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

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2837-2845 ◽  
Author(s):  
Lubka T. Roumenina ◽  
Mathieu Jablonski ◽  
Christophe Hue ◽  
Jacques Blouin ◽  
Jordan D. Dimitrov ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Umbilical Vein ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Immune Defense ◽  
Factor B ◽  
Uremic Syndrome ◽  
Complement Deposition

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.

scholarly journals Novel Complement Factor H mutation, a case report of atypical hemolytic uremic syndrome

2017 ◽  
Vol 4 (2) ◽  
pp. 13 ◽  
Author(s):  
Rodrigo Andrés Sepúlveda ◽  
Rodrigo Tagle ◽  
Aquiles Jara
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Severe Renal Failure ◽  
Uremic Syndrome ◽  
I Factor

 Atypical hemolytic uremic syndrome (aHUS) is a rare but catastrophic disease. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. When the aHUS is primary, the cause is due to mutations in proteins that regulate the alternative pathway of complement, such as Factor H, Factor I, Factor B, C3, Membrane Co-Factor Protein and Thrombomodulin. Usually primary aHUS is associated with other amplifiers complement factors. We present a case of aHUS in a 25-year-old female patient; she presented with malignant hypertension and severe renal failure. After a widespread study, the etiology of the aHUS was a mutation in the complement factor H, not previously described in the literature (p.Tyr1177His). After treatment with Eculizumab (C5 inhibitor monoclonal antibody), she recovered renal function with not hemodialysis requirements. 

scholarly journals Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

2007 ◽  
Vol 204 (6) ◽  
pp. 1249-1256 ◽  
Author(s):  
Matthew C. Pickering ◽  
Elena Goicoechea de Jorge ◽  
Rubén Martinez-Barricarte ◽  
Sergio Recalde ◽  
Alfredo Garcia-Layana ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Risk Haplotype ◽  
Complement Factor ◽  
Age Related ◽  
Uremic Syndrome

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

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

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4948-4952 ◽  
Author(s):  
Veronique Frémeaux-Bacchi ◽  
Elizabeth C. Miller ◽  
M. Kathryn Liszewski ◽  
Lisa Strain ◽  
Jacques Blouin ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement C3 ◽  
Central Component ◽  
Factor B ◽  
Factor I ◽  
Complement Dysregulation ◽  
Genes Encoding ◽  
Uremic Syndrome

Abstract Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

scholarly journals COVID-19: a trigger for severe thrombotic microangiopathy in a patient with complement gene variant

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Larisa Pinte ◽  
Bogdan Marian Sorohan ◽  
Zoltán Prohászka ◽  
Mihaela Gherghiceanu ◽  
Cristian Băicuş
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement C3 ◽  
Uncontrolled Hypertension ◽  
Complement Factor ◽  
Uremic Syndrome ◽  
Complement Gene

Abstract The evidence regarding thrombotic microangiopathy (TMA) related to Coronavirus Infectious Disease 2019 (COVID-19) in patients with complement gene mutations as a cause of acute kidney injury (AKI) are limited. We presented a case of a 23-year-old male patient admitted with an asymptomatic form of COVID-19, but with uncontrolled hypertension and AKI. Kidney biopsy showed severe lesions of TMA. In evolution patient had persistent microangiopathic hemolytic anemia, decreased level of haptoglobin and increased LDH level. Decreased complement C3 level and the presence of schistocytes were found for the first time after biopsy. Kidney function progressively decreased and the patient remained hemodialysis dependent. Complement work-up showed a heterozygous variant with unknown significance in complement factor I (CFI) c.-13G>A, affecting the 5' UTR region of the gene. In addition, the patient was found to be heterozygous for the complement factor H (CFH) H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q and E936D polymorphisms) reported as a risk factor of atypical hemolytic uremic syndrome. This case of AKI associated with severe TMA and secondary hemolytic uremic syndrome highlights the importance of genetic risk modifiers in the alternative pathway dysregulation of the complement in the setting of COVID-19, even in asymptomatic forms.

scholarly journals Atypical Hemolytic Uremic Syndrome after ChAdOx1 nCoV-19 Vaccination in a Patient with Homozygous CFHR3/CFHR1 Gene Deletion

Nephron ◽  
2021 ◽  
pp. 1-5
Author(s):  
Francisco Ferrer ◽  
Marisa Roldão ◽  
Cátia Figueiredo ◽  
Karina Lopes
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Time Lapse ◽  
Normal Activity ◽  
Factor H ◽  
Complement Alternative Pathway ◽  
Uremic Syndrome

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) affecting the kidneys. Compared with typical HUS due to an infection from shiga toxin-producing <i>Escherichia coli</i>, atypical HUS involves a genetic or acquired dysregulation of the complement alternative pathway. In the presence of a mutation in a complement gene, a second trigger is often necessary for the development of the disease. We report a case of a 54-year-old female, with a past medical history of pulmonary tuberculosis, who was admitted to the emergency service with general malaise and reduction in urine output, 5 days after vaccination with ChAdOx1 nCoV-19. Laboratory results revealed microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of TMA, plasma exchange (PEX) was immediately started, along with hemodialysis. Complementary laboratory workup for TMA excluded thrombotic thrombocytopenic purpura and secondary causes. Complement study revealed normal levels of factors H, B, and I, normal activity of the alternate pathway, and absence of anti-factor H antibodies. Genetic study of complement did not show pathogenic variants in the 12 genes analyzed, but revealed a deletion in gene CFHR3/CFHR1 in homozygosity. Our patient completed 10 sessions of PEX, followed by eculizumab, with both clinical and laboratorial improvement. Actually, given the short time lapse between vaccination with ChAdOx1 nCoV-19 and the clinical manifestations, we believe that vaccine was the trigger for the presentation of aHUS in this particular case.

scholarly journals Disturbed sialic acid recognition on endothelial cells and platelets in complement attack causes atypical hemolytic uremic syndrome

Blood ◽  
2016 ◽  
Vol 127 (22) ◽  
pp. 2701-2710 ◽  
Author(s):  
Satu Hyvärinen ◽  
Seppo Meri ◽  
T. Sakari Jokiranta
Keyword(s):  
Endothelial Cells ◽  
Sialic Acid ◽  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Sialic Acids ◽  
Factor H ◽  
Complement Regulation ◽  
Impaired Ability ◽  
Key Points ◽  
Uremic Syndrome

Key Points Sialic acids are critical for factor H–mediated complement regulation on endothelial cells, erythrocytes, and platelets. Impaired ability of factor H mutants to simultaneously bind sialic acid and C3b on cells explains their association with aHUS.

scholarly journals Anti-Factor H Antibodies in Egyptian Children with Hemolytic Uremic Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Shereen Shawky ◽  
Hesham Safouh ◽  
Mona Gamal ◽  
Mohammed M. Abbas ◽  
Azza Aboul-Enein ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
High Frequency ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Disease Onset ◽  
Factor H ◽  
Enzyme Linked Immunosorbent Assay ◽  
Complement Factor ◽  
Egyptian Children ◽  
Uremic Syndrome

Background. Atypical hemolytic uremic syndrome (aHUS) is an important cause of acute kidney injury in children. It is primarily caused by dysregulation of the complement alternative pathway due to genetic mutations, mainly in complement factor H genes, or due to anti-factor H autoantibodies (anti-FH), leading to uncontrolled overactivation of the complement system. Early diagnosis and treatment of autoimmune HUS (AI-HUS) is essential and leads to a favorable outcome. Methods. Fifty pediatric HUS patients and 50 age- and sex-matched controls were included in the study. Patients were subjected to full history taking, clinical examination, and laboratory testing. All candidates were subjected to an assessment of anti-FH in serum by a homemade enzyme-linked immunosorbent assay technique. Results. A high frequency of serum anti-FH was detected in our aHUS patients. The disease onset of AI-HUS was mainly observed in March and April, with significantly higher rates in school-aged males. All patients who started immunosuppressives early together with plasmapheresis upon detection of their anti-FH had complete renal function recovery. Conclusion. The high frequency of AI-HUS revealed in Egyptian HUS children in our study highlights the importance of implementing anti-FH testing in Egypt to provide early recognition for immediate proper management, including early immunosuppressive therapy, and hence improving patient outcomes.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Sigridur Sunna Aradottir ◽  
Ann-Charlotte Kristoffersson ◽  
Lubka T. Roumenina ◽  
Anna Bjerre ◽  
Pavlos Kashioulis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Complement Activation ◽  
Membranoproliferative Glomerulonephritis ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Complement Factor ◽  
Gain Of Function ◽  
Factor B ◽  
Glomerular Endothelial Cells ◽  
Uremic Syndrome

Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.

scholarly journals Unravelling the effect of a potentiating anti-Factor H antibody on atypical hemolytic uremic syndrome associated factor H variants

2020 ◽  
Author(s):  
Gillian Dekkers ◽  
Mieke Brouwer ◽  
Jorn Jeremiasse ◽  
Angela Kamp ◽  
Robyn M. Biggs ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Complement System ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Regulatory Function ◽  
Age Related ◽  
Uremic Syndrome ◽  
The Complement System

AbstractThe complement system plays an important role in our innate immune system. Complement activation results in clearance of pathogens, immune complex and apoptotic cells. The host is protected from complement-mediated damage by several complement regulators. Factor H (FH) is the most important fluid-phase regulator of the alternative pathway of the complement system. Heterozygous mutations in FH are associated with complement-related diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.We recently described an agonistic anti-FH monoclonal antibody that can potentiate the regulatory function of FH. This antibody could serve as a potential new drug for aHUS patients and alternative to C5 blockade by Eculizumab. However, it is unclear whether this antibody can potentiate FH mutant variants in addition to wild type FH. Here, the functionality and potential of the agonistic antibody in the context of pathogenic aHUS-related FH mutant proteins was investigated. The binding affinity of recombinant WT FH, and the FH variants, W1183L, V1197A, R1210C, and G1194D to C3b was increased upon addition of the potentiating antibody and similarly, the decay accelerating activity of all mutants is increased. The potentiating anti-FH antibody is able to restore the surface regulatory function of most of the tested FH mutants to WT FH levels. In conclusion, our potentiating anti-FH is broadly active and able to enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.

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