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Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains
Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glome...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118613/ https://www.ncbi.nlm.nih.gov/pubmed/17517971 http://dx.doi.org/10.1084/jem.20070301 |
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author | Pickering, Matthew C. de Jorge, Elena Goicoechea Martinez-Barricarte, Rubén Recalde, Sergio Garcia-Layana, Alfredo Rose, Kirsten L. Moss, Jill Walport, Mark J. Cook, H. Terence de Córdoba, Santiago Rodriguez Botto, Marina |
author_facet | Pickering, Matthew C. de Jorge, Elena Goicoechea Martinez-Barricarte, Rubén Recalde, Sergio Garcia-Layana, Alfredo Rose, Kirsten L. Moss, Jill Walport, Mark J. Cook, H. Terence de Córdoba, Santiago Rodriguez Botto, Marina |
author_sort | Pickering, Matthew C. |
collection | PubMed |
description | Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS. |
format | Text |
id | pubmed-2118613 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21186132007-12-13 Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains Pickering, Matthew C. de Jorge, Elena Goicoechea Martinez-Barricarte, Rubén Recalde, Sergio Garcia-Layana, Alfredo Rose, Kirsten L. Moss, Jill Walport, Mark J. Cook, H. Terence de Córdoba, Santiago Rodriguez Botto, Marina J Exp Med Brief Definitive Reports Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS. The Rockefeller University Press 2007-06-11 /pmc/articles/PMC2118613/ /pubmed/17517971 http://dx.doi.org/10.1084/jem.20070301 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Reports Pickering, Matthew C. de Jorge, Elena Goicoechea Martinez-Barricarte, Rubén Recalde, Sergio Garcia-Layana, Alfredo Rose, Kirsten L. Moss, Jill Walport, Mark J. Cook, H. Terence de Córdoba, Santiago Rodriguez Botto, Marina Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title | Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title_full | Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title_fullStr | Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title_full_unstemmed | Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title_short | Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains |
title_sort | spontaneous hemolytic uremic syndrome triggered by complement factor h lacking surface recognition domains |
topic | Brief Definitive Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118613/ https://www.ncbi.nlm.nih.gov/pubmed/17517971 http://dx.doi.org/10.1084/jem.20070301 |
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