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Article
Nature Medicine 14, 1088 - 1096 (2008)
Published online: 5 October 2008 | doi:10.1038/nm.1874
Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis
Renate Kain1, Markus Exner2, Ricarda Brandes1, Reinhard Ziebermayr1,7, Dawn Cunningham3, Carol A Alderson3, Agnes Davidovits1, Ingrid Raab1, Renate Jahn1,7, Oliver Ashour1, Susanne Spitzauer2, Gere Sunder-Plassmann4, Minoru Fukuda5, Per Klemm6, Andrew J Rees1,3,8 & Dontscho Kerjaschki1,8
Abstract
Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P41–49) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.
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