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Section for Medical Inflammation Research, Lund University, Lund, Sweden
The view on reactive oxygen species (ROS) in inflammation is currently shifting from being considered damaging toward having a more complex role in regulating inflammatory reactions. We recently demonstrated a role of ROS in regulation of animal models for the autoimmune disease rheumatoid arthritis. Low levels of ROS production, due to a mutation in the Ncf1 gene coding for the Ncf1 (alias p47phox) subunit of the NADPH oxidase complex, was shown to be associated with increased autoimmunity and arthritis severity in both rats and mice. To further investigate the role of ROS in autoimmunity, we studied transgenic mice expressing collagen type II (CII) with a mutation (D266E) in the immunodominant epitope that mimics the rat and human CII (i.e., mutated mouse collagen or MMC). This mutation results in a stronger binding of the epitope to the MHC class II molecule and leads to more pronounced tolerance and resistance to arthritis induced with rat CII. When the Ncf1 mutation was bred into these mice, tolerance was broken, resulting in enhanced T cell autoreactivity, high titers of anti-CII Abs, and development of severe arthritis. These findings highlight the importance of a sufficient ROS production in maintenance of tolerance to self-Ags, a central mechanism in autoimmune diseases such as rheumatoid arthritis. This is important as we, for the first time, can follow the effect of ROS on molecular mechanisms where T cells are responsible for either protection or promotion of arthritis depending on the level of oxygen species produced.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Anna Greta Crafoord, King Gustaf V’s 80th Year; the Nilsson-Ehle; the Kock and Österlund Foundations; the Swedish Association against Rheumatism; Biovitrum AB; the Swedish Medical Research Council; the Swedish Society for Medical Research; the Strategic Research Foundation and the European Union Projects LSHB-CT-2006-018661 (AUTOCURE), LSHM-CT-2005-005223 (EURAPS), and NEUROPROMISE (LSHM-CT-2005-018637).
2 Address correspondence and reprint requests to Dr. Rikard Holmdahl, Medical Inflammation Research, I11 Biomedical Center, Lund University, Lund, Sweden. E-mail address: rikard.holmdahl{at}med.lu.se
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CII, collagen type II; CIA, collagen-induced arthritis; COMP, cartilage oligomeric protein; DTH, delayed-type hypersensitivity; MMC, mutated mouse collagen; ROS, reactive oxygen species; MCS, mean cumulative score; MDO, mean day of onset; MMS, mean maximum score; HAc, acetic acid; PPD, purified protein derivative.
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