PEPTIDE PROJECT

FRRB Project 1737173 - PLA2R-autoreactivE B-cell subsets in membranous nePhropaThy: Identification of outcome predictors and novel insights into Disease pathogenesis

PROJECT SUMMARY

Membranous nephropathy is an autoimmune renal disease caused by autoantibodies against the renal cell surface antigen, phospholipase A2 receptor (PLA2R). The antibody binding on renal cells provokes cell damage and the subsequent loss of their permeability barrier, leading to high levels of proteins in the urine. Therapeutic antibodies against B cells - the immune cells responsible of autoantibody production - are effective only in a subset of patients. In addition, some of these responder patients experience a disease relapse after the initial response while others achieved sustained remission. The reasons of the non-homogeneous efficacy of the B-cell depleting therapy in patients with MN are largely unknown. Our hypothesis is that autoreactive B cells in responder and non-responder patients are present at different stages of their maturation or in different activation status and that these characteristics account for the different sensitivity to the B cell depleting therapy.

During the first two years of activity, we synthesized in lab the recombinant PLA2R protein and developed a method for the detection of PLA2R-specific B cells. The recombinant PLA2R protein had a correct conformation and immunoreactivity and its assembly into tetramers allowed us to identify PLA2R specific B cell among peripheral blood cells in MN patients. The phenotype and transcriptome of these PLA2R-B cells will be characterized in the different groups of MN patients with the aim to develop a biomarker of response to therapy, a marker to predict disease relapse and the development of new therapy for this disease.