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Nat Med. 2008 Oct;14(10):1088-96. doi: 10.1038/nm.1874. Epub 2008 Oct 5.

Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.

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  • 1Department of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria. renate.kain@meduniwien.ac.at

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 P(41-49)) 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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PMID:
18836458
[PubMed - indexed for MEDLINE]
PMCID:
PMC2751601
Free PMC Article

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