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

Eur J Immunol. 2005 Oct;35(10):3064-73. doi: 10.1002/eji.200526167.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites / administration & dosage
  • Arthritis, Experimental / immunology*
  • CD40 Antigens / metabolism
  • Clodronic Acid / administration & dosage
  • Immunohistochemistry
  • Liposomes
  • Macrophages / immunology*
  • Mast Cells / immunology
  • Mice
  • Mice, Transgenic


  • Antimetabolites
  • CD40 Antigens
  • Liposomes
  • Clodronic Acid