Transglutaminase is essential for IgA nephropathy development acting through IgA receptors

被引:152
作者
Berthelot, Laureline [1 ,2 ]
Papista, Christina [1 ,2 ]
Maciel, Thiago T. [1 ,2 ]
Biarnes-Pelicot, Martine [1 ,2 ]
Tissandie, Emilie [1 ,2 ]
Wang, Pamela H. M. [1 ,2 ]
Tamouza, Houda [1 ,2 ]
Jamin, Agnes [1 ,2 ]
Bex-Coudrat, Julie [1 ,2 ]
Gestin, Aurelie [1 ,2 ]
Boumediene, Ahmed [3 ]
Arcos-Fajardo, Michelle [1 ,2 ]
England, Patrick [4 ]
Pillebout, Evangeline [1 ,2 ,5 ]
Walker, Francine [6 ]
Daugas, Eric [1 ,2 ,7 ]
Vrtovsnik, Francois [1 ,2 ,7 ]
Flamant, Martin [1 ,2 ,8 ]
Benhamou, Marc [1 ,2 ]
Cogne, Michel [3 ]
Moura, Ivan C. [1 ,2 ]
Monteiro, Renato C. [1 ,2 ,9 ]
机构
[1] INSERM, UMR 699, F-75870 Paris, France
[2] Univ Paris Diderot, Fac Med, Lab Excellence Inflamex, F-75018 Paris, France
[3] Univ Limoges, CNRS, UMR 6101, F-87000 Limoges, France
[4] Inst Pasteur, F-75015 Paris, France
[5] Hop St Louis, Serv Nephrol, F-75010 Paris, France
[6] Hop Bichat Claude Bernard, Serv Anatomopathol, F-75870 Paris, France
[7] Hop Bichat Claude Bernard, Serv Nephrol, F-75870 Paris, France
[8] Hop Bichat Claude Bernard, Serv Physiol & Explorat Fonct Multidisciplinaire, F-75870 Paris, France
[9] Hop Bichat Claude Bernard, Serv Immunol, F-75870 Paris, France
关键词
FC-ALPHA RECEPTORS; TRANSFERRIN RECEPTOR; IMMUNE-COMPLEXES; TISSUE TRANSGLUTAMINASE; ENHANCED EXPRESSION; MONOCLONAL-ANTIBODY; GLYCOSYLATED IGA1; POLYMERIC IGA1; MESANGIAL IGA; RENAL-DISEASE;
D O I
10.1084/jem.20112005
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:793 / 806
页数:14
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