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Ncf1-Associated Reduced Oxidative Burst Promotes IL-33R⁺ T Cell-Mediated Adjuvant-Free Arthritis in Mice^1,2

Kristin Hagenow^*,3, Kyra A. Gelderman^*,4, Malin Hultqvist^*,3, Patrick Merky^*, Johan Bäcklund^*, Oliver Frey, Thomas Kamradt and Rikard Holmdahl^*,5

*Medical Inflammation Research, Lund University and Karolinska Institute, Stockholm, Sweden; and Institute of Immunology, Universitätsklinikum Jena, Germany

Reactive oxygen species (ROS) are important in the immune defense against invading pathogens, but they are also key molecules in the regulation of inflammatory reactions. Low levels of ROS production due to a polymorphism in the neutrophil cytosolic factor 1 (Ncf1) gene are associated with autoimmunity and arthritis severity in mouse models induced with adjuvant. We established an adjuvant-free arthritis model in which disease is induced by injection of the autoantigen collagen type II (CII) and depends on IL-5-producing T cells and eosinophils. In addition, the transgenic expression of mutated mouse CII allowed us to investigate an autoreactive immune response to an autologous Ag and by that natural tolerance mechanism. We show that a deficient ROS production, due to a spontaneous mutation in Ncf1, leads to increased autoantibody production and expansion of IL-33R-expressing T cells, impaired T cell tolerance toward tissue-specific CII, and severe arthritis in this unique model without disturbing adjuvant effects. These results demonstrate that the insufficient production of ROS promotes the breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL-5- and IL33R-dependent T cell activation pathway.

⁵ Address correspondence and reprint requests to Dr. Rikard Holmdahl, Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail address: Rikard.Holmdahl{at}ki.se

¹ This work was supported by grants from the Strategic Research Foundation and the European Union Projects MRTN-CT-2004-005693 (EURO-RA), LSHB-CT-2006-018661 (AUTOCURE), and LSHG-CT-2005-005203 (MUGEN).

² This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

³ Current address: Redoxis AB, Biotech Building, Gothenburg, Sweden.

⁴ Current address: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.