Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.
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.
Kain
Renate
R
Department of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria. renate.kain@meduniwien.ac.at
Exner
Markus
M
Brandes
Ricarda
R
Ziebermayr
Reinhard
R
Cunningham
Dawn
D
Alderson
Carol A
CA
Davidovits
Agnes
A
Raab
Ingrid
I
Jahn
Renate
R
Ashour
Oliver
O
Spitzauer
Susanne
S
Sunder-Plassmann
Gere
G
Fukuda
Minoru
M
Klemm
Per
P
Rees
Andrew J
AJ
Kerjaschki
Dontscho
D
D018830:Adhesins, Escherichia coli / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000032:analysis; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D036781:Fimbriae Proteins / Q000276:immunology; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D009336:Necrosis; D018375:Neutrophil Activation; D051381:Rats; D011921:Rats, Inbred WKY
D018830:Adhesins, Escherichia coli; D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; C058769:fimH protein, E coli; D036781:Fimbriae Proteins