From AAV to Chronic KIdney disease-contribution of TEnascinC

Our work focuses on pathogenetic mechanisms in small vessel vasculitis which is a characteristic of a group of severe autoimmune diseases almost invariably associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) and commonly referred to as ANCA-associated vasculitis (AAV). AAV is characterised by acute inflammation of capillaries and venules that usually affects the kidney to cause focal necrotizing glomerulonephritis (FNGN) and rapidly worsening renal failure. ANCA that bind myeloperoxidase (MPO) and proteinase 3 (PR3) which are highly prevalent in AAV suggest a role in pathogenesis which is supported by in vitro studies and experimental models at least for MPO-ANCA. Unfortunately, regardless of any role in pathogenesis and despite early enthusiasm it is now established that these ANCA correlate poorly, if at all, with clinical disease activity. Other approaches to monitor disease activity through insights into pathogenesis of AAV was provided by the discovery of antibodies to human lysosome-associated membrane protein-2 (hLAMP-2). We originally identified these autoantibodies and have shown in multiple cohorts that they can be detected in 80-90% of patients with active AAV, and that they are pathogenic in rodent models. Despite increasing knowledge about the pathogenesis of acute injury in AAV, there is little known about mechanisms of chronic injury leading to severe organ damage. This is however essential if appropriate treatment is to be introduced before the inflammation intensifies to cause organ loss. The group of our French cooperation partner, G. Orend, at INSERM Unit 1109 in Strasbourg, has been working on tenascin-C in cancer and inflammation where tenascin-C is expressed in stem cell niches as well as in inflammatory niches. Experiments in tenascin-C knockout mice provide evidence that tenascin-C is crucial in tissue regeneration as well as in worsening inflammatory conditions. Tenascin-C is upregulated early after initial inflammatory injury and is thus a candidate molecule for investigations into repair processes and progression into chronic injury in AAV. Together we have established a work program to investigate the role of tenascin-C as a prime candidate (amongst others that will be identified here as well) in response to injury caused by ANCA to MPO and to hLAMP-2 in biopsies of human tissue and in vivo and in vitro models.

ANCA associated vasculitis (AAV) presents in the kidney as focal necrotizing glomerulonephritis (FNGN) often leading to organ failure due to progressive scarring which results in chronic kidney disease (CKD) and the need for organ replacement. Current treatments can end an acute phase and aim at slowing disease progression however the drugs used are accompanied by severe side effect and can often not prevent a relapsing and recurrent course. Established murine models of AAV mimic the acute phase of the human disease and are designed to investigate the underlying disease mechanisms however a model that emulates the chronic course of AAV and can be used to therapeutically target progression had not been developed. We successfully developed a novel and robust murine AAV model that demonstrated a course from acute to chronic injury as seen also in the human disease and characterized it at tissue and molecular level. The results revealed novel insights into disease mechanisms and targeting opportunities which may provide means to use the model for the development of therapies to ameliorate the disease pathology and for progress management in AAV.