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Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis

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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Figure 1: Antibodies to human LAMP-2 (hLAMP-2) in pauci-immune FNGN.
Figure 2: Antibodies to hLAMP-2 activate neutrophils and kill human microvascular endothelium.
Figure 3: Autoantibodies to hLAMP-2 cross-react with the bacterial adhesin FimH.
Figure 4: Immunization with FimH induces antibodies to LAMP-2 and FNGN in rats.
Figure 5: Antibodies induced by FimH immunization bind human glomerular endothelium.

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Acknowledgements

This paper is dedicated to the memory of Fokko van der Woude. We thank A. Jungbauer (University of Agriculture and Forestry, Vienna) for synthetic peptides. We thank Kidney Research UK, who generously funded R.K.'s Senior Research Fellowship (KRUK SF3/2000-2005) at the University of Aberdeen and Scottish Hospitals Endowment Research Trust (RG15/02) for supporting parts of this project. A.R. is funded by an EU Marie Curie Excellence Chair (MEXC-CT-2006-042742). Parts of this work were funded by the Austrian Federal Ministry of Science and Research. M.F.'s research is supported by grant RO1CA48737. We are indebted to H. Schachner for technical assistance and to A. Jäger for his help in preparing the figures. We also would like to thank the many physicians who provided sera and subject details.

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Contributions

R.K.: design, execution, supervision and analysis of experiments, and manuscript writing. M.E.: development of human LAMP-2 ELISA and usage of SPOT assays. R.B.: cloning and generation of fusion proteins, western blots, human LAMP-2 and inhibition ELISA. R.Z.: collection and analysis of subject data. D.C.: in vivo experiments. C.A.L.: human LAMP-2 and inhibition ELISA of subject sera. A.D.: glycoepitope analysis. I.R.: experimental tissue culture work. R.J.: western blot analysis of antibody binding to bacterial proteins. O.A.: in vitro experiments with polymorphonuclear and endothelial cells. S.S.: myeloperoxidase and proteinase-3 ELISA. G.S.-P.: collection and analysis of subject data. M.F.: provision of human LAMP-2 complementary DNA constructs, antibodies and advice. P.K.: provision of FimH cDNA construct, antibodies and advice. A.J.R.: design and analysis of experiments and manuscript writing. D.K.: design and analysis of experiments and manuscript writing.

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Correspondence to Renate Kain.

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Kain, R., Exner, M., Brandes, R. et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 14, 1088–1096 (2008). https://doi.org/10.1038/nm.1874

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