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Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

AutorPickering, Matthew C.; Goicoechea de Jorge, Elena ; Martínez-Barricarte, Rubén ; Recalde, Sergio; García-Layana, Alfredo; Rose, Kirsten L.; Moss, Jill; Walport, Mark J.; Cook, H. Terence; Rodríguez de Córdoba, Santiago ; Botto, Marina
Fecha de publicación11-jun-2007
EditorRockefeller University Press
CitaciónThe Journal of Experimental Medicine 2007 June 11; 204(6): 1249–1256
PMCID: 2118613
ResumenFactor 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.
DescripciónWe are grateful to all patients and the collaborating clinicians for their participation in this study. We thank Mr. Ian Shore for his technical assistance with the preparation of tissue for electron microscopy, Mrs. Margarita Lewis for technical assistance with the processing of histological specimens, and the staff of the Biological Services Unit at Imperial College for the care of the animals involved in this study. We also thank the members of the DNA sequencing laboratory at the Centro de Investigaciones Biologicas, as well as Dr. Elena Aller and Ms. Sheila Pinto for invaluable technical assistance with patient genotyping
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