title: Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.
abstract: Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage, and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated Ag-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2, and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease.
authors.affiliation: VA Portland Health Care System, Portland, OR 97239; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239;
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: VA Portland Health Care System, Portland, OR 97239;
authors.forename: Brieanna R
authors.initials: BR
authors.lastname: Brown
authors.affiliation: VA Portland Health Care System, Portland, OR 97239; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239;
authors.forename: Emily E
authors.identifier: http://orcid.org/0000-0001-8289-2775
authors.initials: EE
authors.lastname: Vance
authors.affiliation: VA Portland Health Care System, Portland, OR 97239;
authors.forename: Paige E
authors.identifier: http://orcid.org/0000-0001-9836-7705
authors.initials: PE
authors.lastname: Snow
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.affiliation: VA Portland Health Care System, Portland, OR 97239;
authors.forename: David
authors.initials: D
authors.lastname: Heinrichs
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Tokyo University of Science, Tokyo 278-0022, Japan; and.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Christine A
authors.identifier: http://orcid.org/0000-0003-3133-3628
authors.initials: CA
authors.lastname: Wells
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rachel R
authors.identifier: http://orcid.org/0000-0002-7140-7671
authors.initials: RR
authors.lastname: Caspi
authors.affiliation: VA Portland Health Care System, Portland, OR 97239; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239; rosenzwh@ohsu.edu.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Rosenzweig
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012177:Retinol-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome; D014605:Uveitis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000099214:Retinol-Binding Proteins, Interstitial; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D058286:Calcitonin Receptor-Like Protein; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases; D012177:Retinol-Binding Proteins; D000072377:Syk Kinase; D000099214:Retinol-Binding Proteins, Interstitial; D000099181:Dectin-1; C513280:Card9 protein, mouse; C113583:Clecsf8 protein, mouse; C445340:dectin-2, mouse; C000606896:SYK protein, human; C000606897:Syk protein, mouse