title: B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production.
abstract: Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Unit of Dermatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ia
authors.initials: Ia
authors.lastname: Khmaladze
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kutty Selva
authors.initials: KS
authors.lastname: Nandakumar
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Unit of Medical Inflammation Research, Southern Medical University, Guangzhou, China.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D018985:Epitopes, B-Lymphocyte; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: Arthritis; Auto-reactive B cells; Autoantibodies; Epitope spreading; ROS