Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI)

Objectif

Membranous nephropathy (MN) is a paradigm of organ-specific autoimmune disease which affects the kidney glomerulus, resulting in the formation of immune deposits, complement-mediated proteinuria, and renal failure. My group has recently identified 2 causative antigens (neutral endopeptidase and bovine serum albumin) in children, and 2 predisposing genes HLA-DQA1 and PLA2R1 coding for another antigen in adult MN. However, MN is most likely more complex, involving several antigen-antibody systems and immune response genes. To get a comprehensive view of self and food/environmental antigenic targets and of HLA and non-HLA trigger genes, and to design new rapidly acting therapies, I will develop novel technological approaches such as immunopeptidomics, and explore new pathophysiological and therapeutic concepts with 3 major objectives:
1. Identify the immune response targets (epitopes) using unbiased approaches such as HLA-class II peptidomics, random peptide libraries, and sequencing of candidate genes starting with PLA2R1
2. Investigate trigger genes by next generation sequencing (NGS) of the HLA-D locus and of other genes involved in autoimmunity and disease progression, in 150 pairs of donors and recipients with or without recurrence of MN, a situation offering a unique opportunity to analyze effects of genetic background
3. Revisit complement-related innate immunity by NGS sequencing of 18 complement regulatory protein genes in search of variants which may account for disease heterogeneity, by blocking C5b-9 formation with recombinant factor H in 2 murine models of MN, and by searching for C5b-9 antagonists by high-throughput screening of chemical libraries in podocyte cell-based assays.
Our project will provide new biomarkers that will be used to set up reliable tests for diagnosis, monitoring, and prediction of outcome and recurrence of MN. It will result in new therapies, improved monitoring and ontology, and better understanding of organ-specific autoimmunity.

Champ scientifique

Régime de financement

ERC-AG - ERC Advanced Grant

Institution d’accueil

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Contribution de l’UE

€ 2 500 000,00

Adresse

RUE DE TOLBIAC 101
75654 Paris
France

Région

Ile-de-France Ile-de-France Paris

Type d’activité

Research Organisations

Chercheur principal

Pierre Marie Victor Ronco (Prof.)

Contact administratif

Akouavi Ekoue (Mrs.)

Liens

Contacter l’organisation Site web

Coût total

Aucune donnée

Bénéficiaires (1)