Molecular Mimicry in Pauci-Immune Focal Necrotizing Glomerulonephritis

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adhesins, Escherichia coli / immunology
  • Amino Acid Sequence
  • Animals
  • Antibodies, Antineutrophil Cytoplasmic / analysis
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes
  • Fimbriae Proteins / immunology
  • Glomerulonephritis / etiology*
  • Glomerulonephritis / immunology
  • Gram-Negative Bacterial Infections
  • Humans
  • Immunization
  • Immunoglobulin G / immunology
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins / chemistry
  • Lysosome-Associated Membrane Glycoproteins / immunology*
  • Molecular Sequence Data
  • Necrosis
  • Neutrophil Activation
  • Rats
  • Rats, Inbred WKY

Substances

  • Adhesins, Escherichia coli
  • Antibodies, Antineutrophil Cytoplasmic
  • Autoantibodies
  • Epitopes
  • Immunoglobulin G
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • fimH protein, E coli
  • Fimbriae Proteins