Biomedical research institute

    Research project 3

    Mechanisms of immune dysregulation in ANCA-associated vasculitis : role of the autoantigen proteinase 3.

    ANCA-associated vasculitis are characterized by systemic inflammation associated with an immune dysregulation and an autoimmunity targeting neutrophils.

    To date, the cause of these diseases are unknown. Our research project is aimed at understanding the role of neutrophils in the immune dysregulation in GPA and more specifically the role of the traget autoantigen PR3.

    In 2015, the team has discovered a novel pathway by which PR3 expressed on apoptotic neutrophils could initiate a cascade of proinflammatory reaction and favor autoimmunity. This study show for the first time that autoimmune vasculitis could have an autoinflammatory component involving interleukin-1 beta.

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    Proteinase 3 (PR3) is stored into the azurophil granules of circulating neutrophils.  During vascular inflammation, neutrophils are activated by ANCA and undergo apoptosis. During this process, they can express PR3 at the plasma membrane, which can interfere with phagocytosis (Kantari et al Blood 2007) and activate macrophages through the MYD88/interleukin 1 pathway inducing the production of inflammatory cytokines and chemokines (Gabillet et al J Immunol 2012). PR3 mimics a danger signal for macrophages resulting in a microenvironment favouring activation of pDCs, which are key cells in the immune silencing associated with the phagocytosis of apoptotic cells. Phagocytosis of apoptotic cells expressing PR3 results in an inhibition of the generation of regulatory T cells and a polarization of CD4 positive T helper cells into a Th9 profile. In addition, anti-PR3 ANCA further enhances the generation of Th17 cells thus potentiating inflammation. Generation of G-CSF potentiates PR3 synthesis in myeloid precursors leading to increased PR3 expression in mature neutrophils, and thus in turn potentiating inflammation (Millet et al J Clin Invest 2015)

    Figure 12 : The autoantigen PR3 is a danger signal to activate the immune system

    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. Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis. J Clin Invest. 2015 Nov 2;125(11):4107-21.

    Witko-Sarsat V & Thieblemont N. Granulomatosis with polyangiitis (Wegener granulomatosis): A proteinase-3 driven disease ? Joint Bone Spine. 2018 Mar;85(2):185-189.