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    The dual role of neutrophil proteinase 3 in autoimmune vasculitis: when an autoantigen become a danger signal for the immune system

    The team of Véronique Witko-Sarsat, in collaboration with the Department of Internal Medicine, have demonstrated a new driver in a pathway that promotes inflammation in a particular type of autoimmune vasculitis called the granulomatosis with polyangiitis. 

     shemaFor the first time, this study published in The Journal of Clinical Investigation suggests that this disease may combine both autoimmune and auto-inflammatory components and will open the way for new targeted therapeutic strategies.


    Granulomatosis with polyangiitis (formerly Wegener's granulomatosis) is a necrotizing vasculitis affecting both lung and kidney. This rare disease can be lethal if left untreated and current treatment strategies include a combination of corticosteroids and immunosuppressive drugs, and more recently, the B lymphocyte-targeted anti-CD20 therapy. Neutrophils are a key players in this disease as they are both the promoters of endothelium damage and also the target of autoimmunity.

    We have discovered that proteinase 3, the target autoantigen in GPA, is expressed at the membrane of apoptotic neutrophils and can disturb their normal elimination by macrophages. While phagocytosis of apoptotic cells by macrophages normally produces an anti-inflammatory effect, proteinase 3 expressed at the membrane acts as a danger signal for the macrophages, triggering an « alarm response » by the immune system and favoring autoimmunity.

     In collaboration with Sylvain Perruche and his team at Besançon, we show that this inappropriate » activation of macrophages can also instruct plasmacytoid dendritic cells, a key cell type involved in the immune silencing associated with clearance of apoptotic cells. This programming of plasmacytoid dendritic cells in turn promotes the production of  Th9/Th2 cells and prevent the generation of regulatory T cells, and this microenvironment can favour autoimmunity. The PR3-induced microenvironment facilitated the recruitment of inflammatory cells such as macrophages, plasmacytoid dendritic cells (pDC) and neutrophils, all of which were observed in close proximity within granulomatous lesions in the lung of GPA patients.

     videoFinally, this study has demonstrated a pivotal role for the interleukin-1 receptor signalling pathway.  This pathway that has various inhibitors available that have never been tested in this type of vasculitis and could have potential therapeutic benefits. According to this study, modulation of plasmacytoid dendritic cells may also provide a novel therapeutic approach in treating this disease.


    Further work will be required to determine whether this unique mechanism, where the autoantigen plays a dual role in autoinflammatory and autoimmunity processes represents a novel eccentricity for proteinase 3 or whether it is indeed a new model to understand other systemic inflammatory diseases.


    Contact : Véronique Witko-Sarsat


    Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis.
    Millet A, Martin KR, Bonnefoy F, Saas P, Mocek J, Alkan M, Terrier B, Kerstein A, Tamassia N, Satyanarayanan SK, Ariel A, Ribeil JA, Guillevin L, Cassatella MA, Mueller A, Thieblemont N, Lamprecht P, Mouthon L, Perruche S, Witko-Sarsat V.
    J Clin Invest. 2015 Oct 5. pii: 78182. doi: 10.1172/JCI78182. [Epub ahead of print]
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