Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway.
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Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. / Csernok, Elena; Ai, MaiXing; Gross, Wolfgang L; Wicklein, Daniel; Petersen, Arnd; Lindner, Buko; Lamprecht, Peter; Holle, Julia U; Hellmich, Bernhard.
in: BLOOD, Jahrgang 107, Nr. 11, 11, 2006, S. 4440-4448.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway.
AU - Csernok, Elena
AU - Ai, MaiXing
AU - Gross, Wolfgang L
AU - Wicklein, Daniel
AU - Petersen, Arnd
AU - Lindner, Buko
AU - Lamprecht, Peter
AU - Holle, Julia U
AU - Hellmich, Bernhard
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Case-Control Studies
KW - Cell Differentiation
KW - Th1 Cells/immunology
KW - Antigen Presentation/immunology
KW - Autoantigens
KW - Crohn Disease/immunology
KW - Dendritic Cells/cytology/immunology
KW - Interferon-gamma/analysis
KW - Myeloblastin
KW - Receptor, PAR-2/metabolism
KW - Serine Endopeptidases/physiology
KW - Wegener Granulomatosis/immunology
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Case-Control Studies
KW - Cell Differentiation
KW - Th1 Cells/immunology
KW - Antigen Presentation/immunology
KW - Autoantigens
KW - Crohn Disease/immunology
KW - Dendritic Cells/cytology/immunology
KW - Interferon-gamma/analysis
KW - Myeloblastin
KW - Receptor, PAR-2/metabolism
KW - Serine Endopeptidases/physiology
KW - Wegener Granulomatosis/immunology
M3 - SCORING: Journal article
VL - 107
SP - 4440
EP - 4448
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 11
M1 - 11
ER -
