Dynamics of anti-PLA2R1 and anti-THSD7A autoantibodies in patients with membranous nephropathy: from early steps to overt disease – AirMN

Membranous nephropathy (MN) is a rare but life-threatening autoimmune kidney disease, with about 1,300 and 10,000 new cases/year in France and Europe, respectively. It is a major cause of nephrotic syndrome. Patients have variable disease onset, clinical outcome and response to immunosuppressive treatment, and may progress to severe disease and end-stage kidney disease over 5-10 years, requiring dialysis and transplantation. Better diagnosis and prognosis tools are needed to identify patients with MN and those at risk of severe disease. MN is characterized by the presence of immune complexes at the surface of podocytes, leading to heavy proteinuria.
Over recent years, Partner 1 (P1) and Partner 4 (P4) have identified key antigens involved in MN. Relevant to this project, P1 and collaborators have identified the phospholipase A2 receptor (PLA2R1, NEJM, 2009) and thrombospondin type-1 domain-containing 7A (THSD7A, NEJM, 2014) as key autoantigens in adult primary MN. Nowadays, PLA2R1-associated MN appears as the major form of MN, with anti-PLA2R1 autoantibodies in about 70% of patients, and THSD7A-associated MN as a minor form, with anti-THSD7A autoantibodies in another group of 3% of patients.
Of clinical importance, the discoveries of PLA2R1 and THSD7A have led to a rapid paradigm shift in patients' healthcare, with patenting and licensing to a German company and development of commercial biomarker assays with P1. These assays are now available worldwide in the clinics to detect circulating anti-PLA2R1 and anti-THSD7A autoantibodies for diagnosis and prognosis (https://www.pla2r.com).
Recent and preliminary data from P1 and P4 have shown that patients' sera at diagnosis contain a diversity of circulating autoantibodies targeting multiple epitopes in PLA2R1 and THSD7A, which is associated with disease worsening and response to treatment, and may result from a previous mechanism of epitope spreading (JASN, 2016&2018, unpublished data and patents).
The AirMN project proposes to analyze "deeper and earlier" the autoimmune response in PLA2R1- and THSD7A-associated MN "backwards", from overt disease to the early events that might be associated with the break in immune self-tolerance.
The consortium assembles 4 French partners from Sophia Antipolis, Marseille and Paris. While P1 and P4 have complementary expertise from biochemistry and immunology to clinical investigation, P2 provides a key expertise in high-throughput protein expression and P3 in structural biology. Importantly, all partners have already worked together. Thanks to P1 and P4 and their networks of clinicians, the project will benefit from swift access to several cohorts in the smoldering and overt phases. Thanks to P1, P2 and P3, the project will benefit from swift access to cutting-edge platforms.
There are two workpackages:
WP1. During overt MN, we will identify the portfolio of molecular epitopes and corresponding autoantibodies by high-throughput technologies (library of PLA2R1/THSD7A mutants, antibody phage display, B cell receptor repertoire), up to resolution of the structure of immune complexes at the atomic level.
WP2. During smoldering MN, we will determine the epitope profile from patients' sera collected before diagnosis. We will finally test the hypothesis that the origin of PLA2R1- and THSD7A-associated MN is associated with specific post-translational modifications of the autoantigens.
Our project should lead to a better understanding of the autoimmune response, which is a key component in the pathophysiology of MN. We expect to provide new knowledge in the mechanisms of disease initiation, antigen modification, and epitope spreading with deep structural insights, which may be transposed to other autoimmune diseases. Our data may also lead to the identification of novel strategies to better diagnose patients and pave the way for innovative personalized therapy based on the identification of key B cell epitopes.