PMID- 26567246 OWN - NLM STAT- MEDLINE DCOM- 20170524 LR - 20220318 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 27 IP - 5 DP - 2016 May TI - Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy. PG - 1517-33 LID - 10.1681/ASN.2014111061 [doi] AB - 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. CI - Copyright (c) 2016 by the American Society of Nephrology. FAU - Seitz-Polski, Barbara AU - Seitz-Polski B AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; Service de Nephrologie, CHU de Nice, Universite de Nice-Sophia Antipolis, France; Laboratoire d'Immunologie. FAU - Dolla, Guillaume AU - Dolla G AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; FAU - Payre, Christine AU - Payre C AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; FAU - Girard, Christophe A AU - Girard CA AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; FAU - Polidori, Joel AU - Polidori J AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; FAU - Zorzi, Kevin AU - Zorzi K AD - Centre de Recherche Clinique, CHU de Nice, Universite de Nice-Sophia Antipolis, France; FAU - Birgy-Barelli, Eleonore AU - Birgy-Barelli E AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; FAU - Jullien, Perrine AU - Jullien P AD - Service de Nephrologie Dialyse Transplantation Renale, CHU Hopital Nord, Saint-Etienne, and Universite de Saint-Etienne PRES Universite de Lyon, Saint-Etienne, France; FAU - Courivaud, Cecile AU - Courivaud C AD - Service de Nephrologie Dialyse Transplantation Renale, CHU de Besancon, France; FAU - Krummel, Thierry AU - Krummel T AD - Service de Nephrologie et dialyse, CHU de Strasbourg, Strasbourg, France; and. FAU - Benzaken, Sylvia AU - Benzaken S AD - Laboratoire d'Immunologie. FAU - Bernard, Ghislaine AU - Bernard G AD - Laboratoire d'Immunologie. FAU - Burtey, Stephane AU - Burtey S AD - Service de Nephrologie Dialyse Transplantation Renale, Assistance Publique-Hopitaux de Marseille, Hopital de la Conception, Marseille, France et UMR S1076, Universite Aix-Marseille, France. FAU - Mariat, Christophe AU - Mariat C AD - Service de Nephrologie Dialyse Transplantation Renale, CHU Hopital Nord, Saint-Etienne, and Universite de Saint-Etienne PRES Universite de Lyon, Saint-Etienne, France; FAU - Esnault, Vincent L M AU - Esnault VL AD - Service de Nephrologie, CHU de Nice, Universite de Nice-Sophia Antipolis, France; FAU - Lambeau, Gerard AU - Lambeau G AD - Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS and Universite de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; seitz-polski.b@chu-nice.fr lambeau@ipmc.cnrs.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151113 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (Autoantibodies) RN - 0 (Epitopes) RN - 0 (Receptors, Phospholipase A2) SB - IM CIN - J Am Soc Nephrol. 2016 May;27(5):1275-7. PMID: 26657866 MH - Autoantibodies/*immunology MH - Epitopes/*immunology MH - Female MH - Glomerulonephritis, Membranous/*immunology MH - Humans MH - Male MH - Middle Aged MH - Prognosis MH - Receptors, Phospholipase A2/*immunology PMC - PMC4849812 OTO - NOTNLM OT - chronic kidney disease OT - epidemiology and outcomes OT - membranous nephropathy EDAT- 2015/11/15 06:00 MHDA- 2017/05/26 06:00 PMCR- 2017/05/01 CRDT- 2015/11/15 06:00 PHST- 2014/11/02 00:00 [received] PHST- 2015/08/06 00:00 [accepted] PHST- 2015/11/15 06:00 [entrez] PHST- 2015/11/15 06:00 [pubmed] PHST- 2017/05/26 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - ASN.2014111061 [pii] AID - 2014111061 [pii] AID - 10.1681/ASN.2014111061 [doi] PST - ppublish SO - J Am Soc Nephrol. 2016 May;27(5):1517-33. doi: 10.1681/ASN.2014111061. Epub 2015 Nov 13.