HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status
Abstract Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-medi...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53072-0 |
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| author | Anne-Laure Leblond Birgit Helmchen Maliki Ankavay Daniela Lenggenhager Jasna Jetzer Fritjof Helmchen Hueseyin Yurtsever Rossella Parrotta Marc E. Healy Amiskwia Pöschel Enni Markkanen Nasser Semmo Martin Ferrié Laurence Cocquerel Harald Seeger Helmut Hopfer Beat Müllhaupt Jérôme Gouttenoire Darius Moradpour Ariana Gaspert Achim Weber |
| author_facet | Anne-Laure Leblond Birgit Helmchen Maliki Ankavay Daniela Lenggenhager Jasna Jetzer Fritjof Helmchen Hueseyin Yurtsever Rossella Parrotta Marc E. Healy Amiskwia Pöschel Enni Markkanen Nasser Semmo Martin Ferrié Laurence Cocquerel Harald Seeger Helmut Hopfer Beat Müllhaupt Jérôme Gouttenoire Darius Moradpour Ariana Gaspert Achim Weber |
| author_sort | Anne-Laure Leblond |
| collection | DOAJ |
| description | Abstract Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications. |
| format | Article |
| id | doaj-art-2e0acd6efb7748d6ab4fa79b0d50a92c |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2e0acd6efb7748d6ab4fa79b0d50a92c2025-08-20T02:17:50ZengNature PortfolioNature Communications2041-17232024-10-0115111210.1038/s41467-024-53072-0HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune statusAnne-Laure Leblond0Birgit Helmchen1Maliki Ankavay2Daniela Lenggenhager3Jasna Jetzer4Fritjof Helmchen5Hueseyin Yurtsever6Rossella Parrotta7Marc E. Healy8Amiskwia Pöschel9Enni Markkanen10Nasser Semmo11Martin Ferrié12Laurence Cocquerel13Harald Seeger14Helmut Hopfer15Beat Müllhaupt16Jérôme Gouttenoire17Darius Moradpour18Ariana Gaspert19Achim Weber20Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of LausanneDepartment of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Brain Research Institute, University of ZurichInstitute of Pathology, Cantonal HospitalDepartment of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Institute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse FacultyInstitute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse FacultyDepartment of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of BernUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 - CIIL - Center for Infection and Immunity of LilleUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 - CIIL - Center for Infection and Immunity of LilleClinic of Nephrology, University Hospital ZurichInstitute of Medical Genetics and Pathology, University Hospital Basel, University of BaselDepartment of Gastroenterology and Hepatology, University Hospital ZurichDivision of Gastroenterology and Hepatology, Lausanne University Hospital and University of LausanneDivision of Gastroenterology and Hepatology, Lausanne University Hospital and University of LausanneDepartment of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ)Abstract Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications.https://doi.org/10.1038/s41467-024-53072-0 |
| spellingShingle | Anne-Laure Leblond Birgit Helmchen Maliki Ankavay Daniela Lenggenhager Jasna Jetzer Fritjof Helmchen Hueseyin Yurtsever Rossella Parrotta Marc E. Healy Amiskwia Pöschel Enni Markkanen Nasser Semmo Martin Ferrié Laurence Cocquerel Harald Seeger Helmut Hopfer Beat Müllhaupt Jérôme Gouttenoire Darius Moradpour Ariana Gaspert Achim Weber HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status Nature Communications |
| title | HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status |
| title_full | HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status |
| title_fullStr | HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status |
| title_full_unstemmed | HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status |
| title_short | HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status |
| title_sort | hev orf2 protein antibody complex deposits are associated with glomerulonephritis in hepatitis e with reduced immune status |
| url | https://doi.org/10.1038/s41467-024-53072-0 |
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