scholarly journals Functional properties of membrane cofactor protein of complement

1989 ◽  
Vol 264 (2) ◽  
pp. 581-588 ◽  
Author(s):  
T Seya ◽  
J P Atkinson
Keyword(s):  
Complement System ◽  
Fluid Phase ◽  
Factor H ◽  
Classical Pathway ◽  
Membrane Cofactor Protein ◽  
Cleavage Reaction ◽  
Factor I ◽  
Thioester Bond ◽  
Cofactor Activity ◽  
The Complement System

Membrane cofactor protein (MCP or gp45-70) of the complement system is a cofactor for factor I-mediated cleavage of fluid-phase C3b and C3b-like C3, which opens the thioester bond. In the present study the activity of MCP was further characterized. Unexpectedly, in the absence of factor I, MCP stabilized the alternative- and, to a lesser extent, the classical-pathway cell-bound C3 convertases and thereby enhanced C3b deposition. Soluble MCP, if added exogenously, hardly functioned as cofactor for the cleavage of erythrocyte-bound C3b to iC3b; i.e. its activity, compared with the cofactor activity of factor H, was inefficient, since less than 10% of the bound C3b was MCP-sensitive. Further, exogenously added soluble MCP was also a weak cofactor for the cleavage of C3b bound to zymosan. Likewise, factor I, in the presence of cells bearing MCP, cleaved fluid-phase C3b inefficiently. These results imply that MCP has very little extrinsic cofactor activity for factor I. In contrast, exogenously added MCP and factor I mediated efficient cleavage of erythrocyte-bound C3b if the concentration of Nonidet P40 was sufficient to solubilize the cells. Interestingly, soluble MCP and factor I degraded C3b attached to certain solubilized acceptor membrane molecules more readily than others. The cleavage reaction of fluid-phase and cell-bound C3b by soluble MCP and factor I produced iC3b, but no C3c and C3dg. These and prior data indicate that soluble MCP has potent cofactor activity for fluid-phase C3b or C3b bound to solubilized molecules, but acts inefficiently towards C3b on other cells. This functional profile is unique for a C3b/C4b binding protein and, taken together with its wide tissue distribution, suggests an important role for MCP in the regulation of the complement system.

Inherited complement deficiencies

1984 ◽  
Vol 306 (1129) ◽  
pp. 419-430 ◽  
Keyword(s):  
Immune Complex ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Strong Association ◽  
Factor H ◽  
Complement Deficiency ◽  
Classical Pathway ◽  
The Complement System

Isolated genetic deficiencies of individual components of the complement system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases - especially systemic lupus erythematosus — was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

scholarly journals Hijacking Factor H for Complement Immune Evasion

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara R. Moore ◽  
Smrithi S. Menon ◽  
Claudio Cortes ◽  
Viviana P. Ferreira
Keyword(s):  
Host Cell ◽  
Complement System ◽  
Alternative Pathway ◽  
Expression Patterns ◽  
Fluid Phase ◽  
Factor H ◽  
Host Cells ◽  
Complement C3 ◽  
Complement Regulators ◽  
The Complement System

The complement system is an essential player in innate and adaptive immunity. It consists of three pathways (alternative, classical, and lectin) that initiate either spontaneously (alternative) or in response to danger (all pathways). Complement leads to numerous outcomes detrimental to invaders, including direct killing by formation of the pore-forming membrane attack complex, recruitment of immune cells to sites of invasion, facilitation of phagocytosis, and enhancement of cellular immune responses. Pathogens must overcome the complement system to survive in the host. A common strategy used by pathogens to evade complement is hijacking host complement regulators. Complement regulators prevent attack of host cells and include a collection of membrane-bound and fluid phase proteins. Factor H (FH), a fluid phase complement regulatory protein, controls the alternative pathway (AP) both in the fluid phase of the human body and on cell surfaces. In order to prevent complement activation and amplification on host cells and tissues, FH recognizes host cell-specific polyanionic markers in combination with complement C3 fragments. FH suppresses AP complement-mediated attack by accelerating decay of convertases and by helping to inactivate C3 fragments on host cells. Pathogens, most of which do not have polyanionic markers, are not recognized by FH. Numerous pathogens, including certain bacteria, viruses, protozoa, helminths, and fungi, can recruit FH to protect themselves against host-mediated complement attack, using either specific receptors and/or molecular mimicry to appear more like a host cell. This review will explore pathogen complement evasion mechanisms involving FH recruitment with an emphasis on: (a) characterizing the structural properties and expression patterns of pathogen FH binding proteins, as well as other strategies used by pathogens to capture FH; (b) classifying domains of FH important in pathogen interaction; and (c) discussing existing and potential treatment strategies that target FH interactions with pathogens. Overall, many pathogens use FH to avoid complement attack and appreciating the commonalities across these diverse microorganisms deepens the understanding of complement in microbiology.

Complement System in Healthy Term Newborns: Reference Values in Umbilical Cord Blood

1998 ◽  
Vol 1 (2) ◽  
pp. 131-135 ◽  
Author(s):  
J. Sonntag ◽  
U. Brandenburg ◽  
D. Polzehl ◽  
E. Strauss ◽  
M. Vogel ◽  
...  
Keyword(s):  
Cord Blood ◽  
Reference Values ◽  
Complement System ◽  
Alternative Pathway ◽  
Factor H ◽  
Reference Ranges ◽  
Complement Proteins ◽  
Factor I ◽  
Term Newborns ◽  
The Complement System

Activation of the complement system occurs in several diseases. For reliable identification of complement activation in neonates, we establish reference ranges of several components in cord blood of healthy term newborns. For this study cord blood samples were taken from 125 healthy term newborns. Concentrations of C1r, C2, C5, C7, Properdin, and factors D, H, and I were determined by single radial immunodiffusion. C3a and C5a were measured by specific EIA and complement function was measured by hemolytic assays. The results were expressed as 5th percentile, median, and 95th percentile. The following respective concentrations were found: C1r: 27, 47, 65 mg/l; C2: 12.0, 18.0, 24.0 mg/l; C5: 64, 92, 127 mg/l; C7: 32, 60, 89 mg/l; Properdin: 5.6, 9.7, 14.2 mg/l; factor D: 3.6, 5.2, 7.3 mg/l; factor H: 178, 234, 296 mg/l; and factor I: 15, 24, 32 mg/l. The functional activity of the whole complement system was 24%, 43%, 97% and for the alternative pathway 39%, 58%, 76%. The concentration of the activated split products C3a was 4, 65, 255 μg/l and of C5a, 0.11, 0.26, 1.19 μg/l. These reference values may be important for the detection of deficiencies of native complement proteins or perinatal processes leading to an activation of the complement system.

scholarly journals A Factor I-Like Activity Associated with Chikungunya Virus Contributes to Its Resistance to the Human Complement System

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Joydeep Nag ◽  
Reshma Koolaparambil Mukesh ◽  
Sreenath Muraleedharan Suma ◽  
Umerali Kunnakkadan ◽  
Nisha Asok Kumar ◽  
...  
Keyword(s):  
Disease Severity ◽  
Complement System ◽  
Chikungunya Virus ◽  
Factor H ◽  
Host Immune System ◽  
Dependent Manner ◽  
Human Complement ◽  
Chikv Infection ◽  
Factor I ◽  
The Complement System

ABSTRACT Chikungunya virus (CHIKV) is an emerging pathogen capable of causing explosive outbreaks. Prior studies showed that exacerbation in arthritogenic alphavirus-induced pathogenesis is attributed to its interaction with multiple immune components, including the complement system. Viremia concomitant to CHIKV infection makes exposure of the virus to complement unavoidable, yet very little is known about CHIKV-complement interactions. Here, we show that CHIKV activated serum complement to modest levels in a concentration- and time-dependent manner, but the virus effectively resisted complement-mediated neutralization. Heat-inactivated serum from seropositive donors could actively neutralize CHIKV due to the presence of potent anti-CHIKV antibodies. Deposition of key complement components C3 and C4 did not alter the resistance of CHIKV to complement. Further, we identified a factor I-like activity in CHIKV that limited complement by inactivating C3b into inactive C3b (iC3b), the complement component known to significantly contribute to disease severity in vivo, but this activity had no effect on C4b. Inactivation of C3b by CHIKV was largely dependent on the concentration of the soluble host cofactor factor H and the virus concentration. A factor I function-blocking antibody had only a negligible effect on the factor I-like activity associated with CHIKV, suggesting that this activity is independent of host factor I and could be of viral origin. Thus, our findings suggest a complement modulatory action of CHIKV which not only helps the virus to evade human complement but may also have implications in alphavirus-induced arthritogenic symptoms. IMPORTANCE Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated with chikungunya virus (CHIKV) infection, neurovirulence and adaptability to Aedes albopictus, necessitates a deeper understanding of the interaction of CHIKV with the host immune system. Here, we demonstrate that CHIKV is resistant to neutralization by one of the potent barriers of the innate immune arm, the complement system. Chikungunya virus showed marked resistance to complement despite activation and deposition of complement proteins. Interestingly the C3 component associated with the virion was found to be inactive C3b (iC3b), a key factor implicated in the pathogenesis and disease severity in the mouse model of Ross River virus infection. CHIKV also had an associated unique factor I-like activity that mediated the inactivation of C3b into iC3b. We have unraveled a smart strategy adopted by CHIKV to limit complement which has serious implications in viral dissemination, pathogenesis, and disease.

scholarly journals Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein.

1995 ◽  
Vol 181 (1) ◽  
pp. 151-159 ◽  
Author(s):  
Y U Kim ◽  
T Kinoshita ◽  
H Molina ◽  
D Hourcade ◽  
T Seya ◽  
...  
Keyword(s):  
Cell Surface ◽  
Measles Virus ◽  
Host Cells ◽  
Regulatory Proteins ◽  
Classical Pathway ◽  
Membrane Cofactor Protein ◽  
Decay Accelerating Factor ◽  
Complement Regulatory Proteins ◽  
Factor I ◽  
Cofactor Activity

Normal host cells are protected from the destructive action of complement by cell surface complement regulatory proteins. In humans, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) play such a biologic role by inhibiting C3 and C5 convertases. DAF and MCP accomplish this task by specific mechanisms designated decay-accelerating activity and factor I cofactor activity, respectively. In other species, including mice, structural and/or functional homologues of these proteins are not yet well characterized. Previous studies have shown that the mouse protein Crry/p65 has certain characteristics of self-protecting complement regulatory proteins. For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway. We have now studied factor I cofactor and decay-accelerating activities of Crry/p65. Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b. Surprisingly, Crry/p65 also exhibits decay-accelerating activity for the classical pathway C3 convertase strongly and for the alternative pathway C3 convertase weakly. Therefore, mouse Crry/p65 uses the specific mechanisms of both human MCP and DAF. Although Crry/p65, like MCP and DAF, contains tandem short consensus repeats (SCR) characteristic of C3/C4 binding proteins, Crry/p65 is not considered to be a genetic homologue of either MCP or DAF. Thus, Crry/p65 is an example of evolutionary conservation of two specific activities in a single unique protein in one species that are dispersed to individual proteins in another. We propose that the repeating SCR motif in this family has allowed this unusual process of evolution to occur, perhaps driven by the use of MCP and DAF as receptors by human pathogens such as the measles virus.

scholarly journals Profiling Complement System Components in Primary CNS Vasculitis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1139
Author(s):  
Milani Deb-Chatterji ◽  
Christian W. Keller ◽  
Simon Koch ◽  
Heinz Wiendl ◽  
Christian Gerloff ◽  
...  
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Factor H ◽  
Classical Pathway ◽  
Cns Vasculitis ◽  
Inflammatory Conditions ◽  
Csf Levels ◽  
General Activation ◽  
The Complement System ◽  
Multiplex System

Complement activation has been implicated in the pathogenesis of many vasculitic syndromes such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Using an array-based multiplex system, we simultaneously quantified serum and CSF levels of activated and regulatory complement system proteins in patients with primary CNS vasculitis (PACNS; n = 20) compared to patients with non-inflammatory conditions (n = 16). Compared to non-inflammatory controls, levels of C3a, C5a, and SC5b-9, indicative for general activation of the complement system, of C4a, specific for the activation of the classical pathway, Ba and Bb, reflective for alternative complement activation as well as concentrations of complement-inhibitory proteins factor H and factor I were unchanged in patients with PACNS. Our study does not support the hypothesis that complement activation is systemically increased in patients with PACNS.

scholarly journals Localization of the complement-component-C3b-binding site and the cofactor activity for factor I in the 38kDa tryptic fragment of factor H

1984 ◽  
Vol 224 (2) ◽  
pp. 389-398 ◽  
Author(s):  
J Alsenz ◽  
J D Lambris ◽  
T F Schulz ◽  
M P Dierich
Keyword(s):  
Binding Site ◽  
Gel Filtration ◽  
Fluid Phase ◽  
Factor H ◽  
Tryptic Fragment ◽  
Factor I ◽  
Close Proximity ◽  
Cofactor Activity ◽  
A Site ◽  
Sepharose 4B

Trypsin treatment of human factor H (H160) [enzyme/substrate ratio 1:100 (w/w), 30 min, 37 degrees C] generated a 38 kDa (H38) and a 142 kDa (H142) fragment linked by disulphide bonds (H38/142). The fragments were purified by reduction with 2-mercapto-ethanol, gel filtration on a Sephadex G-200 column and affinity chromatography with monoclonal anti-(factor H) antibody coupled to Sepharose 4B. This monoclonal antibody bound to a site in the 38 kDa fragment. To localize the C3b binding site in factor H we used two enzyme-linked immunosorbent assays (e.l.i.s.a.). For the first test, e.l.i.s.a. plates were coated with C3b; H160, H38/142, H38 and H142 were added, and their binding was monitored by goat anti-(factor H) and peroxidase-labelled rabbit anti-goat antibodies. Only intact factor H bound to the C3b-coated plates. For the second test, e.l.i.s.a. plates were coated with comparable amounts of factor H or its fragments, and C3b was offered at several dilutions. In contrast with the results from the first assay, C3b bound to intact factor H, H38/142 and H38 but not to H142, thus characterizing H38 as the fragment carrying the C3b-binding site. To identify the fragment responsible for the cofactor activity of factor H (cleavage of fluid-phase C3b by factor I), 125I-C3b was incubated with either H38 or H142 and factor I. H142 had no cofactor activity, whereas H38 had the same cofactor function as intact H. To further investigate the relationship between the C3b-binding site and the site of factor H essential for its cofactor activity, we made use of monoclonal antibodies directed against the H38. Those antibodies inhibiting the binding of C3b to H160 also inhibited the cofactor function, whereas those without effect on the C3b binding also did not interfere with the cofactor activity. This suggests that the C3b-binding site and the site essential for the cofactor activity of factor H are both localized in the 38 kDa tryptic fragment of factor H in close proximity or are identical.

scholarly journals Effect of sodium chloride concentration on fluid-phase assembly and stability of the C3 convertase of the classical pathway of the complement system

1990 ◽  
Vol 271 (3) ◽  
pp. 749-754 ◽  
Author(s):  
S Maeda ◽  
S Nagasawa
Keyword(s):  
Ionic Strength ◽  
Chloride Concentration ◽  
Fluid Phase ◽  
Classical Pathway ◽  
Factor I ◽  
Nacl Concentration ◽  
The Stability ◽  
Low Ionic Strength ◽  
The Complement System ◽  
Strength Medium

The assembly of the classical-pathway C3 convertase from C4 and I2-treated C2 by the action of C1s is an Mg2(+)-dependent reaction. The Mg2+ concentration necessary for the assembly of C3 convertase in the fluid phase was found to be dependent on NaCl concentration. In the absence of NaCl more than 5 mM-MgCl2 was found to be required, whereas 0.5 mM-MgCl2 was adequate for the assembly of C3 convertase in the presence of 150 mM-NaCl. The C3 convertase assembled in a low-ionic-strength buffer was extremely labile compared with that assembled in buffer of physiological ionic strength, and the stability of C3 convertase was improved with the increase in NaCl concentration. It was found that the stabilizing effect of NaCl on C3 convertase was due to inhibition of the dissociating activity of C2b, which was formed during the assembly of C3 convertase. In addition to the dissociation-accelerating effect, C2b inhibited the assembly of C3 convertase in low-ionic-strength buffer, and this effect also was diminished with increase in NaCl concentration. An increase in NaCl concentration to more than 200 mM resulted in a decrease in the assembly of C3 convertase. This effect was not due to the lability of the assembled C3 convertase but due rather to the inhibition of C2 cleavage by C1s. Purified C3 convertase itself is stable in dilute medium or high-ionic-strength medium such as 500 mM-NaCl, suggesting that the interactions between C4b and C2a are hydrophobic. In these respects C2b seemed to be functionally similar to C4bp, but C2b failed to act as a cofactor for the Factor I-catalysed C4b cleavage.

scholarly journals Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Amer Toutonji ◽  
Mamatha Mandava ◽  
Silvia Guglietta ◽  
Stephen Tomlinson
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Complement System ◽  
Classical Pathway ◽  
Post Injury ◽  
Complement Inhibition ◽  
Time Points ◽  
Complement Gene ◽  
The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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.

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