THSD7A, the second autoantigen in membranous nephropathy : new diagnostic test and identification of the immunodominant epitopes ; THSD7A, le second auto-antigène de la glomérulonéphrite extra-membraneuse : nouveau test diagnostique et identification des épitopes immunodominants

Membranous nephropathy (MN) is a rare autoimmune kidney disease with an incidence of 1.3/100,000 in Europe yet it is a leading cause of nephrotic syndrome in adults. Histologically, MN is characterized by the accumulation of immune deposits along the glomerular basement membrane leading to podocyte injury. Clinically, the outcome of the disease varies from spontaneous remission to end–stage kidney disease, with high proteinuria. Considerable advances have been made in the understanding of the pathophysiology of MN with the identification of the phospholipase A2 receptor 1 (PLA2R1) as the major autoantigen for about 70% of patients and of thrombospondin–type 1 domain containing 7A (THSD7A) as a second autoantigen for another group of patients of 2–5%. MN treatment is controversial, and clinical biomarkers of the disease are needed to identify patients at risk of severe disease and to guide therapy. Anti–PLA2R1 titers correlate with disease severity and have a predictive value for prognosis. Moreover, three distinct epitope domains of PLA2R1 have been identified and linked by a mechanism of epitope spreading. This mechanism was associated with disease worsening and a poor prognosis. We believe that a similar disease mechanism holds for THSD7A. In this thesis, we focused on the identification of the molecular properties of THSD7A in the context of MN. THSD7A is different from PLA2R1 and is a member of the thrombospondin repeats superfamily. It is a large type I transmembrane protein (250 kDa) with an extracellular region mainly composed of 21 alternating domains of thrombospondin–type 1 like repeat as in thrombospondin–1 or complement component 6. Little is known about THSD7A. It is implicated in cell migration and angiogenesis but its function in the podocyte is unknown. The first objective was to develop a clinical assay to identify patients with THSD7A–associated MN. We thus designed the first robust ELISA for sensitive and quantitative detection of anti–THSD7A autoantibodies in serum from MN patients. We ...