Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway.
Autoantibodies to proteinase 3 (PR3) are involved in the pathogenesis of autoimmune-mediated vasculitis in Wegener granulomatosis (WG). To address the question how the autoantigen PR3 becomes a target of adaptive immunity, we investigated the effect of PR3 on immature dendritic cells (iDCs) in patients with WG, healthy blood donors, and patients with Crohn 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, the DCs become fully competent antigen-presenting cells and can induce stimulation of PR3-specific CD4(+) T cells, which produce IFN-gamma. PR3-maturated DCs derived from WG patients induce a higher IFN-gamma response of PR3-specific CD4(+) T cells compared with patients with CD and healthy controls. The maturation of DCs 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 autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)-type response potentially favoring granuloma formation in WG.
Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Lübeck, Germany. csernok@r-on-klinik.de
Elena
E
Csernok
MaiXing
M
Ai
Wolfgang L
WL
Gross
Daniel
D
Wicklein
Arnd
A
Petersen
Buko
B
Lindner
Peter
P
Lamprecht
Julia U
JU
Holle
Bernhard
B
Hellmich
D000328:Adult; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology*; D001324:Autoantigens; D016022:Case-Control Studies; D002454:Cell Differentiation; D003424:Crohn Disease / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*
D001324:Autoantigens; D044464:Receptor, PAR-2; D007371:Interferon-gamma; D012697:Serine Endopeptidases; D053146:Myeloblastin