Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis

R. Kain, M. Exner, R. Brandes, R. Ziebermayr, D. Cunningham, C.A. Alderson, A. Davidovits, I. Raab, R. Jahn, O. Ashour, S. Spitzauer, G. Sunder-Plassmann, M. Fukuda, Per Klemm, A.J. Rees, D. Kerjaschki

    Research output: Contribution to journalJournal articleResearchpeer-review

    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 Ill 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.
    Original languageEnglish
    JournalNature Medicine
    Volume14
    Issue number10
    Pages (from-to)1088-1096
    ISSN1078-8956
    DOIs
    Publication statusPublished - 2008

    Fingerprint Dive into the research topics of 'Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis'. Together they form a unique fingerprint.

    Cite this