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

  title={Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.},
  author={Lubka T. Roumenina and Mathieu Jablonski and Christophe Hue and Jacques Blouin and Jordan D. Dimitrov and Marie-Agn{\`e}s Dragon-Durey and Mathieu Cayla and Wolf Herman Fridman and Marie Alice Macher and David Ribes and Luc Moulonguet and Lionel Rostaing and Simon C. Satchell and Peter W. Mathieson and Catherine Saut{\`e}s-Fridman and Chantal Loirat and Catherine H. R{\'e}gnier and Lise Halbwachs‐Mecarelli and V{\'e}ronique Fr{\'e}meaux-Bacchi},
  volume={114 13},
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… 

Figures and Tables from this paper

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome.

Results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS.

Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1

The results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype, and indicate that the vulnerability of glomersular EC to hemolytic syndrome is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

Atypical Hemolytic Uremic Syndrome Formation of the C3 Convertase in Familial A Novel C3 Mutation Causing Increased

The C3 mutation found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis is presented, thus explaining enhanced activation of the alternative pathway of complement.

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome.

This study expands the knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity.

A Novel C3 Mutation Causing Increased Formation of the C3 Convertase in Familial Atypical Hemolytic Uremic Syndrome

This study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.

A Familial C3GN Secondary to Defective C3 Regulation by Complement Receptor 1 and Complement Factor H.

The results reveal that a CR1 functional deficiency is a mechanism of intraglomerular AP dysregulation and could influence the localization of the glomerular C3 deposits.

Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis

Results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.

Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign?

Functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association and suggests that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis.

A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function.

It is demonstrated that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.



Mutations of Factor H Impair Regulation of Surface-bound C3b by Three Mechanisms in Atypical Hemolytic Uremic Syndrome*

It is concluded that binding of FH19–20 to C3b/C3d is essential for target discrimination by the alternative pathway.

Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H-associated form

Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome

Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators.

Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome.

This study looked for IF mutations in a panel of 76 patients with HUS, finding two patients, both of whom had reduced serum IF levels and had a history of recurrent HUS after transplantation.

Complement regulatory genes and hemolytic uremic syndromes.

Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development, and Mutations of the activating components factor B and complement C3 have also been reported.

C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack*

During late apoptosis, cells acquire fluid phase complement inhibitors that compensate for the down-regulation of m-C-Reg and protect against excessive complement activation and lysis.

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.

9 novel C3 mutations are described in 14 aHUS patients with a persistently low serum C3 level and it is demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating, establishing C3 as a susceptibility factor for aH US.

Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions.

This study aimed to examine the functional effects of clinically reported mutations in these SCR structure and identified two types of residues: buried type B mutations seem to affect ligand interaction of factor H more severely than the surface-exposed mutations.