Publications by authors named "John V Forrester"

152 Publications

Immune Privilege: The Microbiome and Uveitis.

Front Immunol 2020 25;11:608377. Epub 2021 Jan 25.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier - an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated "non-infectious" uveitis. Dysbiosis accompanies the commonest form, HLA-B27-associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.
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http://dx.doi.org/10.3389/fimmu.2020.608377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868421PMC
January 2021

Severity of Experimental Autoimmune Uveitis Is Reduced by Pretreatment with Live Probiotic Nissle 1917.

Cells 2020 Dec 25;10(1). Epub 2020 Dec 25.

Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic.

Non-infectious uveitis is considered an autoimmune disease responsible for a significant burden of blindness in developed countries and recent studies have linked its pathogenesis to dysregulation of the gut microbiota. We tested the immunomodulatory properties of two probiotics, Nissle 1917 (EcN) and O83:K24:H31 (EcO), in a model of experimental autoimmune uveitis (EAU). To determine the importance of bacterial viability and treatment timing, mice were orally treated with live or autoclaved bacteria in both preventive and therapeutic schedules. Disease severity was assessed by ophthalmoscopy and histology, immune phenotypes in mesenteric and cervical lymph nodes were analyzed by flow cytometry and the gut immune environment was analyzed by RT-PCR and/or gut tissue culture. EcN, but not EcO, protected against EAU but only as a live organism and only when administered before or at the time of disease induction. Successful prevention of EAU was accompanied by a decrease in IRBP-specific T cell response in the lymph nodes draining the site of immunization as early as 7 days after the immunization and eye-draining cervical lymph nodes when the eye inflammation became apparent. Furthermore, EcN promoted an anti-inflammatory response in Peyer's patches, increased gut antimicrobial peptide expression and decreased production of inducible nitric oxide synthase in macrophages. In summary, we show here that EcN controls inflammation in EAU and suggest that probiotics may have a role in regulating the gut-eye axis.
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http://dx.doi.org/10.3390/cells10010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823395PMC
December 2020

The Role of Inflammation in Diabetic Retinopathy.

Front Immunol 2020 6;11:583687. Epub 2020 Nov 6.

Institute of Medical Sciences, University of Aberdeen, Scotland, United Kingdom.

Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5CD11b monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.
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http://dx.doi.org/10.3389/fimmu.2020.583687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677305PMC
November 2020

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

Front Immunol 2020 4;11:2071. Epub 2020 Sep 4.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.

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 HEL-activation of 3A9 anergic T cells (T) 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+CD25CD4+ T regulatory cells (T) comprised ∼18%, while FR4+CD73+FoxP3-CD25CD4+ T comprised ∼1.2% of total cells. Further T-enrichment (∼80%) of the AgX population indicated FoxP3+CD25CD4+ T played a key role in EAU-suppression while FoxP3-CD25CD4+ 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 induction and subsequent imbalance in the [T:T] cell ratio. The reduced numbers of T, normally sustaining T to prevent autoimmunity, are the trigger for disease, while immune homeostasis can be restored by supplementation with AgX, but not naïve, antigen-specific T.
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http://dx.doi.org/10.3389/fimmu.2020.02071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498671PMC
September 2020

Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition.

J Tissue Eng Regen Med 2019 09 18;13(9):1528-1543. Epub 2019 Jul 18.

School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.

Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen-containing matrices, Matrigel and de-cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a "tolerogenic" phenotype. The same applied to singly crosslinked CMP-PEG gels. RHCIII gels singly crosslinked using either N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide with the coinitiator N-hydroxy succinimide (EDC-NHS) or N-cyclohexyl-N-(2-morpholinoethyl)carbodiimide metho-p-toulenesulfonate with NHS (CMC-NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2-methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte-associated immunoglobulin-like receptor-1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.
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http://dx.doi.org/10.1002/term.2903DOI Listing
September 2019

TGF-β1-activated type 2 dendritic cells promote wound healing and induce fibroblasts to express tenascin c following corneal full-thickness hydrogel transplantation.

J Tissue Eng Regen Med 2019 09 25;13(9):1507-1517. Epub 2019 Jul 25.

School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.

We showed previously that 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDC) cross-linked recombinant human collagen III hydrogels promoted stable regeneration of the human cornea (continued nerve and stromal cell repopulation) for over 4 years. However, as EDC cross linking kinetics were difficult to control, we additionally tested a sterically bulky carbodiimide. Here, we compared the effects of two carbodiimide cross linkers-bulky, aromatic N-cyclohexyl-N0-(2-morpholinoethyl)-carbodiimide (CMC), and nonbulky EDC-in a mouse corneal graft model. Murine corneas undergoing full-thickness implantation with these gels became opaque due to dense retro-corneal membranes (RCM). Corneal epithelial cytokeratin 12 and alpha smooth muscle actin indicative of functional tissue regeneration and wound contraction were observed in RCM surrounding both hydrogel types. However, quantitatively different levels of infiltrating CD11c dendritic cells (DC) were found, suggesting a hydrogel-specific innate immune response. More DC infiltrated the stroma surrounding EDC-N-hydroxysuccinimide (NHS) hydrogels concurrently with higher fibrosis-associated tenascin c expression. The opposite was true for CMC-NHS gels that had previously been shown to be more tolerising to DC. In vitro studies showed that DC cultured with transforming growth factor β1 (TGF-β1) induced fibroblasts to secrete more tenascin c than those cultured with lipopolysaccharide and this effect was blocked by TGF-β1 neutralisation. Furthermore, tenascin c staining was found in 40- to 50μm long membrane nanotubes formed in fibroblast/DC cocultures. We suggest that TGF-β1 alternatively activated (tolerising) DC regulate fibroblast-mediated tenascin c secretion, possibly via local production of TGF-β1 in early wound contraction, and that this is indirectly modulated by different hydrogel chemistries.
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http://dx.doi.org/10.1002/term.2853DOI Listing
September 2019

Retinoic acid-induced autoantigen-specific type 1 regulatory T cells suppress autoimmunity.

EMBO Rep 2019 05 20;20(5). Epub 2019 Mar 20.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3 Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.
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http://dx.doi.org/10.15252/embr.201847121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500997PMC
May 2019

Ebola virus and persistent chronic infection: when does replication cease?

Authors:
John V Forrester

Ann Transl Med 2018 Nov;6(Suppl 1):S39

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.

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http://dx.doi.org/10.21037/atm.2018.09.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291550PMC
November 2018

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

Data Brief 2019 Feb 6;22:140-144. Epub 2018 Dec 6.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.

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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http://dx.doi.org/10.1016/j.dib.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299122PMC
February 2019

CNS infection and immune privilege.

Nat Rev Neurosci 2018 11;19(11):655-671

Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.

Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNS infections and ask whether immune privilege may provide protection for certain pathogens and promote their latency.
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http://dx.doi.org/10.1038/s41583-018-0070-8DOI Listing
November 2018

Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology.

J Cell Mol Med 2018 11 30;22(11):5552-5564. Epub 2018 Aug 30.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.

The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction "seals" between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age-related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na /K -ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50-100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age-reduced TEP may offer a new way of preventing or reversing retinal dysfunction.
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http://dx.doi.org/10.1111/jcmm.13829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201363PMC
November 2018

Cytomegalovirus establishes a latent reservoir and triggers long-lasting inflammation in the eye.

PLoS Pathog 2018 05 31;14(5):e1007040. Epub 2018 May 31.

Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia.

Recent outbreaks of Ebola and Zika have highlighted the possibility that viruses may cause enduring infections in tissues like the eye, including the neural retina, which have been considered immune privileged. Whether this is a peculiarity of exotic viruses remains unclear, since the impact of more common viral infections on neural compartments has not been examined, especially in immunocompetent hosts. Cytomegalovirus is a common, universally distributed pathogen, generally innocuous in healthy individuals. Whether in immunocompetent hosts cytomegalovirus can access the eye, and reside there indefinitely, was unknown. Using the well-established murine cytomegalovirus infection model, we show that systemic infection of immunocompetent hosts results in broad ocular infection, chronic inflammation and establishment of a latent viral pool in the eye. Infection leads to infiltration and accumulation of anti-viral CD8+ T cells in the eye, and to the development of tissue resident memory T cells that localize to the eye, including the retina. These findings identify the eye as an unexpected reservoir for cytomegalovirus, and suggest that common viruses may target this organ more frequently than appreciated. Notably, they also highlight that infection triggers sustained inflammatory responses in the eye, including the neural retina.
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http://dx.doi.org/10.1371/journal.ppat.1007040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978784PMC
May 2018

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

Exp Eye Res 2018 07 21;172:54-65. Epub 2018 Mar 21.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia. Electronic address:

Organ-specific transgenic membrane expression of hen egg lysozyme (HEL) as a "neo-self antigen" has been used in several models to study immunological tolerance. In this study we report the changes which occur in the B10.BR mouse retina when membrane-bound HEL is expressed in photoreceptors under the control of the promoter for interphotoreceptor retinoid binding protein (IRBP, RBP3). On direct clinical examination of the single transgenic (sTg-IRBP:HEL) mouse fundus, a low-level increase in retinal degeneration compared to non-transgenic controls was observed, presenting as drusenoid deposits and occasional small patches of atrophy. On histological examination, there was an overall shortening of outer segments and loss of photoreceptor nuclei in sTg-IRBP:HEL mice, which was more pronounced in the retinal periphery, particularly inferiorly. The fundoscopically observed lesions did not correlate with the photoreceptor shortening/loss but appeared to be located at the level of the retinal pigment epithelium/choriocapillaris layer and were an exaggeration in size and number of similar age-related changes found in wild type (WT) mice. In addition, neither the atrophic lesions nor the photoreceptor shortening were associated with common retinal degeneration genes, nor were they caused by exposure to light damage since mice housed at both high and low ambient light levels had similar degrees of retinal degeneration. Instead, sTg-IRBP:HEL mice expressed reduced levels of soluble retinal IRBP compared to WT mice which were present from postnatal day16 (P16) and preceded development of photoreceptor shortening (onset P21). We propose that insertion of the HEL transgene in the photoreceptor membrane disrupted normal photoreceptor function and led to reduced levels of soluble IRBP and retinal thinning. A similar phenotype has been observed in IRBP deficient mice. Despite the retinal thinning, the amount of HEL expressed in the retina was sufficient to act as an autoantigenic target when the mice were crossed to the HEL T cell receptor Tg mouse, since double transgenic (dTg-IRBP:HEL) mice spontaneously developed a severe uveoretinitis with onset at weaning. We suggest that, although membrane expression of foreign transgene products is likely to modify the structure and function of tissues and cells, the technology provides useful models to investigate mechanisms of antigen-specific immunological tolerance.
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http://dx.doi.org/10.1016/j.exer.2018.03.020DOI Listing
July 2018

Autoimmunity, Autoinflammation, and Infection in Uveitis.

Am J Ophthalmol 2018 05 2;189:77-85. Epub 2018 Mar 2.

Translational Health Sciences (Ophthalmology), University of Bristol, Bristol, United Kingdom; University College London, Institute of Ophthalmology, and the National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital and UCL-Institute of Ophthalmology, London, United Kingdom.

Purpose: To review the pathogenesis of uveitis in light of recent advances in our understanding of innate and adaptive immune responses and their regulation.

Design: Perspective.

Methods: Methods included a review of prevailing views on the pathogenesis of uveitis and an analysis of developments in immunology that impact on its conceptual basis, particularly the concept of immunologic tolerance and its loss in autoimmunity. Importantly, the role of infection in the pathogenesis of uveitis is evaluated.

Results: The results comprise a reappraisal of the pathogenesis of anterior vs posterior uveitis in the context of the blood-retinal barrier and its relation to autoimmune, autoinflammatory, and infectious uveitis. Autoimmunity is seen as a possible cause of certain forms of uveitis but definitive proof is lacking. Autoinflammatory disease, involving activated innate immune mechanisms, is considered causative in a second set of uveitis conditions. A place for infection in uveitis generally is proposed within a unifying concept for the pathogenesis of uveitis.

Conclusion: Infection may be implicated directly or indirectly in many forms of noninfectious or undifferentiated uveitis. In addition to the growing recognition that foreign antigen, including reactivatable infectious agents, might hide within ocular tissues, the possibility that a dysregulated microbiome might generate T cells that cause immune-mediated ocular inflammation has now been demonstrated experimentally. An uncontrolled, overexuberant host immune response may cause continuing irreversible tissue damage even after the infection has been cleared.
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http://dx.doi.org/10.1016/j.ajo.2018.02.019DOI Listing
May 2018

Ocular antigen does not cause disease unless presented in the context of inflammation.

Sci Rep 2017 10 27;7(1):14226. Epub 2017 Oct 27.

Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia.

Ocular antigens are sequestered behind the blood-retina barrier and the ocular environment protects ocular tissues from autoimmune attack. The signals required to activate autoreactive T cells and allow them to cause disease in the eye remain in part unclear. In particular, the consequences of peripheral presentation of ocular antigens are not fully understood. We examined peripheral expression and presentation of ocular neo-self-antigen in transgenic mice expressing hen egg lysozyme (HEL) under a retina-specific promoter. High levels of HEL were expressed in the eye compared to low expression throughout the lymphoid system. Adoptively transferred naïve HEL-specific CD4 T cells proliferated in the eye draining lymph nodes, but did not induce uveitis. By contrast, systemic infection with a murine cytomegalovirus (MCMV) engineered to express HEL induced extensive proliferation of transferred naïve CD4 T cells, and significant uveoretinitis. In this model, wild-type MCMV, lacking HEL, did not induce overt uveitis, suggesting that disease is mediated by antigen-specific peripherally activated CD4 T cells that infiltrate the retina. Our results demonstrate that retinal antigen is presented to T cells in the periphery under physiological conditions. However, when the same antigen is presented during viral infection, antigen-specific T cells access the retina and autoimmune uveitis ensues.
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http://dx.doi.org/10.1038/s41598-017-14618-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660195PMC
October 2017

Mesenchymal stem cell therapy for retro-corneal membrane - A clinical challenge in full-thickness transplantation of biosynthetic corneal equivalents.

Acta Biomater 2017 12 10;64:346-356. Epub 2017 Oct 10.

Section of Immunity, Infection and Inflammation, University of Aberdeen, Aberdeen, Scotland, United Kingdom. Electronic address:

Artificial corneas (keratoprostheses) and biosynthetic collagen-based corneal equivalents are surgical implants designed to ease the global burden of corneal blindness. However, keratoprostheses in many cases fail due to development of fibrous retro-corneal membranes (RCM). Fibrous membranes which develop in the anterior chamber after prosthesis implantation do so on a matrix of fibrin. This study investigated fibrin deposition and RCM formation after full-thickness collagen-based hydrogel implants and compared them with syngeneic and allogeneic corneal grafts in mice. Fibrin cleared from the anterior chamber within 14 days in both allo- and syn-grafts but, persisted in hydrogel implants and developed into dense retro-corneal membrane (RCM) which were heavily infiltrated by activated myofibroblasts. In contrast, the number of CD11b macrophages infiltrating the initial deposition of fibrin in the anterior chamber (AC) after hydrogel implantation was markedly reduced compared to syn- and allo-grafts. Inoculation of mesenchymal stem cells prior to collagen gel implant promoted clearance of gel-associated fibrin from the anterior chamber. We propose that a failure of macrophage-mediated clearance of fibrin may be the cause of RCM formation after collagen-based hydrogel implants and that mesenchymal stem cell therapy promotes clearance of fibrin and prevents RCM formation.

Statement Of Significance: The manuscript addresses the potential value of bone marrow-derived mesenchymal stem cell therapy for retro-corneal membrane (RCM) formation in full-thickness transplantation of biosynthetic corneal equivalents. This work reports the pathophysiological changes in the anterior chamber of the mouse eye following full-thickness recombinant human cross-linked collagen-based hydrogel implants in which persistent fibrin promotes the development of dense RCM. Furthermore, pre-treatment with mesenchymal stem cells reduces RCM formation and enhances corneal transparency.
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http://dx.doi.org/10.1016/j.actbio.2017.10.011DOI Listing
December 2017

Endogenous bioelectric currents promote differentiation of the mammalian lens.

J Cell Physiol 2018 Mar 30;233(3):2202-2212. Epub 2017 Aug 30.

Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

The functional roles of bioelectrical signals (ES) created by the flow of specific ions at the mammalian lens equator are poorly understood. We detected that mature, denucleated lens fibers expressed high levels of the α1 and β1 subunits of Na /K -ATPase (ATP1A1 and ATP1B1 of the sodium pump) and had a hyperpolarized membrane potential difference (V ). In contrast, differentiating, nucleated lens fiber cells had little ATP1A1 and ATP1B1 and a depolarized V . Mimicking the natural equatorial ES with an applied electrical field (EF) induced a striking reorientation of lens epithelial cells to lie perpendicular to the direction of the EF. An EF also promoted the expression of β-crystallin, aquaporin-0 (AQP0) and the Beaded Filament Structural Protein 2 (BFSP2) in lens epithelial cells (LECs), all of which are hallmarks of differentiation. In addition, applied EF activated the AKT and CDC2 and inhibition of AKT reduced the activation of CDC2. Our results indicate that the endogenous bioelectrical signal at the lens equator promotes differentiation of LECs into denucleated lens fiber cells via depolarization of V Development of methods and devices of EF application or amplification in vivo may supply a novel treatment for lens diseases and even promote regeneration of a complete new lens following cataract surgery.
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http://dx.doi.org/10.1002/jcp.26074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724684PMC
March 2018

Post-infectious Uveitis.

Ocul Immunol Inflamm 2016 Dec;24(6):603-606

f Centre for Ophthalmology , University Tuebingen , Tuebingen , Germany.

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http://dx.doi.org/10.1080/09273948.2016.1253983DOI Listing
December 2016

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

Immunology 2017 03 18;150(3):364-377. Epub 2016 Dec 18.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.

Exposure 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.
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http://dx.doi.org/10.1111/imm.12691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290303PMC
March 2017

The Microbiota Determines Susceptibility to Experimental Autoimmune Uveoretinitis.

J Immunol Res 2016 17;2016:5065703. Epub 2016 May 17.

Section of Immunology and Infection, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK; Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, 2 Verdun Street, Nedlands, WA 6009, Australia.

The microbiota is a crucial modulator of the immune system. Here, we evaluated how its absence or reduction modifies the inflammatory response in the murine model of experimental autoimmune uveoretinitis (EAU). We induced EAU in germ-free (GF) or conventionally housed (CV) mice and in CV mice treated with a combination of broad-spectrum antibiotics either from the day of EAU induction or from one week prior to induction of disease. The severity of the inflammation was assessed by fundus biomicroscopy or by histology, including immunohistology. The immunophenotyping of T cells in local and distant lymph nodes was performed by flow cytometry. We found that GF mice and mice where the microbiota was reduced one week before EAU induction were protected from severe autoimmune inflammation. GF mice had lower numbers of infiltrating macrophages and significantly less T cell infiltration in the retina than CV mice with EAU. GF mice also had reduced numbers of IFN-γ and IL-17-producing T cells and increased numbers of regulatory T cells in the eye-draining lymph nodes. These data suggest that the presence of microbiota during autoantigen recognition regulates the inflammatory response by influencing the adaptive immune response.
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http://dx.doi.org/10.1155/2016/5065703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886056PMC
March 2017

High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection.

Invest Ophthalmol Vis Sci 2016 Apr;57(4):1578-87

Division of Applied Medicine, Section of Immunity, Infection and Inflammation (Ocular Immunology), Institute of Medical Sciences, School of Medicine and Dentistry, Foresterhill, University of Aberdeen, Aberdeen, Scotland, United Kingdom 4Ocular Immunology.

Purpose: The "high-risk phenotype" of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.

Methods: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell-deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.

Results: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.

Conclusions: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.
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http://dx.doi.org/10.1167/iovs.15-17894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824377PMC
April 2016

Retinal Pigment Epithelial Cell Apoptosis is Influenced by a Combination of Macrophages and Soluble Mediators Present in Age-Related Macular Degeneration.

Curr Eye Res 2016 09 25;41(9):1235-44. Epub 2016 Mar 25.

a Division of Applied Medicine , University of Aberdeen Institute of Medical Sciences , Aberdeen , Scotland , UK.

Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly population aged ≥60 years. Previous studies have shown that retinal pigment epithelial cell (RPE) degeneration is one of the early and crucial stages in AMD. It has been suggested that microglia and macrophages may be involved in the impairment of RPE, but how they and RPE are influenced by other factors present as AMD develops is unclear. Therefore the purpose of this study was to determine the role of macrophages in RPE degeneration in the presence of cytokines and oxidative stress likely to be present as AMD develops.

Methods: A co-culture model system was set up using bone marrow-derived macrophages and brain or retinal microglia cultured with RPE. Cytokines (IL-1β, TNF-α, IFN-γ, and IL-6) and oxidized low-density lipoprotein were included in the culture at concentrations estimated to be likely during AMD, and apoptosis of RPE cells determined using flow cytometry to detect annexin V.

Results: Macrophages were shown capable of enhancing the apoptosis of RPE cells in a contact-dependent manner. IL-1β, IFN-γ, IL-6, TNF-α, and oxLDL increased apoptosis; they increased RPE cell apoptosis directly, increased the susceptibility of RPE to subsequent apoptosis in the presence of microglia/macrophages, and increased the ability of microglia/macrophages to cause apoptosis.

Conclusions: These findings indicate that microglia and macrophages are capable of enhancing the degeneration of RPE, which are crucial in AMD development. However this is dependent on the microenvironment present as AMD develops.
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http://dx.doi.org/10.3109/02713683.2015.1109129DOI Listing
September 2016

High-risk corneal allografts: A therapeutic challenge.

World J Transplant 2016 Mar;6(1):10-27

Tian Yu, Vijayalakshmi Rajendran, John V Forrester, Lucia Kuffová, Section of Immunity, Infection and Inflammation, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, Scotland AB25 2ZD, United Kingdom.

Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in "low-risk" settings. Furthermore, although corneal graft survival in "low-risk" recipients is favourable, the prognosis in "high-risk" recipients for corneal graft is poor. In "high-risk" grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of "high-risk" recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in "high-risk" recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicine may be able to solve both important short comings of allotransplantation: (1) graft rejection and ultimate graft failure; and (2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both "low-risk" and "high-risk" hosts.
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http://dx.doi.org/10.5500/wjt.v6.i1.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801785PMC
March 2016

In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin.

Neurobiol Dis 2016 07 24;91:59-68. Epub 2016 Feb 24.

School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK. Electronic address:

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells - including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.
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http://dx.doi.org/10.1016/j.nbd.2016.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867789PMC
July 2016

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.

Aging Cell 2016 06 15;15(3):436-45. Epub 2016 Feb 15.

Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7 BL, UK.

Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age-related retinal degenerative disorders particularly age-related macular degeneration. During aging RPE cells decline in number, suggesting an age-dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose-dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted 'postmitotic' status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long-standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age-related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.
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http://dx.doi.org/10.1111/acel.12447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854907PMC
June 2016

Retinal Microglial Activation Following Topical Application of Intracellular Toll-Like Receptor Ligands.

Invest Ophthalmol Vis Sci 2015 Nov;56(12):7377-86

Department of Anatomy & Developmental Biology, School of Biomedical Sciences, Monash University, Victoria, Australia.

Purpose: We previously have reported that application of the intracellular toll-like receptor (TLR)-9 ligand CpG-ODN onto the injured corneal surface induces widespread inflammation within the eye, including the retina. We tested the hypothesis that topical application of two other intracellular TLR agonists, Poly I:C and R848, would cause retinal microglial activation and migration into the subretinal space.

Methods: C57BL/6J wild-type and Cx3cr1gfp/+ mice were anesthetized and received central corneal abrasions followed by topical application of Poly I:C (TLR3 agonist), R848 (TLR7/8 agonist), or CpG-ODN (TLR9 agonist). Eyes were imaged in vivo by using spectral-domain optical coherence tomography to assess and quantify vitreous cells and retinal edema. Tissues were processed for whole-mount immunofluorescence staining or gene expression studies. Microglial activation was determined by morphologic changes, major histocompatibility complex (MHC) class II reactivity, and migration to the subretinal space. Expression of proinflammatory cytokine gene IL-6, IL-1β, IFN-γ, and MCP-1 in retinal tissues were analyzed.

Results: At 24 hours, topical treatment with CpG-ODN and R848, but not Poly I:C, led to altered microglial morphology. One week after CpG-ODN and R848-treatment, eyes exhibited vitritis and mild inner retinal edema, increased number of subretinal Iba-1+ cells, and an increase in MHC II+ cells in the neural retina. Proinflammatory cytokine genes were upregulated after R848 treatment, whereas in the CpG-ODN group, only IL-1β and MCP-1 were significantly upregulated. Retinal microglial activation was not observed in the Poly I:C-treated group.

Conclusions: Topical application of CpG-ODN and R848, but not Poly I:C, to the damaged corneal surface can cause activation and migration of retinal microglia.
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http://dx.doi.org/10.1167/iovs.15-17587DOI Listing
November 2015

The critical points in induction of experimental autoimmune uveitis.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016 Mar 10;160(1):140-2. Epub 2015 Nov 10.

Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.

Background: Autoimmune uveitis is a leading cause of visual impairment in developed countries in patients of working age. Animal models of experimental autoimmune uveitis (EAU) have been established to serve as a useful template for novel therapeutic approaches.

Methods: Experimental autoimmune uveitis is induced in C57BL/6 mice by subcutaneous application of interphotoreceptor retinoid binding protein in complete Freund's adjuvant and pertussis toxin. Clinical and histological grading is used to assess the inflammation intensity of EAU.

Results: The protocol of induction of EAU in mice hides several important aspects, which are crucial for developing the disease. These details have to be addressed to ensure reproducible disease induction. We describe our experience in establishing the model by pointing out the critical steps in EAU protocol which we found important.

Conclusion: The mouse model of EAU has practical value for preclinical studies, is robust and well established. However, the induction of inflammation of the eye can be quite challenging when important details of the protocol are not recognized and adhered to.
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http://dx.doi.org/10.5507/bp.2015.056DOI Listing
March 2016

Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease.

Glia 2016 Mar 29;64(3):386-95. Epub 2015 Oct 29.

Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.

Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post-mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In wild-type mice MHC II levels in the ventral midbrain were upregulated 1-2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP-induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon-γ or tumour necrosis factor-α in the brain after MPTP treatment, as was found in wild-type mice. However, interleukin-1β was significantly increased in both wild-type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II-mediated T cell activation is required for the full expression of pathology in this model of PD.
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http://dx.doi.org/10.1002/glia.22935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855685PMC
March 2016

Assessing the painful, uninflamed eye in primary care.

BMJ 2015 Aug 4;351:h3216. Epub 2015 Aug 4.

Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London EC1V 2PD, UK.

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http://dx.doi.org/10.1136/bmj.h3216DOI Listing
August 2015

Murine pattern recognition receptor dectin-1 is essential in the development of experimental autoimmune uveoretinitis.

Mol Immunol 2015 Oct 26;67(2 Pt B):398-406. Epub 2015 Jul 26.

Section of Immunology and Infection, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, United Kingdom. Electronic address:

Mycobacteria in complete Freund's adjuvant (CFA) are an essential component of immunization protocols in a number of autoimmune disease animal models including experimental autoimmune encephalomyelitis and uveoretinitis (EAE and EAU, respectively). We determined the role in EAU of two C-type lectin receptors on myeloid cells that recognize and respond to mycobacteria. Using receptor-specific antibodies and knockout mice, we demonstrated for the first time that the macrophage mannose receptor delays disease development but does not affect severity. In contrast, dectin-1 is critically involved in the development of CFA-mediated EAU. Disease severity is reduced in dectin-1 knockout mice and antibody blockade of dectin-1 during the induction, but not the effector phase, prevents EAU development. Significantly, similar blockade of dectin-1 in vivo has no effect in non-CFA-mediated, spontaneously induced or adoptive transfer models of EAU. Thus dectin-1 plays a critical role in the ability of complete Freund's adjuvant to induce EAU in mice.
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http://dx.doi.org/10.1016/j.molimm.2015.07.002DOI Listing
October 2015