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  • Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice.

Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice.

Journal of immunology (Baltimore, Md. : 1950) (2007-07-21)
Malin Hultqvist, Johan Bäcklund, Kristin Bauer, Kyra A Gelderman, Rikard Holmdahl
ABSTRACT

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 p47(phox)) 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Collagen from bovine nasal septum, Bornstein and Traub Type II, powder
Sigma-Aldrich
Collagen from bovine tracheal cartilage, Bornstein and Traub Type II, powder

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