scholarly journals Venom fromBothrops lanceolatus, a Snake Species Native to Martinique, Potently Activates the Complement System

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Marie Delafontaine ◽  
Isadora Maria Villas-Boas ◽  
Giselle Pidde ◽  
Carmen W. van den Berg ◽  
Laurence Mathieu ◽  
...  
Keyword(s):  
Complement System ◽  
Biologically Active ◽  
Local Inflammation ◽  
Complement Inhibitors ◽  
Coagulation Proteins ◽  
Local Inflammatory Reaction ◽  
Activation Pathways ◽  
The Complement System ◽  
Soluble C

Bothrops lanceolatussnake venom causes systemic thrombotic syndrome but also local inflammation involving extensive oedema, pain, and haemorrhage. Systemic thrombotic syndrome may lead to fatal pulmonary embolism and myocardial and cerebral infarction. Here, we investigated the ability ofB. lanceolatusvenom to activate the Complement system (C) in order to improve the understanding of venom-induced local inflammation. Data presented show thatB. lanceolatusvenom is able to activate all C-pathways. In human serum, the venom strongly induced the generation of anaphylatoxins, such as C5a and C4a, and the Terminal Complement complex. The venom also induced cleavage of purified human components C3, C4, and C5, with the production of biologically active C5a. Furthermore, the venom enzymatically inactivated the soluble C-regulator and the C1-inhibitor (C1-INH), and significantly increased the expression of bound C-regulators, such as MCP and CD59, on the endothelial cell membrane. Our observations thatB. lanceolatusvenom activates the three Complement activation pathways, resulting in anaphylatoxins generation, may suggest that this could play an important role in local inflammatory reaction and systemic thrombosis caused by the venom. Inactivation of C1-INH, which is also an important inhibitor of several coagulation proteins, may also contribute to inflammation and thrombosis. Thus, furtherin vivostudies may support the idea that therapeutic management of systemicB. lanceolatusenvenomation could include the use of Complement inhibitors as adjunct therapy.

scholarly journals Structural basis for activation of the complement system by component C4 cleavage

2012 ◽  
Vol 109 (38) ◽  
pp. 15425-15430 ◽  
Author(s):  
Rune T. Kidmose ◽  
Nick S. Laursen ◽  
József Dobó ◽  
Troels R. Kjaer ◽  
Sofia Sirotkina ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Complement System ◽  
Serine Proteases ◽  
Structural Basis ◽  
Classical Pathway ◽  
Substrate Complex ◽  
Scissile Bond ◽  
Activation Pathways ◽  
The Complement System

An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.

scholarly journals Halting targeted and collateral damage to red blood cells by the complement system

2021 ◽  
Author(s):  
M. Jalink ◽  
E. C. W. de Boer ◽  
D. Evers ◽  
M. Q. Havinga ◽  
J. M. I. Vos ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Complement System ◽  
Blood Cells ◽  
Defense Mechanism ◽  
Standard Of Care ◽  
Complement Protein ◽  
Complement Inhibition ◽  
Complement Inhibitors ◽  
The Complement System ◽  
Patient Burden

AbstractThe complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

scholarly journals Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽  
2021 ◽  
Author(s):  
Anna K. Dreismann ◽  
Michelle E. McClements ◽  
Alun R. Barnard ◽  
Elise Orhan ◽  
Jane P. Hughes ◽  
...  
Keyword(s):  
Complement System ◽  
Functional Expression ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related ◽  
The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).

Interaction with complement proteins and dendritic cells implicates LCCL domain-containing proteins (CCps) of malaria parasites in immunomodulation

2018 ◽  
Vol 475 (21) ◽  
pp. 3311-3314 ◽  
Author(s):  
Puran Singh Sijwali
Keyword(s):  
Dendritic Cells ◽  
Complement System ◽  
Protein Complexes ◽  
Immune Defense ◽  
Malaria Parasites ◽  
Classical Complement Pathway ◽  
Soluble Immune Complexes ◽  
Multimeric Protein ◽  
The Complement System

The evasion of host immune defense is critical for pathogens to invade, establish infection and perpetuate in the host. The complement system is one of the first lines of innate immune defense in humans that destroys pathogens in the blood circulation. Activation of the complement system through direct encounter with pathogens or some other agents leads to osmolysis of pathogens, clearance of soluble immune complexes and recruitment of lymphocytes at the site of activation. Although malaria parasites are not exposed to the complement system owing to their intracellular development for most part of their life cycle in the human host, the extracellular stages must face the complement system of human or mosquito or both. In a recent issue of the Biochemical Journal, Sharma et al. reported that Plasmodiumfalciparum LCCL domain-containing protein 1 (PfCCp1) inhibited activation of the classical complement pathway and down-regulated effector responses of dendritic cells, which implicate PfCCp1 and related proteins in immunomodulation of the host that likely benefits the parasite. PfCCp1 belongs to a multi-domain protein family that exists as multimeric protein complexes. It needs to be investigated whether PfCCp1 or its multimeric protein complexes have an immunomodulatory effect in vivo and on the mosquito complement system

scholarly journals Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma

2021 ◽  
Vol 9 (10) ◽  
pp. e003163
Author(s):  
Mitchell Evers ◽  
Marjolein Stip ◽  
Kaylee Keller ◽  
Hanneke Willemen ◽  
Maaike Nederend ◽  
...  
Keyword(s):  
High Risk ◽  
Sensory Neurons ◽  
Complement System ◽  
Severe Pain ◽  
Neuroblastoma Cells ◽  
Antibody Therapy ◽  
Preclinical Treatment ◽  
The Complement System

BackgroundThe addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons.MethodsTo reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89).ResultsIgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo.ConclusionsOur results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.

The Interaction of Liposomes with the Complement System: In Vitro and In Vivo Assays

2003 ◽  
pp. 136-154 ◽  
Author(s):  
Janos Szebeni ◽  
Lajos Baranyi ◽  
Sandor Savay ◽  
Janos Milosevits ◽  
Michael Bodo ◽  
...  
Keyword(s):  
Complement System ◽  
In Vivo Assays ◽  
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.

Introduction to the complement system

1984 ◽  
Vol 306 (1129) ◽  
pp. 279-281 ◽  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Bacterial Infections ◽  
Cross Linking ◽  
Complement Components ◽  
The Third ◽  
Effector Mechanism ◽  
The Complement System

Complement is the essential effector mechanism in humoral immunity to infection. Combination of antibody with antigen causes cross-linking, leading to precipitation of soluble antigens and agglutination of particular antigens, but no more. Unless complement is also present, agglutinated microorganisms can, in appropriate media in vitro grow out and form as lethal a culture as if not reacted with antibody. That this is also true in vivo is apparent from experience with patients with inherited deficiencies in complement components. The pattern is complex because of the presence of two pathways of activation, but in the rare cases of deficiency of the third component, C3, which is central to both pathways, the individuals are susceptible to repeated bacterial infections similar to aggammaglobulinaemics who are unable to synthesize antibodies. Both antibodies and complement are essential for effective humoral immunity.

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