title: Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of uveitis and identify autoaggressive T cells.
abstract: Noninfectious uveitis is a leading cause of blindness and thought to involve autoimmune T cell responses to retinal proteins (e.g., retinal arrestin [soluble-Ag (S-Ag)]). There are no known biomarkers for the disease. Susceptibility is associated with HLA, but little is known about susceptible class II alleles or the potentially pathogenic epitopes that they present. Using a humanized HLA-transgenic mouse model of S-Ag-induced autoimmune uveitis, we identified several susceptible and resistant alleles of HLA-DR and -DQ genes and defined pathogenic epitopes of S-Ag presented by the susceptible alleles. The sequences of these epitopes overlap with some previously identified peptides of S-Ag ("M" and "N"), known to elicit memory responses in lymphocytes of uveitis patients. HLA-DR-restricted, S-Ag-specific CD4(+) T cells could be detected in blood and draining lymph nodes of uveitic mice with HLA class II tetramers and transferred the disease to healthy mice. Importantly, tetramer-positive cells were detected in peripheral blood of a uveitis patient. To our knowledge, these findings provide the first tangible evidence that an autoimmune response to retina is causally involved in pathogenesis of human uveitis, demonstrating the feasibility of identifying and isolating retinal Ag-specific T cells from uveitis patients and may facilitate their development as biomarkers for the disease.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. mattapallilm@nei.nih.gov
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mattapallil
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Mattapallil
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Zaruhi
authors.initials: Z
authors.lastname: Karabekian
authors.forename: J Hugh
authors.initials: JH
authors.lastname: McDowell
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Eddie A
authors.initials: EA
authors.lastname: James
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: H Nida
authors.initials: HN
authors.lastname: Sen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nussenblatt
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000483:Alleles; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005136:Eye Proteins / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000276:immunology* / Q000473:pathology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens