A crucial role for macrophages in the pathology of K/B × N serum-induced arthritis

Authors

  • Samuel Solomon,

    1. Immunology, Department of Biology, Faculty of Sciences, University of Konstanz, Konstanz, Germany
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  • Narendiran Rajasekaran,

    1. Immunology, Department of Biology, Faculty of Sciences, University of Konstanz, Konstanz, Germany
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  • Elvira Jeisy-Walder,

    1. Biotechnology Institute Thurgau, Tägerwilen, Switzerland
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  • Scott B. Snapper,

    1. Massachusetts General Hospital, Boston, MA, USA
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  • Harald Illges

    Corresponding author
    1. Immunology, Department of Biology, Faculty of Sciences, University of Konstanz, Konstanz, Germany
    2. Biotechnology Institute Thurgau, Tägerwilen, Switzerland
    3. University of Applied Sciences, Department of Natural Sciences, Immunology and Cell Biology, Rheinbach, Germany
    • University of Applied Sciences, Department of Natural Sciences, Immunology and Cell Biology, Bonn Rhein Sieg von-Liebig-Strasse 20, 53359 Rheinbach, Germany, Fax: +49–2241–865–570
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Abstract

Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen II antibody-induced arthritis animal model for a long time now. Recently, in the K/B × N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B × N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and FcγRIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-α, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokine-producing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B × N serum-induced arthritis. Reconstituting clodronate liposome-treated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis.

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