title: Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases.
abstract: Antigen presentation by the MHC-II to CD4+T cells is important in adaptive immune responses. The class II transactivator (CIITA in human and C2TA in mouse) is the master regulator of MHC-II gene expression. It coordinates the transcription factors necessary for the transcription of MHC-II molecules. In humans, genetic variations in CIITA have been associated with differential expression of MHC-II and susceptibility to autoimmune diseases. Here we made use of a C2ta congenic mouse strain (expressing MHC-II haplotype H-2q) to investigate the effect of the natural genetic polymorphisms in type I promoter of C2ta on MHC-II expression and function. We demonstrate that an allelic variant in the type I promoter of C2ta resulted in an increased expression of MHC-II on macrophages (72-151% higher mean florescence intensity) and conventional dendritic cells (13-65% higher mean florescence intensity) in both spleen and peripheral blood. The increase in MHC-II expression resulted in an increase in antigen presentation to T cells in vitro and increased T-cell activation. The differential MHC-II expression in B6Q.C2ta, however, did not alter the disease development in models of rheumatoid arthritis (collagen-induced arthritis and human glucose-6-phosphate-isomerase325-339-peptide-induced arthritis), or multiple sclerosis (MOG1-125protein-induced and MOG79-96peptide-induced experimental autoimmune encephalomyelitis). This is the first study to address the role of an allelic variant in type I promoter of C2ta in MHC-II expression and autoimmune diseases; and shows that C2ta polymorphisms regulate MHC-II expression and T-cell responses but do not necessarily have a strong impact on autoimmune diseases.
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anthony C Y
authors.identifier: 0000-0002-1570-7813
authors.initials: AC
authors.lastname: Yau
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000483:Alleles; D000818:Animals; D017951:Antigen Presentation; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators
keywords: antigen presentation; class II transactivator; collagen-induced arthritis; experimental autoimmune encephalomyelitis; major histocompatibility complex