Linda Reinhard1, Maya Machalitza2, Thorsten Wiech3, Hermann-Josef Groene4, Moritz Lassé5, Markus Rinschen6, Nicoletta Ferru7, Jan Bräsen8, Friederike Drömann9, Peter Rob10, Sanjeev Sethi11, Elion Hoxha12, Rolf Stahl13. 1. L Reinhard, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. M Machalitza, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. T Wiech, Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. H Groene, Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. M Lassé, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. M Rinschen, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 7. N Ferru, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. J Bräsen, Institute of Pathology, Nephropathology Section, Hannover Medical School, Hannover, Germany. 9. F Drömann, Nierenzentrum, Sana Kliniken Lubeck GmbH, Lubeck, Germany. 10. P Rob, Nierenzentrum, Sana Kliniken Lubeck GmbH, Lubeck, Germany. 11. S Sethi, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States. 12. E Hoxha, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e.hoxha@uke.de. 13. R Stahl, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
Background: Primary membranous nephropathy (MN) is caused by circulating autoantibodies (ab) 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-ab in the serum of the index MN patient, which binds an antigen endogenously expressed on podocyte membranes. These IgG4-ab were used to immunoprecipitate the target antigen and mass spectrometry used to identify Netrin G1 (NTNG1). Native Western blot and ELISA analyzed NTNG1-ab 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 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-ab, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1-ab were identified in 561 PLA2R1-ab positive patients, 27 THSD7A-ab positive patients, and 77 patients with other glomerular diseases. In two patients with available followup of 2 and 4 years, both NTNG1-ab and proteinuria persisted. Conclusions: NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1-ab remains to be defined.
Background: Primary membranous nephropathy (MN) is caused by circulating autoantibodies (ab) 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-ab in the serum of the index MN patient, which binds an antigen endogenously expressed on podocyte membranes. These IgG4-ab were used to immunoprecipitate the target antigen and mass spectrometry used to identify Netrin G1 (NTNG1). Native Western blot and ELISA analyzed NTNG1-ab 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 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-ab, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1-ab were identified in 561 PLA2R1-ab positive patients, 27 THSD7A-ab positive patients, and 77 patients with other glomerular diseases. In two patients with available followup of 2 and 4 years, both NTNG1-ab and proteinuria persisted. Conclusions: NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1-ab remains to be defined.
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