title: Genetically determined severity of anti-myeloperoxidase glomerulonephritis.
abstract: Myeloperoxidase (MPO) is a target antigen for antineutrophil cytoplasmic autoantibodies (ANCA). There is evidence that MPO-ANCA cause necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. NCGN severity varies among patients with ANCA disease, and genetic factors influence disease severity. The role of genetics in MPO-ANCA NCGN severity was investigated using 13 inbred mouse strains, F1 and F2 hybrids, bone marrow chimeras, and neutrophil function assays. Mouse strains include founders of the Collaborative Cross. Intravenous injection of anti-MPO IgG induced glomerular crescents in >60% of glomeruli in 129S6/SvEv and CAST/EiJ mice, but <1% in A/J, DBA/1J, DBA/2J, NOD/LtJ, and PWK/PhJ mice. C57BL6J, 129S1/SvImJ, LP/J, WSB/EiJ, NZO/HILtJ, and C3H mice had intermediate severity. High-density genotypes at 542,190 single nucleotide polymorphisms were used to identify candidate loci for disease severity by identifying genomic regions that are different between 129S6/SvEv and 129S1/SvImJ mice, which are genetically similar but phenotypically distinct. C57BL/6 × 129S6 F2 mice were genotyped at 76 SNPs to capture quantitative trait loci for disease severity. The absence of a dominant quantitative trait locus suggests that differences in severity are the result of multiple gene interactions. In vivo studies using bone marrow chimeric mice and in vitro studies of neutrophil activation by anti-MPO IgG indicated that severity of NCGN is mediated by genetically determined differences in the function of neutrophils.
authors: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: Hong
authors: H
authors: Xiao
authors: Dominic
authors: D
authors: Ciavatta
authors: David L
authors: DL
authors: Aylor
authors: Peiqi
authors: P
authors: Hu
authors: Fernando Pardo-Manuel
authors: FP
authors: de Villena
authors: Ronald J
authors: RJ
authors: Falk
authors: J Charles
authors: JC
authors: Jennette
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D001854:Bone Marrow Cells / Q000473:pathology; D002678:Chimera; D003433:Crosses, Genetic; D005260:Female; D008040:Genetic Linkage; D016678:Genome / Q000235:genetics; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018375:Neutrophil Activation / Q000235:genetics; D009195:Peroxidase / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D007074:Immunoglobulin G; D009195:Peroxidase
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