Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations

Kerr, Emma C.; Raveney, Ben J. E.; Copland, David A; Dick, Andrew D.; Nicholson, Lindsay B.

doi:10.1016/j.jaut.2008.08.006

Cited by 144 publications

(156 citation statements)

References 37 publications

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“…2 Microglia form a network throughout the retina, and display regulatory phenotypes and functions consistent with other tissue-resident macrophages elsewhere in the body. 4 Furthermore, although we are still awaiting the advent of live in vivo imaging of immune cell trafficking to understand the dynamics and kinetics of cell trafficking and/or turnover, the results experimentally demonstrate a persistence of macrophages throughout disease 7,8 and where myeloid, macrophage, and T-cell accumulations are noted in later disease. 9 The activity and extent of immune surveillance and cell traffic is yet to be determined in man.…”

Section: Keeping the Peacementioning

confidence: 99%

“…35 The animal models, such as experimental autoimmune uveoretinitis (EAU), support a role for autoimmunity with clinical-pathological features bearing remarkable similarity to man. 7,8,36,37 The currently held notion is that of a CD4 + T helper cell-driven process and supported in man by the association of sympathetic ophthalmia and Vogt-Koyanagi-Harada disease with specific HLA class II alleles as well as the identification of ocular antigen-responsive T cells in both the peripheral blood and eyes of patients. [38][39][40] When T cells are activated, they assume different functional phenotypes directed through canonical transcription factors 41,42 and characterised by the secretion of signature cytokines.…”

Section: Understanding Uveitismentioning

confidence: 99%

“…43,44 In EAU, both Th1 and Th17 T helper cells are important inducers of autoimmune disease. 35,45 It is the cytokines (especially IFN-γ produced by Th1 cells) produced by these cells that activate the non-specific mononuclear tissue infiltration (principally macrophages) and recruit neutrophils as seen in EAU (eg, through interleukin (IL)-17 produced from Th17 cells 7,8,23,24,[26][27][28] ).…”

Section: Understanding Uveitismentioning

confidence: 99%

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Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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Section: Keeping the Peacementioning

confidence: 99%

Section: Understanding Uveitismentioning

confidence: 99%

Section: Understanding Uveitismentioning

confidence: 99%

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Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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“…30,31 In support of this concept of ongoing chronic immune dysregulation retinal cell analysis in EAU shows persistence of a significant sustained infiltrate and an appearance, which is atypical for normal retina long after resolution of clinically evident disease. 32,33 So irrespective of the danger signal that drives inflammation (autoimmunity vs autoinflammation vs degeneration), dysregulation of immunity within the eye, innate immune activation, and macrophage infiltration remain common to many chorioretinal diseases. A current paradigm of macrophage activation recognises that their phenotype is dependent upon the signals (from cytokines and ligands expressed on other cell types) they receive.…”

Section: Understanding Immunopathologymentioning

confidence: 99%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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The blockbuster drug paradigm is under increasing scrutiny across the biopharmaceutical industry. Intraocular inflammation poses particular challenges to this, given the heterogeneity of conditions in the uveitis spectrum, and the increasing acknowledgement of individual patient and disease variance in underlying immune responses. This need has triggered a drive towards personalised and stratified medicine, supported and enabled as a result of continued development of both experimental models and molecular biological techniques and improved clinical classification. As such we have the ability now to systematically appraise at a genomic, transcriptomic, and proteomic level individual immunophenotype, and the promise that in the eye this can be augmented by in vivo immune imaging to identify individual immunopathology. With such advances all running in parallel, we are entering an era of experimental medicine that will facilitate early diagnosis, generate biomarkers for accurate prognostication, and enable the development of individualised and targeted therapies, which can progress rapidly into clinical practice.

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“…[27][28][29][30][31][32]33 In the B10.RIII mouse, disease progression 33 is similarly aggressive 31 but in the C57/BL6 mouse, EAU onset and development is less aggressive and inflammation settles considerably after a variable period of 3-4 weeks. 31,34 Immunopathological studies reveal that there is a contest between different types of inflammatory cells: T effector cells compete with T regulatory cells which both are induced by the same antigen but with different kinetics 34 while inflammatory macrophages, such as those expressing sialoadhesin 35 compete with suppressive macrophages (myeloid suppressor cells, MSCs). 36 If the suppressor mechanisms win, then the disease resolves.…”

Section: Resolution Of Ioi and Eaumentioning

confidence: 99%