emission detected with 515/30 (emerald-GFP, green) and 600/40 (mCherry, red), as described (26,31).…”

Section: Methodsmentioning

confidence: 99%

“…Clinical disease was scored by fundoscopy (31) and histological analysis (32), as detailed in SI Materials and Methods. Tissue sections were also examined using a multiphoton laser-scanning confocal microscope with fluorescence emission detected with 515/30 (emerald-GFP, green) and 600/40 (mCherry, red), as described (26,31). For adoptive transfer experiments, draining LN cells from WT and Il21r −/− EAU mice (at day 21) were stimulated with IRBP 20 μg/mL for 4 d, and 10 7 cells in 200 μL of PBS were injected i.v.…”

Section: Methodsmentioning

confidence: 99%

Key role for IL-21 in experimental autoimmune uveitis

Wang

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

IL-21 is a pleiotropic type 1 cytokine that shares the common cytokine receptor γ-chain, γ c , with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is most homologous to IL-2. These cytokines are encoded by adjacent genes, but they are functionally distinct. Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmune disease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases, including type 1 diabetes and systemic lupus erythematosus. However, the roles of IL-21 and IL-2 in CNS autoimmune diseases such as multiple sclerosis and uveitis have been controversial. Here, we generated Il21 -mCherry/ Il2 -emGFP dual-reporter transgenic mice and showed that development of experimental autoimmune uveitis (EAU) correlated with the presence of T cells coexpressing IL-21 and IL-2 into the retina. Furthermore, Il21r −/− mice were more resistant to EAU development than wild-type mice, and adoptive transfer of Il21r −/− T cells induced much less severe EAU, underscoring the need for IL-21 in the development of this disease and suggesting that blocking IL-21/γ c –signaling pathways may provide a means for controlling CNS auto-inflammatory diseases.

show abstract

“…This clinical grading system was adapted from ref. 15 and has been previously published. 16 Scoring was carried out independently by trained assessors for whom the origin of the data was masked.…”

Section: Clinical Assessment By Topical Endoscopic Fundal Imagingmentioning

confidence: 99%

“…Human RBP-3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Peptide (GPTHLFQPSLVLDMAKV LLD) and chicken ovalbumin (OVA) (ISQAVHAAHAEIN EAGR) were synthesized by Sigma-Aldrich (Poole, UK).…”

Section: Reagentsmentioning

confidence: 99%

A novel pathogenic RBP‐3 peptide reveals epitope spreading in persistent experimental autoimmune uveoretinitis

et al. 2015

View full text Add to dashboard Cite

SummaryExperimental autoimmune uveoretinitis (EAU) in the C57BL/6J mouse is a model of non-infectious posterior segment intraocular inflammation that parallels clinical features of the human disease. The purpose of this study was to analyse the immune response to the four murine subunits of retinol binding protein-3 (RBP-3) to identify pathogenic epitopes to investigate the presence of intramolecular epitope spreading during the persistent inflammation phase observed in this model of EAU. Recombinant murine subunits of the RBP-3 protein were purified and used to immunize C57BL/6J mice to induce EAU. An overlapping peptide library was used to screen RBP-3 subunit 3 for immunogenicity and pathogenicity. Disease phenotype and characterization of pathogenic subunits and peptides was undertaken by topical endoscopic fundal imaging, immunohistochemistry, proliferation assays and flow cytometry. RBP-3 subunits 1, 2 and 3 induced EAU in the C57BL/6J mice, with subunit 3 eliciting the most destructive clinical disease. Within subunit 3 we identified a novel uveitogenic epitope, 629-643. The disease induced by this peptide was comparable to that produced by the uveitogenic 1-20 peptide. Following immunization, peptide-specific responses by CD4 + and CD8 + T-cell subsets were detected, and cells from both populations were present in the retinal inflammatory infiltrate. Intramolecular epitope spreading between 629-643 and 1-20 was detected in mice with clinical signs of disease. The 629-643 RBP-3 peptide is a major uveitogenic peptide for the induction of EAU in C57BL/6J mice and the persistent clinical disease induced with one peptide leads to epitope spreading.

show abstract

A clinical grading system for retinal inflammation in the chronic model of experimental autoimmune uveoretinitis using digital fundus images

Cited by 117 publications

References 17 publications

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Key role for IL-21 in experimental autoimmune uveitis

A novel pathogenic RBP‐3 peptide reveals epitope spreading in persistent experimental autoimmune uveoretinitis

Contact Info

Product

Resources

About