The immunopathogenesis of chronic and relapsing autoimmune uveitis – Lessons from experimental rat models

Adamus, 2001, Expression of CC chemokines and their receptors in the eye in autoimmune anterior uveitis associated with EAE, Invest. Ophthalmol. Vis. Sci., 42, 2894 Allan, 2007, Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production, Int. Immunol., 19, 345, 10.1093/intimm/dxm014 Amadi-Obi, 2007, TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1, Nat. Med., 13, 711, 10.1038/nm1585 Avichezer, 2000, Residues 1-20 of IRBP and whole IRBP elicit different uveitogenic and immunological responses in interferon gamma deficient mice, Exp Eye Res., 71, 111, 10.1006/exer.2000.0860 Baba, 2006, CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype, Blood, 107, 2004, 10.1182/blood-2005-06-2345 Battaglia Parodi, 2010, Antivascular endothelial growth factors for inflammatory chorioretinal disorders, Develop. Ophthalmol., 46, 84, 10.1159/000320011 Billiau, 2001, Modes of action of Freund's adjuvants in experimental models of autoimmune diseases, J. Leukoc. Biol., 70, 849, 10.1189/jlb.70.6.849 Bose, 2016, Dry eye disease and uveitis: a closer look at immune mechanisms in animal models of two ocular autoimmune diseases, Autoimmun. Rev., 15, 1181, 10.1016/j.autrev.2016.09.001 Brandner, 2009, Engineering the glycosaminoglycan-binding affinity, kinetics and oligomerization behavior of RANTES: a tool for generating chemokine-based glycosaminoglycan antagonists, Protein Eng. Des. Sel., 22, 367, 10.1093/protein/gzp013 Brewer, 1996, In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to Freund's complete adjuvant, but continues to induce T helper 2 cytokine production, Eur. J. Immunol., 26, 2062, 10.1002/eji.1830260915 Brewerton, 1985, The genetics of acute anterior uveitis, Trans. Ophthalmol. Soc. U. K., 104, 248 Broderick, 2002, Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis, Am. J. Pathol., 161, 1669, 10.1016/S0002-9440(10)64444-6 Broekhuyse, 1993, Experimental autoimmune anterior uveitis (EAAU): induction by melanin antigen and suppression by various treatments, Pigment Cell Res., 6, 1, 10.1111/j.1600-0749.1993.tb00574.x Broekhuyse, 1986, Induction of experimental autoimmune uveoretinitis and pinealitis by IRBP. Comparison to uveoretinitis induced by S-antigen and opsin, Curr. Eye Res., 5, 231, 10.3109/02713688609020048 Broekhuyse, 1984, Opsin-induced experimental autoimmune retinitis in rats, Curr. Eye Res., 3, 1405, 10.3109/02713688409000836 Burns, 2000, Analysis of tight junctions during neutrophil transendothelial migration, J. Cell Sci., 113, 45, 10.1242/jcs.113.1.45 Caspi, 1988, A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens, J. Immunol., 140, 1490, 10.4049/jimmunol.140.5.1490 Catz, 2014, The role of Rab27a in the regulation of neutrophil function, Cell Microbiol., 16, 1301, 10.1111/cmi.12328 Chelluboina, 2015, Matrix Metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia, Stroke, 46, 3523, 10.1161/STROKEAHA.115.011031 Chuang, 1997, Immune effector cells induced by complete Freund's adjuvant exert an inhibitory effect on antigen-specific type 2 T helper responses, Clin. Exp. Allergy, 27, 315, 10.1111/j.1365-2222.1997.tb00710.x Cohen, 1996, Interleukin 6 induces the expression of vascular endothelial growth factor, J. Biol. Chem., 271, 736, 10.1074/jbc.271.2.736 Crane, 1998, Cytokine regulation of RANTES production by human retinal pigment epithelial cells, Cell. Immunol., 184, 37, 10.1006/cimm.1997.1235 Crane, 2001, Expression of the chemokines MIP-1alpha, MCP-1, and RANTES in experimental autoimmune uveitis, Invest. Ophthalmol. Vis. Sci., 42, 1547 Crane, 2000, Control of chemokine production at the blood-retina barrier, Immunology, 101, 426, 10.1046/j.0019-2805.2000.01105.x Crocker, 1987, Species heterogeneity in macrophage expression of the CD4 antigen, J. Exp. Med., 166, 613, 10.1084/jem.166.2.613 Curnow, 2005, Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis, Invest. Ophthalmol. Vis. Sci., 46, 4251, 10.1167/iovs.05-0444 Dagur, 2011, MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases, J. Autoimmun., 37, 319, 10.1016/j.jaut.2011.09.003 de Boer, 1994, Low mature TGF-beta 2 levels in aqueous humor during uveitis, Invest. Ophthalmol. Vis. Sci., 35, 3702 de Kozak, 1981, S antigen-induced experimental autoimmune uveo-retinitis in rats, Curr. Eye Res., 1, 327, 10.3109/02713688108998359 de Menthon, 2009, HLA–B51/B5 and the risk of Behçet’s disease: a systematic review and meta-analysis of case–control genetic association studies, Arthritis Rheum., 61, 1287, 10.1002/art.24642 de Smet, 2001, Regulation of ocular inflammation — what experimental and human studies have taught Us, Prog. Retin. Eye Res., 20, 761, 10.1016/S1350-9462(01)00011-8 Deeg, 2006, Inter- and intramolecular epitope spreading in equine recurrent uveitis, Invest. Ophthalmol. Vis. Sci., 47, 652, 10.1167/iovs.05-0789 Deeg, 2006, Identification and functional validation of novel autoantigens in equine uveitis.[Erratum appears in Mol Cell Proteomics. 2006 Sep;5(9):1718], Mol. Cell. Proteomics, 5, 1462, 10.1074/mcp.M500352-MCP200 Deeg, 2007, CRALBP is a highly prevalent autoantigen for human autoimmune uveitis, Clin. Dev. Immunol., 2007, 39245, 10.1155/2007/39245 Deeg, 2004, The uveitogenic potential of retinal S-antigen in horses, Invest. Ophthalmol. Vis. Sci., 45, 2286, 10.1167/iovs.03-1226 Deeg, 2002, Uveitis in horses induced by interphotoreceptor retinoid-binding protein is similar to the spontaneous disease, Eur. J. Immunol., 32, 2598, 10.1002/1521-4141(200209)32:9<2598::AID-IMMU2598>3.0.CO;2-# Dejana, 2001, Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration, Thromb. Haemostasis, 86, 308, 10.1055/s-0037-1616228 Deuter, 2010, Long-term remission after cessation of interferon-alpha treatment in patients with severe uveitis due to Behcet's disease, Arthritis Rheum., 62, 2796, 10.1002/art.27581 Deuter, 2008, Behçet's disease: ocular effects and treatment, Prog. Retin. Eye Res., 27, 111, 10.1016/j.preteyeres.2007.09.002 Dick, 1995, Flow cytometric identification of a minority population of MHC class II positive cells in the normal rat retina distinct from CD45lowCD11b/c+CD4low parenchymal microglia, Br. J. Ophthalmol., 79, 834, 10.1136/bjo.79.9.834 Diedrichs, 1989, Differential surface expression of class II isotypes on activated CD4 and CD8 cells correlates with levels of locus-specific mRNA, J. Immunol., 142, 3275, 10.4049/jimmunol.142.9.3275 Diedrichs-Möhring, 2008, Antigen-dependent monophasic or recurrent autoimmune uveitis in rats, Int. Immunol., 20, 365, 10.1093/intimm/dxm148 Diedrichs-Möhring, 2015, A new small molecule for treating inflammation and chorioretinal neovascularization in relapsing-remitting and chronic experimental autoimmune UveitisA new small molecule to treat monophasic and chronic EAU, Invest. Ophthalmol. Vis. Sci., 56, 1147, 10.1167/iovs.14-15518 Diedrichs-Möhring, 2005, The effect of the CC chemokine receptor antagonist Met-RANTES on experimental autoimmune uveitis and oral tolerance, J. Neuroimmunol., 164, 22, 10.1016/j.jneuroim.2005.02.023 Diedrichs-Möhring, 2018, Intraocular DHODH inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells, J. Neuroinflammation, 15, 54, 10.1186/s12974-018-1088-6 Diedrichs-Möhring, 2005, Immunostimulatory and immunomodulatory peptides derived from the alpha1 domain of HLA-B27 in experimental autoimmune diseases in Lewis rats, Immunobiology, 209, 711, 10.1016/j.imbio.2004.12.004 Diller, 2016 Dua, 1992, Induction of experimental autoimmune uveitis by the retinal photoreceptor cell protein, phosducin, Curr. Eye Res., 11, 107, 10.3109/02713689208999519 Fang, 2010, The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model, Invest. Ophthalmol. Vis. Sci., 51, 3092, 10.1167/iovs.09-4754 Fasler-Kan, 1998, Interferon-alpha activates signal transducers and activators of transcription 5 and 6 in Daudi cells, Eur. J. Biochem., 254, 514, 10.1046/j.1432-1327.1998.2540514.x Flugel, 1999, Gene transfer into CD4+ T lymphocytes: green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses, Nat. Med., 5, 843, 10.1038/10567 Forrester, 1998, Marrow-derived activated macrophages are required during the effector phase of experimental autoimmune uveoretinitis in rats, Curr. Eye Res., 17, 426, 10.1080/02713689808951224 Freeman, 1995, Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential Role for T Cells in angiogenesis, Canc. Res., 55, 4140 Gagliani, 2015, Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation, Nature, 523, 221, 10.1038/nature14452 Gansbacher, 1989, HLA class II mRNA accumulation by activated human T cells following growth in conditioned medium, Clin. Exp. Immunol., 76, 440 Garrett, 2006, S100A4, a mediator of metastasis, J. Biol. Chem., 281, 677, 10.1074/jbc.R500017200 Gery, 1994, Recoverin is highly uveitogenic in Lewis rats, Invest. Ophthalmol. Vis. Sci., 35, 3342 Gibbings, 2009, CD4 and CD8: an inside-out coreceptor model for innate immune cells, J. Leukoc. Biol., 86, 251, 10.1189/jlb.0109040 Gonzalez-Navajas, 2012, Immunomodulatory functions of type I interferons., Nat. Rev. Immunol., 12, 125, 10.1038/nri3133 Graham, 1987, Neovascularisation associated with posterior uveitis, Br. J. Ophthalmol., 71, 826, 10.1136/bjo.71.11.826 Gregerson, 2003, CD45-Positive cells of the retina and their responsiveness to in vivo and in vitro treatment with IFN-γ or anti-CD40, Invest. Ophthalmol. Vis. Sci., 44, 3083, 10.1167/iovs.02-1014 Gschwandtner, 2017, Glycosaminoglycans are important mediators of neutrophilic inflammation in vivo, Cytokine, 91, 65, 10.1016/j.cyto.2016.12.008 Harbour, 2015, Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis, Proc. Natl. Acad. Sci. U. S. A., 112, 7061, 10.1073/pnas.1415675112 Heldwein, 2002, The role of Toll-like receptors in immunity against mycobacterial infection, Microb. Infect., 4, 937, 10.1016/S1286-4579(02)01611-8 Heuss, 2012, Local activation of dendritic cells alters the pathogenesis of autoimmune disease in the retina, J. Immunol., 188, 1191, 10.4049/jimmunol.1101621 Hines, 1984, Immunologically mediated ocular disease in the horse, Vet Clin North Am Large Anim Pract, 6, 501, 10.1016/S0196-9846(17)30006-X Hines, 1990, Equine recurrent uveitis: immunsation of ponies with retinal S Antigen, Prog. in Vet. Comp. Ophthalmol., 2, 3 Hirji, 1997, A novel CD8 molecule expressed by alveolar and peritoneal macrophages stimulates nitric oxide production, J. Immunol., 158, 1833, 10.4049/jimmunol.158.4.1833 Hirose, 1987, Uveitis induced in primates by IRBP: humoral and cellular immune responses, Exp. Eye Res., 45, 695, 10.1016/S0014-4835(87)80118-5 Hu, 2001, High IFN-alpha expression is associated with the induction of experimental autoimmune uveitis (EAU) in Fischer 344 rat, Cell Res, 11, 293, 10.1038/sj.cr.7290099 Huber, 2015, Spontaneously relapsing-remitting experimental autoimmune uveitis in rats allows successful therapeutic oral tolerance induction in ongoing disease, Mol. Immunol., 63, 215, 10.1016/j.molimm.2014.07.009 Huber, 2011, Th17 cells express interleukin-10 receptor and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner, Immunity, 34, 554, 10.1016/j.immuni.2011.01.020 Ishikawa, 2009, Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle, J. Exp. Med., 206, 2879, 10.1084/jem.20091750 Jo, 2003, Upregulation of chemokine expression in the retinal vasculature in ischemia-reperfusion injury, Invest. Ophthalmol. Vis. Sci., 44, 4054, 10.1167/iovs.02-1308 Jones, 1997, IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response, J. Immunol., 158, 5997, 10.4049/jimmunol.158.12.5997 Karpus, 1998, Monocyte chemotactic protein 1 regulates oral tolerance induction by Inhibition of T Helper cell 1–related cytokines, J. Exp. Med., 187, 733, 10.1084/jem.187.5.733 Kaufmann, 2001, Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1 alpha during differentiation of human monocytes to macrophages, J. Leukoc. Biol., 69, 248, 10.1189/jlb.69.2.248 Kaufmann, 2012, Dynamics of intraocular IFN-gamma, IL-17 and IL-10-producing cell populations during relapsing and monophasic rat experimental autoimmune uveitis, PLoS One, 7, 10.1371/journal.pone.0049008 Ke, 2008, Ocular regulatory T cells distinguish monophasic from recurrent autoimmune uveitis, Invest. Ophthalmol. Vis. Sci., 49, 3999, 10.1167/iovs.07-1468 Kim, 2010, Wnt5a induces endothelial inflammation via beta-catenin-independent signaling, J. Immunol., 185, 1274, 10.4049/jimmunol.1000181 Kimura, 2010, IL-6: regulator of Treg/Th17 balance, Eur. J. Immunol., 40, 1830, 10.1002/eji.201040391 Kluger, 2014, Stat3 programs Th17-Specific regulatory T cells to control GN, J. Am. Soc. Nephrol., 25, 1291, 10.1681/ASN.2013080904 Konkel, 2010, PD-1 signalling in CD4(+) T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced tolerance, Immunology, 130, 92, 10.1111/j.1365-2567.2009.03216.x Korn, 2009, IL-17 and Th17 cells, Annu. Rev. Immunol., 27, 485, 10.1146/annurev.immunol.021908.132710 Kurz, 2016, MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane, J. Clin. Invest., 126, 4125, 10.1172/JCI87043 LaSalle, 1992, Early signaling defects in human T cells anergized by T cell presentation of autoantigen, J. Exp. Med., 176, 177, 10.1084/jem.176.1.177 Lehmann, 1987, Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,000, Canc. Res., 47, 841 Lipski, 2017, MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis, J. Neuroinflammation, 14, 136, 10.1186/s12974-017-0915-5 Liu, 2011, The emerging role of CXCL10 in cancer (Review), Oncol. Lett., 2, 583, 10.3892/ol.2011.300 Liu, 2017, The role of IFN-alpha in experimental and clinical uveitis, Ocul. Immunol. Inflamm. Luger, 2008, Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category, J. Exp. Med., 205, 799, 10.1084/jem.20071258 Luo, 2015, FSP-1 impairs the function of endothelium leading to failure of arteriovenous grafts in diabetic mice, Endocrinology, 156, 2200, 10.1210/en.2014-1841 Manczak, 2002, Crucial role of CCL3/MIP-1alpha in the recurrence of autoimmune anterior uveitis induced with myelin basic protein in Lewis rats, J. Autoimmun., 18, 259, 10.1006/jaut.2002.0591 Matikainen, 1999, Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells, Blood, 93, 1980, 10.1182/blood.V93.6.1980.406k20_1980_1991 Matsubara, 1999, Retinal microglia differentially express phenotypic markers of antigen-presenting cells in vitro, Invest. Ophthalmol. Vis. Sci., 40, 3186 Matsuoka, 2001, Monocytes are differentially activated through HLA-DR, -DQ, and -DP molecules via mitogen-activated protein kinases, J. Immunol., 166, 2202, 10.4049/jimmunol.166.4.2202 Mattapallil, 2011, Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of uveitis and identify autoaggressive T cells, J. Immunol., 187, 1977, 10.4049/jimmunol.1101247 May, 2003, CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats, J. Immunol., 170, 1099, 10.4049/jimmunol.170.2.1099 McGeachy, 2007, TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology, Nat. Immunol., 8, 1390, 10.1038/ni1539 McPherson, 2013, Local “On-Demand” generation and function of antigen-specific Foxp3+ regulatory T cells, J. Immunol., 190, 4971, 10.4049/jimmunol.1202625 McPherson, 2014, Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells, J. Neuroinflammation, 11, 205, 10.1186/s12974-014-0205-4 Means, 1999, Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis, J. Immunol., 163, 3920, 10.4049/jimmunol.163.7.3920 Mesquida, 2014, Interleukin-6 blockade in ocular inflammatory diseases, Clin. Exp. Immunol., 176, 301, 10.1111/cei.12295 Meyers-Elliott, 1982, Experimental uveitis induced by products of activated lymphocytes: intraocular effects of rhodopsin-induced lymphokines, Cell. Immunol., 66, 240, 10.1016/0008-8749(82)90176-9 Mizuki, 1992, Association of HLA-B51 and lack of association of class II alleles with Behcet's disease, Tissue Antigens, 40, 22, 10.1111/j.1399-0039.1992.tb01953.x Montgomery, 1993, Production and regulation of gelatinase B by human T-cells, Biochim. Biophys. Acta, 1176, 265, 10.1016/0167-4889(93)90054-S Mor, 2004, Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization, J. Immunol., 172, 4618, 10.4049/jimmunol.172.7.4618 Nagineni, 2015, Inflammatory cytokines induce expression of chemokines by human retinal cells: role in chemokine receptor mediated age-related macular degeneration, Aging Disease, 6, 444, 10.14336/AD.2015.0323 Nakamura, 2005, Experimental autoimmune uveitis induced by immunization with retinal pigment epithelium-specific 65-kDa protein peptides, Curr. Eye Res., 30, 673, 10.1080/02713680590968330 Neri, 2009, Inflammatory choroidal neovascularization, Middle East Afr. J. Ophthalmol., 16, 245 Nigou, 2002, Mycobacterial lipoarabinomannans: modulators of dendritic cell function and the apoptotic response, Microb. Infect., 4, 945, 10.1016/S1286-4579(02)01621-0 Noster, 2016, Dysregulation of proinflammatory versus anti-inflammatory human TH17 cell functionalities in the autoinflammatory Schnitzler syndrome, J. Allergy Clin. Immunol., 138, 1161, 10.1016/j.jaci.2015.12.1338 Nourshargh, 2014, Leukocyte migration into inflamed tissues, Immunity, 41, 694, 10.1016/j.immuni.2014.10.008 Nussenblatt, 1990, Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen, J. Immunol., 144, 1689, 10.4049/jimmunol.144.5.1689 Nussenblatt, 1982, Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen, Am. J. Ophthalmol., 94, 147, 10.1016/0002-9394(82)90069-1 Nussenblatt, 1983, Treatment of intraocular inflammatory disease with cyclosporin A, Lancet, 2, 235, 10.1016/S0140-6736(83)90230-1 Nussenblatt, 1982, Modulation of experimental autoimmune uveitis with cyclosporin A, Arch. Ophthalmol., 100, 1146, 10.1001/archopht.1982.01030040124022 Nussenblatt, 1981, Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats, J. Clin. Invest., 67, 1228, 10.1172/JCI110138 Oh, 2011, Autoreactive memory CD4+ T lymphocytes that mediate chronic uveitis reside in the bone marrow through STAT3-dependent mechanisms, J. Immunol., 187, 3338, 10.4049/jimmunol.1004019 Okada, 1998, Intraocular cytokine quantification of experimental autoimmune uveoretinitis in rats, Ocul. Immunol. Inflamm., 6, 111, 10.1076/ocii.6.2.111.4046 Opdenakker, 2001, Gelatinase B: a tuner and amplifier of immune functions, Trends Immunol., 22, 571, 10.1016/S1471-4906(01)02023-3 Penfold, 1993, Human retinal microglia express phenotypic characteristics in common with dendritic antigen-presenting cells, J. Neuroimmunol., 45, 183, 10.1016/0165-5728(93)90179-3 Pennesi, 2003, A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice, J. Clin. Invest., 111, 1171, 10.1172/JCI15155 Perez, 2004, Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: the Massachusetts eye & ear experience and review of previous studies, Ocul. Immunol. Inflamm., 12, 205, 10.1080/092739490500282 Piccinini, 2010, Rationally evolving MCP-1/CCL2 into a decoy protein with potent anti-inflammatory activity in vivo, J. Biol. Chem., 285, 8782, 10.1074/jbc.M109.043299 Pickl, 1997, MUC18/MCAM (CD146), an activation antigen of human T lymphocytes, J. Immunol., 158, 2107, 10.4049/jimmunol.158.5.2107 Pillai, 2007, Transient regulatory T-cells: a state attained by all activated human T-cells, Clin. Immunol., 123, 18, 10.1016/j.clim.2006.10.014 Prendergast, 1998, T cell traffic and the inflammatory response in experimental autoimmune uveoretinitis, Invest. Ophthalmol. Vis. Sci., 39, 754 Qing, 2004, Alternative activation of STAT1 and STAT3 in response to interferon-gamma, J. Biol. Chem., 279, 41679, 10.1074/jbc.M406413200 Robertson, 2002, Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis, Invest. Ophthalmol. Vis. Sci., 43, 2250 Rot, 1991, Chemotactic potency of recombinant human neutrophil attractant/activation protein-1 (interleukin-8) for polymorphonuclear leukocytes of different species, Cytokine, 3, 21, 10.1016/1043-4666(91)90006-Y Sack, 2011, S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells, Mol. Biol. Cell, 22, 3344, 10.1091/mbc.e10-09-0739 Santini, 2011, Interferon-α-conditioned human monocytes combine a Th1-orienting attitude with the induction of autologous Th17 responses: role of IL-23 and IL-12, PLoS One, 6, 10.1371/journal.pone.0017364 Schroeter, 2003, CD8+ phagocyte recruitment in rat experimental autoimmune encephalomyelitis: association with inflammatory tissue destruction, Am. J. Pathol., 163, 1517, 10.1016/S0002-9440(10)63508-0 Shao, 2005, Chronic recurrent autoimmune uveitis with progressive photoreceptor damage induced in rats by transfer of IRBP-specific T cells, J. Neuroimmunol., 163, 102, 10.1016/j.jneuroim.2005.03.004 Shechter, 2013, Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nature reviews, Immunology, 13, 206 Shi, 2011, Monocyte recruitment during infection and inflammation. Nature reviews, Immunology, 11, 762 Silpa-Archa, 2016, Outcome of tocilizumab treatment in refractory ocular inflammatory diseases, Acta Ophthalmol., 94, e400, 10.1111/aos.13015 Silver, 1999, The requirement for pertussis to induce EAU is strain-dependent: B10.RIII, but not B10.A mice, develop EAU and Th1 responses to IRBP without pertussis treatment, Invest. Ophthalmol. Vis. Sci., 40, 2898 Singh, 1990, Molecular mimicry between a uveitopathogenic site of S-antigen and viral peptides. Induction of experimental autoimmune uveitis in Lewis rats, J. Immunol., 144, 1282, 10.4049/jimmunol.144.4.1282 Singh, 1992, Molecular mimicry: uveitis induced in Macaca fascicularis by microbial protein having sequence homology with retinal S-antigen, Jpn. J. Ophthalmol., 36, 108 Singh, 1989, Molecular mimicry. Yeast histone H3-induced experimental autoimmune uveitis, J. Immunol., 142, 1512, 10.4049/jimmunol.142.5.1512 Sonoda, 2003, Immunoregulatory role of ocular macrophages: the macrophages produce RANTES to suppress experimental autoimmune uveitis, J. Immunol., 171, 2652, 10.4049/jimmunol.171.5.2652 Stein, 2006, The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer, Gastroenterology, 131, 1486, 10.1053/j.gastro.2006.08.041 Su, 2007, Altered chemokine profile associated with exacerbated autoimmune pathology under conditions of genetic interferon-gamma deficiency, Invest. Ophthalmol. Vis. Sci., 48, 4616, 10.1167/iovs.07-0233 Su, 2005, Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-Mediated autoimmunity, J. Immunol., 175, 6303, 10.4049/jimmunol.175.10.6303 Suzuki, 2010, VEGFR2 is selectively expressed by FOXP3high CD4+ Treg, Eur. J. Immunol., 40, 197, 10.1002/eji.200939887 Taams, 1999, Antigen presentation by T cells versus professional antigen-presenting cells (APC): differential consequences for T cell activation and subsequent T cell-APC interactions, Eur. J. Immunol., 29, 1543, 10.1002/(SICI)1521-4141(199905)29:05<1543::AID-IMMU1543>3.0.CO;2-R Tacke, 2007, Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques, J. Clin. Invest., 117, 185, 10.1172/JCI28549 Tanabe, 2005, Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-alpha beta responses in T lymphocytes, J. Immunol., 174, 609, 10.4049/jimmunol.174.2.609 Tappeiner, 2016, Evidence for tocilizumab as a treatment option in refractory uveitis associated with juvenile idiopathic arthritis, J. Rheumatol., 43, 2183, 10.3899/jrheum.160231 Taylor, 2016, Ocular immune privilege and transplantation, Front. Immunol., 7, 37, 10.3389/fimmu.2016.00037 Terme, 2013, VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T cell proliferation in colorectal cancer, Canc. Res., 73, 539, 10.1158/0008-5472.CAN-12-2325 Thurau, 1997, Oral tolerance in a murine model of relapsing experimental autoimmune uveoretinitis (EAU): induction of protective tolerance in primed animals, Clin. Exp. Immunol., 109, 370, 10.1046/j.1365-2249.1997.4571356.x Thurau, 1999, Oral tolerance with an HLA-peptide mimicking retinal autoantigen as a treatment of autoimmune uveitis, Immunol. Lett., 68, 205, 10.1016/S0165-2478(99)00071-1 Thurau, 2004, Long-term follow-up of oral tolerance induction with HLA-peptide B27PD in patients with uveitis, Ann. N. Y. Acad. Sci., 1029, 408, 10.1196/annals.1309.048 Thurau, 2004, The fate of autoreactive, GFP+ T cells in rat models of uveitis analyzed by intravital fluorescence microscopy and FACS, Int. Immunol., 16, 1573, 10.1093/intimm/dxh158 Thurau, 2002, Oral tolerance for treating uveitis — new hope for an old immunological mechanism, Prog. Retin. Eye Res., 21, 577, 10.1016/S1350-9462(02)00039-3 Van Den Steen, 2003, Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities, Eur. J. Biochem., 270, 3739, 10.1046/j.1432-1033.2003.03760.x van Maren, 2008, Toll-like receptor signalling on Tregs: to suppress or not to suppress?, Immunology, 124, 445, 10.1111/j.1365-2567.2008.02871.x Vermeer, 2009, MMP9 modulates tight junction integrity and cell viability in human airway epithelia. American journal of physiology, Lung Cell. Mol. Physiol., 296, L751, 10.1152/ajplung.90578.2008 von Toerne, 2010, Effector T cells driving monophasic vs. relapsing/remitting experimental autoimmune uveitis show unique pathway signatures, Mol. Immunol., 48, 272, 10.1016/j.molimm.2010.07.017 Voron, 2015, VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors, J. Exp. Med., 212, 139, 10.1084/jem.20140559 Wacker, 1973, Autoimmune uveo-retinitis in the rat sensitized with retina photoreceptor cell antigen, Int. Arch. Allergy Immunol., 45, 582, 10.1159/000231102 Wallace, 2004, The role of chemokines and their receptors in ocular disease, Prog. Retin. Eye Res., 23, 435, 10.1016/j.preteyeres.2004.04.004 Welsh, 1981, Uveitis, vitreous humour, and klebsiella. II. Cross-reactivity studies with radioimmunoassay, Br. J. Ophthalmol., 65, 323, 10.1136/bjo.65.5.323 Whitcup, 1993, Monoclonal antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) inhibit experimental autoimmune uveitis, Clin. Immunol. Immunopathol., 67, 143, 10.1006/clin.1993.1057 Wildner, 2003, Autoimmune uveitis induced by molecular mimicry of peptides from rotavirus, bovine casein and retinal S-antigen, Eur. J. Immunol., 33, 2577, 10.1002/eji.200324058 Wildner, 2003, Differential recognition of a retinal autoantigen peptide and its variants by rat T cells in vitro and in vivo, Int. Immunol., 15, 927, 10.1093/intimm/dxg090 Wildner, 2004, Autoimmune uveitis and antigenic mimicry of environmental antigens, Autoimmun. Rev., 3, 383, 10.1016/j.autrev.2004.01.002 Wildner, 2008, Rat models of autoimmune uveitis, Ophthalmic Res., 40, 141, 10.1159/000119865 Wildner, 1996, Orally induced, peptide-specific gamma/delta TCR+ cells suppress experimental autoimmune uveitis, Eur. J. Immunol., 26, 2140, 10.1002/eji.1830260927 Wildner, 2013, What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells, Autoimmun. Rev., 12, 1070, 10.1016/j.autrev.2013.04.001 Wildner, 1994, Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease, Eur. J. Immunol., 24, 2579, 10.1002/eji.1830241103 Wildner, 2004, Gamma-delta T cells as orally induced suppressor cells in rats: in vitro characterization, Ann. N. Y. Acad. Sci., 1029, 416, 10.1196/annals.1309.050 Willermain, 2012, Interplay between innate and adaptive immunity in the development of non-infectious uveitis, Prog. Retin. Eye Res., 31, 182, 10.1016/j.preteyeres.2011.11.004 Yang, 2014, S100A4 negatively regulates beta-catenin by inducing the Egr-1-PTEN-Akt-GSK3beta degradation pathway, Cell. Signal., 26, 2096, 10.1016/j.cellsig.2014.06.007 Yoshimura, 2008, Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis, Int. Immunol., 20, 209, 10.1093/intimm/dxm135