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B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0001-7790-8197
Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
2015 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 45, no 8, p. 2243-2251Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlagsgesellschaft, 2015. Vol. 45, no 8, p. 2243-2251
Keywords [en]
Arthritis, Auto-reactive B cells, Autoantibodies, Epitope spreading, ROS
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:hh:diva-48890DOI: 10.1002/eji.201545518ISI: 000359674200010PubMedID: 25989352Scopus ID: 2-s2.0-84938955513OAI: oai:DiVA.org:hh-48890DiVA, id: diva2:1717829
Note

Funding text: We are grateful to Duojia Cao and Hongwei Jia for the pilot experiments. Carlos and Kristina Palestro, Tomasz Klaczkowski and Evelina Wernersson for taking good care of animals. This study was supported by The Swedish Strategic Science Foundation (RH), Knut and Alice Wallenberg foundation (RH), Konung Gustaf V:s 80-ars fond (KSN and RH), Swedish Research Council (KSN and RH), Swedish Rheumatism Association (KSN and RH), the AIM grant from Guangdong province (RH) and the EU Innovative Medicine initiative BeTheCure grant (RH).

Available from: 2022-12-09 Created: 2022-12-09 Last updated: 2023-02-15Bibliographically approved

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Nandakumar, Kutty Selva

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