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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...

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
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.
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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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