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: Ia Khmaladze, Amit Saxena, Kutty Selva Nandakumar, Rikard Holmdahl
• Journal: European journal of immunology (Eur J Immunol) Vol. 45 Issue 8 Pg. 2243-51 (Aug 2015) ISSN: 1521-4141 [Electronic] Germany
• PMID: 25989352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Autoantibodies
• Epitopes, B-Lymphocyte
• Reactive Oxygen Species
• NADPH Oxidases
• neutrophil cytosolic factor 1

Topics

• Animals
• Arthritis, Experimental (genetics, immunology, pathology)
• Autoantibodies (immunology)
• B-Lymphocytes (immunology, pathology)
• Epitopes, B-Lymphocyte (genetics, immunology)
• Germinal Center (immunology, pathology)
• Male
• Mice
• Mutation
• NADPH Oxidases (genetics, immunology)
• Reactive Oxygen Species (immunology)
• T-Lymphocytes (immunology, pathology)