TY - JOUR
T1 - Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome
AU - Roumenina, LT
AU - Jablonski, M
AU - Hue, C
AU - Blouin, J
AU - Dimitrov, JD
AU - Dragon-Durey, MA
AU - Cayla, M
AU - Fridman, WH
AU - Macher, MA
AU - Ribes, D
AU - Moulonquet, L
AU - Rostaing, L
AU - Satchell, SC
AU - Mathieson, PW
AU - Sautes-Fridman, C
AU - Loirat, C
AU - Regnier, CH
AU - Halbwachs-Mecarelli, L
AU - Fremeaux-Bacchi, V
PY - 2009/9/24
Y1 - 2009/9/24
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 (D(254)G and K(325)N) 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.
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 (D(254)G and K(325)N) 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.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-70350475255&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-01-197640
DO - 10.1182/blood-2009-01-197640
M3 - Article (Academic Journal)
C2 - 19584399
SN - 0006-4971
VL - 114
SP - 2837
EP - 2845
JO - Blood
JF - Blood
IS - 13
ER -