scholarly journals Heme Interacts with C1q and Inhibits the Classical Complement Pathway

2011 ◽  
Vol 286 (18) ◽  
pp. 16459-16469 ◽  
Author(s):  
Lubka T. Roumenina ◽  
Maria Radanova ◽  
Boris P. Atanasov ◽  
Krastio T. Popov ◽  
Srinivas V. Kaveri ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Negative Regulator ◽  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Reactive Protein ◽  
Free Heme ◽  
Direct Binding ◽  
Mechanism Of Recognition ◽  
The Complement System ◽  
Classical Complement

C1q is the recognition subunit of the first component of the classical complement pathway. It participates in clearance of immune complexes and apoptotic cells as well as in defense against pathogens. Inappropriate activation of the complement contributes to cellular and tissue damage in different pathologies, urging the need for the development of therapeutic agents that are able to inhibit the complement system. In this study, we report heme as an inhibitor of C1q. Exposure of C1q to heme significantly reduced the activation of the classical complement pathway, mediated by C-reactive protein (CRP) and IgG. Interaction analyses revealed that heme reduces the binding of C1q to CRP and IgG. Furthermore, we demonstrated that the inhibition of C1q interactions results from a direct binding of heme to C1q. Formation of complex of heme with C1q caused changes in the mechanism of recognition of IgG and CRP. Taken together, our data suggest that heme is a natural negative regulator of the classical complement pathway at the level of C1q. Heme may play a role at sites of excessive tissue damage and hemolysis where large amounts of free heme are released.

scholarly journals Comparison of Three Different Methods for Measuring Classical Pathway Complement Activity

1999 ◽  
Vol 6 (1) ◽  
pp. 137-139 ◽  
Author(s):  
Troy D. Jaskowski ◽  
Thomas B. Martins ◽  
Christine M. Litwin ◽  
Harry R. Hill
Keyword(s):  
Host Defense ◽  
Complement System ◽  
Functional Activity ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Complement Activity ◽  
Classical Complement Pathway ◽  
Inflammatory Processes ◽  
The Complement System ◽  
Classical Complement

ABSTRACT The complement system plays an important role in host defense against infection and in most inflammatory processes. The standard 50% hemolytic complement (CH50) assay is the most commonly used method of screening patient sera for functional activity of the classical complement pathway. Our objective in this study was to compare two newer methods (the enzyme immunoassay and the liposome immunoassay) to a commercial CH50 assay for measuring total classical complement activity. We conclude that both newer methods compare well with a CH50 assay and are equally sensitive in screening routine clinical sera.

scholarly journals Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Emil Gregersen ◽  
Cristine Betzer ◽  
Woojin S. Kim ◽  
Gergo Kovacs ◽  
Lasse Reimer ◽  
...  
Keyword(s):  
Complement System ◽  
Cell Model ◽  
Alpha Synuclein ◽  
Postmortem Brain ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Activation Assay ◽  
The Complement System ◽  
Classical Complement

Abstract Background Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer’s disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology. Methods To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients. Results We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls. Conclusion α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

scholarly journals Crystallization and preliminary crystallographic studies of the complement 1qA globular domain from zebrafish,Dare-C1qAgD

2014 ◽  
Vol 70 (7) ◽  
pp. 911-914 ◽  
Author(s):  
Hongyu Yuan ◽  
Rong Chen ◽  
Yanjie Liu ◽  
Mansoor Tariq ◽  
Yaping Sun ◽  
...  
Keyword(s):  
Structural Basis ◽  
Globular Domain ◽  
Immune Functions ◽  
Complement Pathway ◽  
Orthorhombic Space Group ◽  
Cell Parameters ◽  
Classical Complement Pathway ◽  
Reactive Protein ◽  
Antigen Antibody ◽  
Classical Complement

Complement 1q (C1q) is the first component of the complement system which can initiate the classical complement pathway. In human, C1q is composed of 18 polypeptide chains: six C1qA chains, six C1qB chains and six C1qC chains. Each chain has a signal peptide and is comprised of a collagen-like region and a C-terminal C1q globular domain (C1qgD), which is organized as a heterotrimer. C1qgD can recognize antigen–antibody complexes containing IgG and IgM or can bind directly to the C-reactive protein. Although the classical complement pathway is found from fish to mammals, only the human C1qgD structure has been determined. Compared with that of mammals, fish C1q exhibits similar immune functions and genome arrangement. In order to illustrate the structure of C1qgD in fish, zebrafish (Danio rerio) C1qA globular domain (Dare-C1qAgD) was expressed, purified and crystallized. X-ray diffraction data were collected from a crystal to a resolution of 2.05 Å; the crystal belonged to the orthorhombic space groupP212121, with unit-cell parametersa= 50.347,b= 85.059,c= 95.560 Å. It contained three molecules in the asymmetric unit. The Matthews coefficient valueVMwas 2.31 Å3 Da−1, with a calculated solvent content of 46.7%. The data will help to give insight into the structural basis of C1qA in fish species.

Heparin-protamine Complexes and C-reactive Protein Induce Activation of the Classical Complement Pathway: Studies in Patients Undergoing Cardiac Surgery and In Vitro

2000 ◽  
Vol 84 (08) ◽  
pp. 237-243 ◽  
Author(s):  
Henk Velthuis ◽  
Anke Eerenberg-Belmer ◽  
Aria Yazdanbakhsh ◽  
Eddy de Beaumont ◽  
León Eijsman ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Complement Activation ◽  
Complement Pathway ◽  
C Reactive Protein ◽  
Postoperative Arrhythmia ◽  
Classical Complement Pathway ◽  
Reactive Protein ◽  
Protamine Administration ◽  
Classical Complement

SummaryThe administration of protamine to patients undergoing cardiopulmonary bypass (CPB) to neutralize heparin and to reduce the risk of bleeding, induces activation of the classical complement pathway mainly by heparin-protamine complexes. We investigated whether C-reactive protein (CRP) contributes to protamine-induced complement activation.In 24 patients during myocardial revascularization, we measured complement, CRP, and complement-CRP complexes, reflecting CRPmediated complement activation in vivo. We also incubated plasma from healthy volunteers and patients with heparin and protamine in vitro to study CRP-mediated complement activation. During CPB, CRP levels remained unchanged while C3 activation products increased. C4 activation occurred after protamine administration. CRP-complement complexes increased at the end of CPB and upon protamine administration. Incubation of plasma with heparin and protamine in vitro generated complement-CRP complexes, which was blocked by phosphorylcholine and stimulated by exogenous CRP. C4d-CRP complex formation after protamine administration correlated clinically with the incidence of postoperative arrhythmia.Protamine administration during cardiac surgery induces complement activation which in part is CRP-dependent, and correlates with postoperative arrhythmia.

scholarly journals Schizophrenia: Complement Cleaning or Killing

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 259
Author(s):  
Jirrine T.T. Hogenaar ◽  
Hans van Bokhoven
Keyword(s):  
Complement System ◽  
Therapeutic Interventions ◽  
Complement Pathway ◽  
Complement Protein ◽  
Major Pathway ◽  
Classical Complement Pathway ◽  
Collective Data ◽  
The Individual ◽  
The Complement System ◽  
Classical Complement

Schizophrenia is a psychiatric disorder with a typical onset occurring during adolescence or young adulthood. The heterogeneity of the disorder complicates our understanding of the pathophysiology. Reduced cortical synaptic densities are commonly observed in schizophrenia and suggest a role for excessive synaptic elimination. A major pathway hypothesised to eliminate synapses during postnatal development is the complement system. This review provides an overview of genetic and functional evidence found for the individual players of the classical complement pathway. In addition, the consequences of the absence of complement proteins, in the form of complement protein deficiencies in humans, are taken into consideration. The collective data provide strong evidence for excessive pruning by the classical complement pathway, contributing to cognitive impairment in schizophrenia. In future studies, it will be important to assess the magnitude of the contribution of complement overactivity to the occurrence and prevalence of phenotypic features in schizophrenia. In addition, more insight is required for the exact mechanisms by which the complement system causes excessive pruning, such as the suggested involvement of microglial engulfment and degradation of synapses. Ultimately, this knowledge is a prerequisite for the development of therapeutic interventions for selective groups of schizophrenia patients.

scholarly journals Carbamylation of immunoglobulin abrogates activation of the classical complement pathway

2014 ◽  
Vol 44 (11) ◽  
pp. 3403-3412 ◽  
Author(s):  
Catalin Koro ◽  
Ewa Bielecka ◽  
Anders Dahl‐Knudsen ◽  
Jan J. Enghild ◽  
Carsten Scavenius ◽  
...  
Keyword(s):  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Classical Complement
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