Netrin G1 is a Novel Target Antigen in Primary Membranous Nephropathy
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Netrin G1 is a Novel Target Antigen in Primary Membranous Nephropathy. / Reinhard, Linda; Machalitza, Maya; Wiech, Thorsten; Groene, Hermann-Josef; Lassé, Moritz; Rinschen, Markus; Ferru, Nicoletta; Bräsen, Jan; Drömann, Friederike; Rob, Peter; Sethi, Sanjeev; Hoxha, Elion; Stahl, Rolf.
in: J AM SOC NEPHROL, Jahrgang 33, Nr. 10, 10.2022, S. 1823-1831.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Netrin G1 is a Novel Target Antigen in Primary Membranous Nephropathy
AU - Reinhard, Linda
AU - Machalitza, Maya
AU - Wiech, Thorsten
AU - Groene, Hermann-Josef
AU - Lassé, Moritz
AU - Rinschen, Markus
AU - Ferru, Nicoletta
AU - Bräsen, Jan
AU - Drömann, Friederike
AU - Rob, Peter
AU - Sethi, Sanjeev
AU - Hoxha, Elion
AU - Stahl, Rolf
PY - 2022/10
Y1 - 2022/10
N2 - BACKGROUND: Primary membranous nephropathy (MN) is caused by circulating autoantibodies binding to antigens on the podocyte surface. PLA2R1 is the main target antigen in 70%-80% of cases, but the pathogenesis is unresolved in 10%-15% of patients.METHODS: We used native western blotting to identify IgG4 autoantibodies, which bind an antigen endogenously expressed on podocyte membranes, in the serum of the index patient with MN. These IgG4 autoantibodies were used to immunoprecipitate the target antigen, and mass spectrometry was used to identify Netrin G1 (NTNG1). Using native western blot and ELISA, NTNG1 autoantibodies were analyzed in cohorts of 888 patients with MN or other glomerular diseases.RESULTS: NTNG1 was identified as a novel target antigen in MN. It is a membrane protein expressed in healthy podocytes. Immunohistochemistry confirmed granular NTNG1 positivity in subepithelial glomerular immune deposits. In prospective and retrospective MN cohorts, we identified three patients with NTNG1-associated MN who showed IgG4-dominant circulating NTNG1 autoantibodies, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1 autoantibodies were identified in 561 PLA2R1 autoantibodies-positive patients, 27 THSD7A autoantibodies-positive patients, and 77 patients with other glomerular diseases. In two patients with available follow-up of 2 and 4 years, both NTNG1 autoantibodies and proteinuria persisted.CONCLUSIONS: NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1 autoantibodies remains to be defined.
AB - BACKGROUND: Primary membranous nephropathy (MN) is caused by circulating autoantibodies binding to antigens on the podocyte surface. PLA2R1 is the main target antigen in 70%-80% of cases, but the pathogenesis is unresolved in 10%-15% of patients.METHODS: We used native western blotting to identify IgG4 autoantibodies, which bind an antigen endogenously expressed on podocyte membranes, in the serum of the index patient with MN. These IgG4 autoantibodies were used to immunoprecipitate the target antigen, and mass spectrometry was used to identify Netrin G1 (NTNG1). Using native western blot and ELISA, NTNG1 autoantibodies were analyzed in cohorts of 888 patients with MN or other glomerular diseases.RESULTS: NTNG1 was identified as a novel target antigen in MN. It is a membrane protein expressed in healthy podocytes. Immunohistochemistry confirmed granular NTNG1 positivity in subepithelial glomerular immune deposits. In prospective and retrospective MN cohorts, we identified three patients with NTNG1-associated MN who showed IgG4-dominant circulating NTNG1 autoantibodies, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1 autoantibodies were identified in 561 PLA2R1 autoantibodies-positive patients, 27 THSD7A autoantibodies-positive patients, and 77 patients with other glomerular diseases. In two patients with available follow-up of 2 and 4 years, both NTNG1 autoantibodies and proteinuria persisted.CONCLUSIONS: NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1 autoantibodies remains to be defined.
U2 - 10.1681/ASN.2022050608
DO - 10.1681/ASN.2022050608
M3 - SCORING: Journal article
C2 - 35985817
VL - 33
SP - 1823
EP - 1831
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 10
ER -