title: Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy.
abstract: The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in predicting patient outcomes is unknown. Here, we screened serum samples from 50 patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1 deletion mutants covering the extracellular domains. We identified reactive epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1 by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14), and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1 antigens were not statistically different between subgroups. Patients with anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission (P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01) during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR epitope were independent risk factors of poor renal prognosis in multivariable Cox regression analysis. Epitope spreading during follow-up associated with disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back to a CysR profile associated with favorable outcome (n=1). We conclude that analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring disease severity and stratifying patients by renal prognosis.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; Service de Néphrologie, CHU de Nice, Université de Nice-Sophia Antipolis, France; Laboratoire d'Immunologie.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seitz-Polski
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dolla
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Payré
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
authors.forename: Christophe A
authors.initials: CA
authors.lastname: Girard
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
authors.forename: Joel
authors.initials: J
authors.lastname: Polidori
authors.affiliation: Centre de Recherche Clinique, CHU de Nice, Université de Nice-Sophia Antipolis, France;
authors.forename: Kevin
authors.initials: K
authors.lastname: Zorzi
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
authors.forename: Eléonore
authors.initials: E
authors.lastname: Birgy-Barelli
authors.affiliation: Service de Néphrologie Dialyse Transplantation Rénale, CHU Hôpital Nord, Saint-Etienne, and Université de Saint-Etienne PRES Université de Lyon, Saint-Etienne, France;
authors.forename: Perrine
authors.initials: P
authors.lastname: Jullien
authors.affiliation: Service de Néphrologie Dialyse Transplantation Rénale, CHU de Besançon, France;
authors.forename: Cécile
authors.initials: C
authors.lastname: Courivaud
authors.affiliation: Service de Néphrologie et dialyse, CHU de Strasbourg, Strasbourg, France; and.
authors.forename: Thierry
authors.initials: T
authors.lastname: Krummel
authors.affiliation: Laboratoire d'Immunologie.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Benzaken
authors.affiliation: Laboratoire d'Immunologie.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Bernard
authors.affiliation: Service de Néphrologie Dialyse Transplantation Rénale, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France et UMR S1076, Université Aix-Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Burtey
authors.affiliation: Service de Néphrologie Dialyse Transplantation Rénale, CHU Hôpital Nord, Saint-Etienne, and Université de Saint-Etienne PRES Université de Lyon, Saint-Etienne, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Mariat
authors.affiliation: Service de Néphrologie, CHU de Nice, Université de Nice-Sophia Antipolis, France;
authors.forename: Vincent L M
authors.initials: VL
authors.lastname: Esnault
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; seitz-polski.b@chu-nice.fr lambeau@ipmc.cnrs.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
mesh_terms: D001323:Autoantibodies / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D054507:Receptors, Phospholipase A2 / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D054507:Receptors, Phospholipase A2
keywords: chronic kidney disease; epidemiology and outcomes; membranous nephropathy