title: HMGB1 is an early and critical mediator in an animal model of uveitis induced by IRBP-specific T cells.
abstract: It is largely unknown how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in organ-specific autoimmune disease. In this study, we used a chronic uveitis disease model in mice--EAU--induced by adoptive transfer of uveitogenic IRBP-specific T cells and showed that HMGB1, an important endogenous molecule that serves as a danger signal, was released rapidly from retinal cells into the ECM and intraocular fluid in response to IRBP-specific T cell transfer. HMGB1 release required direct cell-cell contact between retinal cells and IRBP-specific T cells and was an active secretion from intact retinal cells. Administration of HMGB1 antagonists inhibited severity of EAU significantly via mechanisms that include inhibition of IRBP-specific T cell proliferation and their IFN-γ and IL-17 production. The inflammatory effects of HMGB1 may signal the TLR/MyD88 pathway, as MyD88(-/-) mice had a high level of HMGB1 in the eye but did not develop EAU after IRBP-specific T cell transfer. Our study demonstrates that HMGB1 is an early and critical mediator of ocular inflammation initiated by autoreactive T cell invasion.
authors.affiliation: 1.Dept. of Ophthalmology and Vision Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA. h0shao01@louisville.edu.
authors.forename: Guomin
authors.initials: G
authors.lastname: Jiang
authors.forename: Deming
authors.initials: D
authors.lastname: Sun
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Qingxian
authors.initials: Q
authors.lastname: Lu
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.forename: Hui
authors.initials: H
authors.lastname: Shao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000276:immunology*; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D012177:Retinol-Binding Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D014605:Uveitis / Q000209:etiology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D024243:HMGB1 Protein; D020382:Interleukin-18; D053594:Myeloid Differentiation Factor 88; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C507780:Myd88 protein, mouse
keywords: autoimmune disease; autoreactive T cells; damage-associated molecular patterns; experimental autoimmune uveitis; immunoregulation; pathogen recognition receptors