Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Abstract

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-γ. PR3-maturated DCs derived from WG patients induce a higher IFN-γ 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.

Antineutrophil cytoplasmic antibody–associated vasculitides: Could geographic patterns be explained by ambient ultraviolet radiation?

“…All 3 are diseases in which Th1 cells play a predominant role (13,14). This type of T cell also appears very important in the pathogenesis of WG (15)(16)(17)(18). More recently, it has become clear that another subset of T cells, Th17 cells, may contribute to the pathogenesis of diseases that were until now considered to be predominantly mediated by Th1 cells (19).…”

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

“…Activated PMN can promote DC migration (28) and also modulate DC maturation and activation through cell-cell contacts (29), ectosome release (30), or mediator secretion. Interestingly, several granule-derived mediators such as lactoferrin, LL-37, calprotectins, a-defensins, elastase, bactericidal/permeability-increasing protein, MPO, and proteinase 3 have been shown to either downregulate (31)(32)(33)(34)(35)(36)(37) or upregulate (33,(38)(39)(40)(41)) DC functions, depending on the study.…”

The Role of Proteinase 3 and Neutrophils in ANCA-Associated Systemic Vasculitis

“…Rarok et al found that the length of time between diagnosis and relapse was significantly shorter in WG patients with high mPR3 expression (total level of mPR3 expression), and that individuals with high total mPR3 expression were more likely to have a relapse than patients with low mPR3 (Rarok, 2002). Csernok et al showed that PR3 induces maturation of a fraction of blood monocyte derived dendritic cells (DC) in vitro (Csernok, 2006). In this context, they also observed that PR3 activates PAR-2 receptor-dependent signaling, which in turn up-regulates HLA-DR, CD80, CD83 and CD86 and down-regulates CD14.…”