Transglutaminase is essential for IgA nephropathy development acting through IgA receptors
Open Access
- 26 March 2012
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (4), 793-806
- https://doi.org/10.1084/jem.20112005
Abstract
IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA–soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1–sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89–TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1–sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1–sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.Keywords
This publication has 44 references indexed in Scilit:
- Premature replacement of μ with α immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturationProceedings of the National Academy of Sciences of the United States of America, 2010
- Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneityJCI Insight, 2009
- Tissue Transglutaminase Contributes to Interstitial Renal Fibrosis by Favoring Accumulation of Fibrillar Collagen through TGF-β Activation and Cell InfiltrationThe American Journal of Pathology, 2008
- Iron Homeostasis: Fitting the Puzzle Pieces TogetherCell Metabolism, 2008
- The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin ExpressionCell Metabolism, 2008
- IgA Glycosylation and IgA Immune Complexes in the Pathogenesis of IgA NephropathySeminars in Nephrology, 2008
- Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac diseaseThe Journal of Experimental Medicine, 2007
- Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenavirusesNature, 2007
- Involvement of Transglutaminase-2 in Pathological Changes in Renal DiseaseNephron Clinical Practice, 2007
- Transglutaminases: crosslinking enzymes with pleiotropic functionsNature Reviews Molecular Cell Biology, 2003