scholarly journals Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

2011 ◽  
Vol 188 (1) ◽  
pp. 426-435 ◽  
Author(s):  
Karita Haapasalo ◽  
Jaana Vuopio ◽  
Jaana Syrjänen ◽  
Jari Suvilehto ◽  
Satu Massinen ◽  
...  
Keyword(s):  
Genetic Association ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
In Vitro Survival

Differential modulation of complement factor H and C3 expression by TNF-α in the rat. In vitro and in vivo studies

1992 ◽  
Vol 29 (7-8) ◽  
pp. 983-988 ◽  
Author(s):  
Nathalie Julen ◽  
Christian Davrinche ◽  
Denyse Ozanne ◽  
Jean-Pierre Lebreton ◽  
Marc Fontaine ◽  
...  
Keyword(s):  
Factor H ◽  
Complement Factor H ◽  
In Vivo Studies ◽  
Complement Factor ◽  
Differential Modulation ◽  
Tnf Α

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 Complement Factor H Is a Serum-binding Protein for Adrenomedullin, and the Resulting Complex Modulates the Bioactivities of Both Partners

2000 ◽  
Vol 276 (15) ◽  
pp. 12292-12300 ◽  
Author(s):  
Rubén Pı́o ◽  
Alfredo Martı́nez ◽  
Edward J. Unsworth ◽  
Jeffrey A. Kowalak ◽  
José A. Bengoechea ◽  
...  
Keyword(s):  
Binding Protein ◽  
Polyacrylamide Gel Electrophoresis ◽  
Cancer Cell Line ◽  
Factor H ◽  
Complement Factor H ◽  
Regulatory Function ◽  
Complement Factor ◽  
Routine Procedure ◽  
Serum Binding Protein

Adrenomedullin (AM) is an important regulatory peptide involved in both physiological and pathological states. We have previously demonstrated the existence of a specific AM-binding protein (AMBP-1) in human plasma. In the present study, we developed a nonradioactive ligand blotting assay, which, together with high pressure liquid chromatography/SDS-polyacrylamide gel electrophoresis purification techniques, allowed us to isolate AMBP-1 to homogeneity. The purified protein was identified as human complement factor H. We show that AM/factor H interaction interferes with the established methodology for quantification of circulating AM. Our data suggest that this routine procedure does not take into account the AM bound to its binding protein. In addition, we show that factor H affects AMin vitrofunctions. It enhances AM-mediated induction of cAMP in fibroblasts, augments the AM-mediated growth of a cancer cell line, and suppresses the bactericidal capability of AM onEscherichia coli. Reciprocally, AM influences the complement regulatory function of factor H by enhancing the cleavage of C3b via factor I. In summary, we report on a potentially new regulatory mechanism of AM biology, the influence of factor H on radioimmunoassay quantification of AM, and the possible involvement of AM as a regulator of the complement cascade.

Platelet-associated complement factor H in healthy persons and patients with atypical HUS

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4538-4545 ◽  
Author(s):  
Christoph Licht ◽  
Fred G. Pluthero ◽  
Ling Li ◽  
Hilary Christensen ◽  
Sandra Habbig ◽  
...  
Keyword(s):  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Laser Fluorescence ◽  
Complement Factor H ◽  
Complement Factor ◽  
Platelet Response ◽  
Dense Granules ◽  
Fluorescence Confocal Microscopy

Abstract Atypical hemolytic uremic syndrome (aHUS) is associated with complement system dysregulation, and more than 25% of pediatric aHUS cases are linked to mutations in complement factor H (CFH) or CFH autoantibodies. The observation of thrombocytopenia and platelet-rich thrombi in the glomerular microvasculature indicates that platelets are intimately involved in aHUS pathogenesis. It has been reported that a releasable pool of platelet CFH originates from α-granules. We observed that platelet CFH can arise from endogenous synthesis in megakaryocytes and that platelets constitutively lacking α-granules contain CFH. Electron and high-resolution laser fluorescence confocal microscopy revealed that CFH was present throughout the cytoplasm and on the surface of normal resting platelets with no evident concentration in α-granules, lysosomes, or dense granules. Therapeutic plasma transfusion in a CFH-null aHUS patient revealed that circulating platelets take up CFH with similar persistence of CFH in platelets and plasma in vivo. Washed normal platelets were also observed to take up labeled CFH in vitro. Exposure of washed normal platelets to plasma of an aHUS patient with CFH autoantibodies produced partial platelet aggregation or agglutination, which was prevented by preincubation of platelets with purified CFH. This CFH-dependent response did not involve P-selectin mobilization, indicating a complement-induced platelet response distinct from α-granule secretion.

scholarly journals Binding of Complement Factor H (fH) to Neisseria meningitidis Is Specific for Human fH and Inhibits Complement Activation by Rat and Rabbit Sera

2008 ◽  
Vol 77 (2) ◽  
pp. 764-769 ◽  
Author(s):  
Dan M. Granoff ◽  
Jo Anne Welsch ◽  
Sanjay Ram
Keyword(s):  
Neisseria Meningitidis ◽  
Complement Activation ◽  
Geometric Mean ◽  
Factor H ◽  
Species Specificity ◽  
Complement Factor H ◽  
Complement Factor ◽  
Bacterial Surface

ABSTRACT Complement factor H (fH), a molecule that downregulates complement activation, binds to Neisseria meningitidis and increases resistance to serum bactericidal activity. We investigated the species specificity of fH binding and the effect of human fH on downregulating rat (relevant for animal models) and rabbit (relevant for vaccine evaluation) complement activation. Binding to N. meningitidis was specific for human fH (low for chimpanzee fH and not detected with fH from lower primates). The addition of human fH decreased rat and rabbit C3 deposition on the bacterial surface and decreased group C bactericidal titers measured with rabbit complement 10- to 60-fold in heat-inactivated sera from human vaccinees. Administration of human fH to infant rats challenged with group B strain H44/76 resulted in an fH dose-dependent increase in CFU/ml of bacteria in blood 8 h later (P < 0.02). At the highest fH dose, 50 μg/rat, the geometric mean number of CFU per ml was higher than that in control animals (1,050 versus 43 [P < 0.005]). The data underscore the importance of binding of human fH for survival of N. meningitidis in vitro and in vivo. The species specificity of binding of human fH adds another mechanism toward our understanding of why N. meningitidis is strictly a human pathogen.

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