title: A crucial role for macrophages in the pathology of K/B x N serum-induced arthritis.
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 x 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 x N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and Fc gammaRIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-alpha, 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 x 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.
authors.affiliation: Immunology, Department of Biology, Faculty of Sciences, University of Konstanz, Konstanz, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Solomon
authors.forename: Narendiran
authors.initials: N
authors.lastname: Rajasekaran
authors.forename: Elvira
authors.initials: E
authors.lastname: Jeisy-Walder
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Harald
authors.initials: H
authors.lastname: Illges
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D004002:Clodronic Acid / Q000008:administration & dosage; D007150:Immunohistochemistry; D008081:Liposomes; D008264:Macrophages / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000963:Antimetabolites; D019013:CD40 Antigens; D008081:Liposomes; D004002:Clodronic Acid