title: β2-Glycoprotein I-specific T cells are associated with epitope spread to lupus-related autoantibodies.
abstract: Systemic lupus erythematosus (SLE) is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous and molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting the apoptotic cell-binding protein β2-glycoprotein I (β2GPI). Notably, mice immunized with β2GPI and LPS display a remarkably similar pattern of autoantibody emergence to that seen in human SLE. Here, we used this model to investigate whether epitope spread to SLE-related autoantibodies is associated with a unique or limited β2GPI-specific T cell response. We ask whether MHC class II haplotype and its associated T cell epitope restriction impact epitope spread to SLE-related autoantibodies. We found that β2GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their β2GPI T cell epitope specificity or MHC class II haplotype. Although β2GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different β2GPI T cell epitopes were associated with epitope spread to SLE-related autoantibodies. Notably, one β2GPI T cell epitope (peptide 23, NTGFYLNGADSAKCT) was also recognized by T cells from an HLA-DRB1*0403(+) autoimmune patient. These data suggest that the generation of a β2GPI-reactive T cell response is associated with epitope spread to SLE-related autoantibodies, independent of epitope specificity or MHC class II restriction. On the basis of these findings, we propose that factors enabling a β2GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype.
authors.affiliation: From the Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Salem
authors.affiliation: From the Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Subang
authors.affiliation: the Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: From the Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Laplante
authors.affiliation: the Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, and the Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
authors.affiliation: the Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
authors.affiliation: From the Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada, joyce.rauch@mcgill.ca.
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006239:Haplotypes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; C526364:HLA-DRB1*04:03 antigen; D000949:Histocompatibility Antigens Class II; D053482:beta 2-Glycoprotein I
keywords: Animal Model; Autoantibodies; Autoimmune Disease; Epitope Mapping; Epitope Spread; Major Histocompatibility Complex (MHC); Systemic Lupus Erythematosus; T Cell; β2-Glycoprotein I