Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome

Lubka T. Roumenina; Mathieu Jablonski; Christophe Hue; Jacques Blouin; Jordan D. Dimitrov; Marie Agnes Dragon-Durey; Mathieu Cayla; Wolf H. Fridman; Marie Alice Macher; David Ribes; Luc Moulonguet; Lionel Rostaing; Simon C. Satchell; Peter W. Mathieson; Catherine Sautes-Fridman; Chantal Loirat; Catherine H. Regnier; Lise Halbwachs-Mecarelli; Veronique Fremeaux-Bacchi

doi:10.1182/blood-2009-01-197640

Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome

Lubka T. Roumenina, Mathieu Jablonski, Christophe Hue, Jacques Blouin, Jordan D. Dimitrov, Marie Agnes Dragon-Durey, Mathieu Cayla, Wolf H. Fridman, Marie Alice Macher, David Ribes, Luc Moulonguet, Lionel Rostaing, Simon C. Satchell, Peter W. Mathieson, Catherine Sautes-Fridman, Chantal Loirat, Catherine H. Regnier, Lise Halbwachs-Mecarelli, Veronique Fremeaux-Bacchi

Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase. © 2009 by The American Society of Hematology.

Original language	Undefined/Unknown
Pages (from-to)	2837-2845
Number of pages	9
Journal	Blood
Volume	114
Issue number	13
DOIs	https://doi.org/10.1182/blood-2009-01-197640
Publication status	Published - 1 Sept 2009

Bibliographical note

Publisher: American Society of Hematology

Keywords

atypical hemolytic-uremic syndrome
complement factor h
complement system proteins
endothelial cells
follicular bronchiolitis
mutation

Access to Document

10.1182/blood-2009-01-197640

Cite this

Roumenina, L. T., Jablonski, M., Hue, C., Blouin, J., Dimitrov, J. D., Dragon-Durey, M. A., Cayla, M., Fridman, W. H., Macher, M. A., Ribes, D., Moulonguet, L., Rostaing, L., Satchell, S. C., Mathieson, P. W., Sautes-Fridman, C., Loirat, C., Regnier, C. H., Halbwachs-Mecarelli, L., & Fremeaux-Bacchi, V. (2009). Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood, 114(13), 2837-2845. https://doi.org/10.1182/blood-2009-01-197640

@article{78a543ce47cc4be08c363ff275f3d795,

title = "Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome",

abstract = "Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase. {\textcopyright} 2009 by The American Society of Hematology.",

keywords = "atypical hemolytic-uremic syndrome, complement factor h, complement system proteins, endothelial cells, follicular bronchiolitis, mutation",

author = "Roumenina, {Lubka T.} and Mathieu Jablonski and Christophe Hue and Jacques Blouin and Dimitrov, {Jordan D.} and Dragon-Durey, {Marie Agnes} and Mathieu Cayla and Fridman, {Wolf H.} and Macher, {Marie Alice} and David Ribes and Luc Moulonguet and Lionel Rostaing and Satchell, {Simon C.} and Mathieson, {Peter W.} and Catherine Sautes-Fridman and Chantal Loirat and Regnier, {Catherine H.} and Lise Halbwachs-Mecarelli and Veronique Fremeaux-Bacchi",

note = "Publisher: American Society of Hematology",

year = "2009",

month = sep,

day = "1",

doi = "10.1182/blood-2009-01-197640",

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Roumenina, LT, Jablonski, M, Hue, C, Blouin, J, Dimitrov, JD, Dragon-Durey, MA, Cayla, M, Fridman, WH, Macher, MA, Ribes, D, Moulonguet, L, Rostaing, L, Satchell, SC, Mathieson, PW, Sautes-Fridman, C, Loirat, C, Regnier, CH, Halbwachs-Mecarelli, L & Fremeaux-Bacchi, V 2009, 'Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome', Blood, vol. 114, no. 13, pp. 2837-2845. https://doi.org/10.1182/blood-2009-01-197640

TY - JOUR

T1 - Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome

AU - Roumenina, Lubka T.

AU - Jablonski, Mathieu

AU - Hue, Christophe

AU - Blouin, Jacques

AU - Dimitrov, Jordan D.

AU - Dragon-Durey, Marie Agnes

AU - Cayla, Mathieu

AU - Fridman, Wolf H.

AU - Macher, Marie Alice

AU - Ribes, David

AU - Moulonguet, Luc

AU - Rostaing, Lionel

AU - Satchell, Simon C.

AU - Mathieson, Peter W.

AU - Sautes-Fridman, Catherine

AU - Loirat, Chantal

AU - Regnier, Catherine H.

AU - Halbwachs-Mecarelli, Lise

AU - Fremeaux-Bacchi, Veronique

N1 - Publisher: American Society of Hematology

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase. © 2009 by The American Society of Hematology.

AB - Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase. © 2009 by The American Society of Hematology.

KW - atypical hemolytic-uremic syndrome

KW - complement factor h

KW - complement system proteins

KW - endothelial cells

KW - follicular bronchiolitis

KW - mutation

U2 - 10.1182/blood-2009-01-197640

DO - 10.1182/blood-2009-01-197640

M3 - Article

SN - 0006-4971

VL - 114

SP - 2837

EP - 2845

JO - Blood

JF - Blood

IS - 13

ER -