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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4440-4448.
Prepublished online as a Blood First Edition Paper on February 14, 2006; DOI 10.1182/blood-2005-05-1875.
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Submitted May 9, 2005
Accepted January 21, 2006
Wegener's autoantigen induces maturation of dendritic cells and licences them for TH1 priming via the protease-activated receptor-2 pathway
Elena Csernok*, Maixing Ai, Wolfgang L Gross, Daniel Wicklein, Arnd Petersen, Buko Lindner, Peter Lamprecht, Julia U Holle, and Bernhard Hellmich
Department of Rheumatology, University-Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
Department of Molecular and Clinical Allergology, Research Center Borstel, Borstel, Germany
Department of Biophysics, Research Center Borstel, Borstel, Germany
* Corresponding author; email: csernok{at}rheuma-zentrum.de.
Autoantibodies to proteinase 3 (PR3) are involved in the pathogenesis of autoimmune-mediated vasculitis in. Wegener's granulomatosis (WG). To address the question how the autoantigen -PR3 becomes target of adaptive immunity, we investigated the effect of PR3 on immature dendritic cells (iDCs) in patients with WG, healthy blood donors and and patients with Crohn's disease (CD), another granulomatous disease. PR3 induces phenotypic and functional maturation of a fraction of blood monocyte-derived iDCs. PR3-treated DCs express high levels of CD83, a DC-restricted marker of maturation, CD80 and CD86, and HLA-DR. Furthermore, they become fully competent antigen presenting cells and can induce stimulation of PR3-specific CD4+ T cells, which produce IFN- . PR3-maturated DCs derived from WG patients induce a higher INF- response of PR3-specific CD4+ T cells as compared to patients with CD and healthy controls. The maturation of DC mediated through PR3 was inhibited by a serine protease inhibitor, by antibodies directed against the protease-activated receptor-2 (PAR-2) and by inhibition of phospholipase C, suggesting that the interactions of PR3 with PAR-2 are involved in the induction of DC maturation. Wegener's autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licences them for a Th1-type response potentially favouring granuloma-formation in WG.
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