Discovery of anti-Formin-like 1 Protein (FMNL1) antibodies in proteinuric nephropathies

Membranous nephropathy (MN) is determined by deposition of autoantibodies targeting glomerular podoyctes antigens. MN progression to renal failure remains a central issue: antibodies modifying the inflammatory course after the first antibody hit may be involved. We investigated sera of MN patient using a high-density peptide array covering the whole coding sequences of the human genome encompassing 7,499,126 tiled peptides. A panel of 258 proteins reactive with MN sera were identified. We focused on Formin-like 1 (FMNL1) protein expressed by macrophages. High levels of anti-FMNL1 IgG4 were demonstrated in sera of MN patient with orthogonal methodologies (ELISA) and were observed co-staining with CD68 in glomeruli. High levels of circulating anti-FMNL1 IgG4 were associated with lack of remission of proteinuria, strengthening the concept that, autoantibodies directed to cells of the tissue repair, might have a definite role in determining the disease outcome. High serum levels of anti-FMNL1 IgGs were also observed in other non-autoimmune glomerolonephrites, ie. idiopathic and genetic FSGS, IgAGN, stressing the non-specificity for MN and suggesting their involvement in glomerular conditions affecting many patients worldwide.