[en] Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n = 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 in the serum. Our biolayer interferometry, yeast two-hybrid and in silico modeling data allowed us to determine that Gp96 binds to a complement C3 fragment encompassing amino acids 749-954, a functional complement C3 hot spot important for binding of different regulators. Accordingly, in vitro experiments with purified proteins demonstrate that Gp96 downregulates several complement C3 functions. Finally, experimental induction of GvHD in complement C3-deficient mice confirms the link between Gp96 and complement C3 in the serum and with the severity of the disease.
Disciplines :
Hematology
Author, co-author :
Seignez, Antoine; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France. ; CHU, Dijon, France.
Joly, Anne-Laure; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Chaumonnot, Killian; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Hazoumé, Adonis; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Sanka, Michel; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Marcion, Guillaume ; Université de Liège - ULiège > GIGA > GIGA I3 - Hematology ; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Boudesco, Christophe; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Hammann, Arlette; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Seigneuric, Renaud; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Jégo, Gaetan; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
Ducoroy, Patrick; Proteomic platform CLIPP, Université de Bourgogne Franche-Comté, Dijon, France.
Delarue, Patrice; UMR 6303 CNRS Institut Carnot, Université de Bourgogne Franche-Comté, Dijon,
Senet, Patrick; UMR 6303 CNRS Institut Carnot, Université de Bourgogne Franche-Comté, Dijon,
Castilla-Llorente, Cristina; Institute Gustave Roussy, Université Paris-Sud 11, Villejuif, France.
Solary, Eric; Institute Gustave Roussy, Université Paris-Sud 11, Villejuif, France. ; INSERM UMR1009, Institute Gustave Roussy, Villejuif, France.
Durey, Marie-Agnès; Immunology Department, Hôpital Européen Georges Pompidou, Assistance
Rubio, Marie-Thérèse; Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint-Antoine, Assistance ; INSERM UMR 938, Université Pierre et Marie Curie, Paris, France.
Hermine, Olivier; Institut Imagine, UMR 8147, Université Paris Descartes, Sorbonne Paris-Cité, ; Laboratoire d'Excellence des Globules Rouges (GR-ex), Paris, France.
Kohli, Evelyne; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France. ; CHU, Dijon, France.
Garrido, Carmen; INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and ; Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France. ; Anticancer Centre Georges-François Leclerc, Dijon, France.
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