scholarly journals New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
Elizabeth Rodriguez ◽  
Pavithra M. Rallapalli ◽  
Amy J. Osborne ◽  
Stephen J. Perkins
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
Membrane Cofactor Protein ◽  
Complement Alternative Pathway ◽  
Factor I ◽  
Mutational Hotspots ◽  
Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

scholarly journals An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy

2018 ◽  
Vol 29 (6) ◽  
pp. 1649-1661 ◽  
Author(s):  
Yi Yang ◽  
Harriet Denton ◽  
Owen R. Davies ◽  
Kate Smith-Jackson ◽  
Heather Kerr ◽  
...  
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Alternative Pathway ◽  
Treatment Options ◽  
Chinese Hamster ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
C3 Glomerulopathy

Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1–5 linked to repeats 18–20 (FH1–5^18–20), that was effective in experimental C3G. However, the serum t1/2 of FH1–5^18–20 was significantly shorter than that of serum-purified FH.Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1–2) at the carboxy or amino terminus of human FH1–5^18–20 to generate two homodimeric mini-FH constructs (FHR1–2^1–5^18–20 and FH1–5^18–20^R1–2, respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh−/− mice.Results FHR1–2^1–5^18–20 and FH1–5^18–20^R1–2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FHR1–2^1–5^18–20. Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH1–5^18–20. FH1–5^18–20^R1–2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH1–5^18–20, and significantly better retention in the kidney than FH or FH1–5^18–20.Conclusions FH1–5^18–20^R1–2 may have utility as a treatment option for C3G or other complement-mediated diseases.

scholarly journals Mutations in Complement Factor H Impair Alternative Pathway Regulation on Mouse Glomerular Endothelial Cellsin Vitro

2016 ◽  
Vol 291 (10) ◽  
pp. 4974-4981 ◽  
Author(s):  
Markus A. Loeven ◽  
Angelique L. Rops ◽  
Markus J. Lehtinen ◽  
Toin H. van Kuppevelt ◽  
Mohamed R. Daha ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Pathway Regulation

scholarly journals Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Neurology ◽  
2017 ◽  
Vol 90 (4) ◽  
pp. e332-e341 ◽  
Author(s):  
Mark McCormack ◽  
Hongsheng Gui ◽  
Andrés Ingason ◽  
Doug Speed ◽  
Galen E.B. Wright ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Alternative Pathway ◽  
Han Chinese ◽  
Factor H ◽  
Complement Factor H ◽  
Chinese Patients ◽  
Complement Factor ◽  
Genetic Associations ◽  
Genetic Predictors ◽  
Maculopapular Exanthema

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

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. 

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis

2020 ◽  
Author(s):  
Ying Zhang ◽  
Chaona Yang ◽  
Xinjin Zhou ◽  
Ruimin Hu ◽  
Songxia Quan ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor ◽  
Complement Alternative Pathway ◽  
Complement Components ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Urinary Levels ◽  
Normal Controls ◽  
Malignant Nephrosclerosis

Abstract Background Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Methods Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Results Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Conclusions Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.

scholarly journals Limited tryptic cleavage of complement factor H abrogates recognition of sialic acid-containing surfaces by the alternative pathway of complement

1992 ◽  
Vol 283 (2) ◽  
pp. 317-319 ◽  
Author(s):  
V Koistinen
Keyword(s):  
Sialic Acid ◽  
Cleavage Site ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Complement Protein ◽  
Sheep Erythrocytes ◽  
Tryptic Cleavage ◽  
N Terminus

The potency of complement factor H (H) in accelerating the decay of the alternative pathway C3 convertase, C3b,Bb (decay-accelerating activity), was used as a measure of the affinity of native versus trypsin-treated H for the complement protein C3b bound to surfaces. When about 99% of H was cleaved at the primary tryptic cleavage site 34 kDa from the N-terminus, its decay-accelerating activity on C3b,Bb on sheep erythrocytes fell about 60-fold, whereas the trypsin-treated H was only 3-4 times less potent than native H in dissociating C3b,Bb on Sepharose 4B. The residual decay-accelerating activity, remaining after the primary cleavage, was not affected by secondary cleavage at a site 120 kDa from the N-terminus, as shown with H preparations cleaved to different degrees. Because cell surface sialic acid is known to be responsible for the high affinity of H for C3b bound on sheep erythrocytes, the results strongly suggest that the integrity of the primary tryptic cleavage site of H is essential for the recognition of sialic acid-containing surfaces by the C3b-H complex.

scholarly journals Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H

2020 ◽  
Vol 11 ◽  
Author(s):  
Anne K. Mühlig ◽  
Lindsay S. Keir ◽  
Jana C. Abt ◽  
Hannah S. Heidelbach ◽  
Rachel Horton ◽  
...  
Keyword(s):  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor

scholarly journals Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase.

2017 ◽  
Vol 292 (15) ◽  
pp. 6094-6094
Author(s):  
Serena Bettoni ◽  
Elena Bresin ◽  
Giuseppe Remuzzi ◽  
Marina Noris ◽  
Roberta Donadelli
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor

scholarly journals Complement factor H and susceptibility to major depressive disorder in Han Chinese

2016 ◽  
Vol 208 (5) ◽  
pp. 446-452 ◽  
Author(s):  
Chen Zhang ◽  
Deng-Feng Zhang ◽  
Zhi-Guo Wu ◽  
Dai-Hui Peng ◽  
Jun Chen ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Alternative Pathway ◽  
Age At Onset ◽  
Han Chinese ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Mrna Levels ◽  
Major Depressive

BackgroundAccumulating evidence suggests that altered immunity contributes to the development of major depressive disorder (MDD).AimsTo examine whether complement factor H (CFH), a regulator of activation of the alternative pathway of the complement cascade, confers susceptibility to MDD.MethodExpression analyses were tested in 53 unmedicated people with MDD and 55 healthy controls. A two-stage genetic association analysis was performed in 3323 Han Chinese with or without MDD. Potential associations between CFH single nucleotide polymorphisms and age at MDD onset were evaluated.ResultsCFH levels were significantly lower in the MDD group at both protein and mRNA levels (P = 0.009 and P = 0.014 respectively). A regulatory variant in the CFH gene, rs1061170, showed statistically significant genotypic and allelic differences between the MDD and control groups (genotypic P = 0.0005, allelic P = 0.0001). Kaplan–Meier survival analysis showed that age at onset of MDD was significantly associated with the C allele of rs1061170 (log rank statistic χ2 = 6.82, P = 0.009). The C-allele carriers had a younger age at onset of MDD (22.2 years, s.d. = 4.0) than those without the C allele (23.6 years, s.d. = 4.3).ConclusionsCFH is likely to play an important role in the development of MDD. rs1061170 has an important effect on age at onset of MDD in Han Chinese and may therefore be related to early pathogenesis of MDD, although further study is needed.

Sign in / Sign up

Export Citation Format

Share Document