scholarly journals Functional Activity of the Complement System in Hospitalized COVID-19 Patients: A Prospective Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Panteleimon Charitos ◽  
Ingmar A. F. M. Heijnen ◽  
Adrian Egli ◽  
Stefano Bassetti ◽  
Marten Trendelenburg ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Disease Severity ◽  
Complement System ◽  
Alternative Pathway ◽  
Lectin Pathway ◽  
Hospital Death ◽  
Classical Pathway ◽  
Phase Reaction ◽  
Significant Difference ◽  
The Complement System

AimsAlthough the exact factors promoting disease progression in COVID-19 are not fully elucidated, unregulated activation of the complement system (CS) seems to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by SARS-CoV-2. In particular, the lectin pathway (LP) has been implicated in previous autopsy studies. The primary purpose of our study is to investigate the role of the CS in hospitalized COVID-19 patients with varying degrees of disease severity.MethodsIn a single-center prospective observational study, 154 hospitalized patients with PCR-confirmed SARS-CoV-2 infection were included. Serum samples on admission to the COVID-19 ward were collected for analysis of CS pathway activities and concentrations of LP proteins [mannose-binding lectin (MBL) and ficolin-3 (FCN-3)] & C1 esterase inhibitor (C1IHN). The primary outcome was mechanical ventilation or in-hospital death.ResultsThe patients were predominately male and had multiple comorbidities. ICU admission was required in 16% of the patients and death (3%) or mechanical ventilation occurred in 23 patients (15%). There was no significant difference in LP activity, MBL and FCN-3 concentrations according to different peak disease severities. The median alternative pathway (AP) activity was significantly lower (65%, IQR 50-94) in patients with death/invasive ventilation compared to patients without (87%, IQR 68-102, p=0.026). An optimal threshold of <65.5% for AP activity was derived from a ROC curve resulting in increased odds for death or mechanical ventilation (OR 4,93; 95% CI 1.70-14.33, p=0.003) even after adjustment for confounding factors. Classical pathway (CP) activity was slightly lower in patients with more severe disease (median 101% for death/mechanical ventilation vs 109%, p=0.014). C1INH concentration correlated positively with length of stay, inflammatory markers and disease severity on admission but not during follow-up.ConclusionOur results point to an overactivated AP in critically ill COVID-19 patients in vivo leading to complement consumption and consequently to a significantly reduced AP activity in vitro. The LP does not seem to play a role in the progression to severe COVID-19. Apart from its acute phase reaction the significance of C1INH in COVID-19 requires further studies.

Response of gene expression to LPS challenge manifests the ontogeny and maturation of the complement system in zebrafish larvae

2013 ◽  
Vol 93 (7) ◽  
pp. 1965-1971
Author(s):  
Zhiping Wang ◽  
Yanjun Han
Keyword(s):  
Complement System ◽  
Alternative Pathway ◽  
Experimental Period ◽  
Lectin Pathway ◽  
Classical Pathway ◽  
Adult Fish ◽  
Zebrafish Larvae ◽  
Lps Challenge ◽  
The Complement System ◽  
Ontogenic Expression

Information on the ontogeny of complement system might help us better understand the anti-infection mechanism in the early fish life. The ontogenic expression of the representative complement genes and their response to lipopolysaccharides (LPS) challenge in zebrafish larvae are reported here. The expression of C1r/s, C3, C4, C6 and MBL steadily increased before 21 days post-fertilization (dpf) and a decrease was detected thereafter. MASP expression elevated and peaked on 14 dpf and a decline followed. Bf expression fluctuated during the experimental period. Moreover, Bf (involved in alternative pathway, AP) expressed at higher levels than C1r/s (involved in classical pathway, CP), MASP (involved in lectin pathway, LP) and C4 (involved in both CP and LP) in the normal adult fish and larvae, suggesting the more significance of AP than CP and LP during the development of zebrafish. LPS challenge induced up-regulation of all the genes at 12 h in the adult fish. For the larvae, Bf, C3 (key complement component) and C6 (involved in lytic pathway) responded to LPS challenge at earlier stages than the other complement genes, with the up-regulation detected since 14, 14 and 7 dpf, respectively. In the larvae at 28 dpf, all the above three genes responded to LPS challenge by up-regulating their expression in a fashion similar to that of the adult fish, hinting that complement operating via AP develops earlier and plays a key role in protecting the larvae; it showed effective responses to LPS challenge from 14 dpf and might mature before 28 dpf.

Schistosoma mansoni: complement activation in human and rodent sera by living parasites of various developmental stages

Parasitology ◽  
1983 ◽  
Vol 87 (1) ◽  
pp. 75-86 ◽  
Author(s):  
A. Ruppel ◽  
U. Rother ◽  
H. Vongerichten ◽  
H. J. Diesfeld
Keyword(s):  
Schistosoma Mansoni ◽  
Complement System ◽  
Developmental Stages ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Factor B ◽  
The Complement System ◽  
Dose Dependent ◽  
Living Adult

SUMMARYLiving Schistosoma mansoni of various developmental stages were studied with respect to their ability to activate the complement system in sera of humans, mice and rats. Immunofluorescence assays demonstrated that binding of human C3 occurred on fresh schistosomula as well as on schistosomula prepared from mouse lymph-nodes or lungs and on adult schistosomes. However, rodent C3 was deposited only on fresh schistosomula. Deposition of human C3 on the worms' surface required activation of the complement system. The alternative pathway was shown to be involved in deposition of human C3 on schistosomes of all ages, whereas activation of the classical pathway was demonstrable only with fresh schistosomula. Immunoelectrophoretic studies demonstrated a dose-dependent cleavage of human C3 and conversion of factor B by living adult schistosomes. The results demonstrate that the ability of living schistosomes to activate complement in vitro is dependent not only on their developmental stage but also on the species of the serum.

scholarly journals Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity

2002 ◽  
Vol 11 (8) ◽  
pp. 787-797 ◽  
Author(s):  
Ryo Suzuki ◽  
Yasuo Yoshioka ◽  
Etsuko Kitano ◽  
Tatsunobu Yoshioka ◽  
Hiroaki Oka ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Complement Components ◽  
Alternative Pathways ◽  
Low Cytotoxicity ◽  
The Complement System

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed “cytomedicine, ” which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic β-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Modulation of CD11b/CD18 on Monocytes and Granulocytes following Hemodialysis Membrane Interaction in vitro

1996 ◽  
Vol 19 (3) ◽  
pp. 156-163 ◽  
Author(s):  
P. Thylén ◽  
E. Fernvik ◽  
J. Lundahl ◽  
J. Hed ◽  
S.H. Jacobson
Keyword(s):  
Complement System ◽  
Blood Donors ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dialysis Membrane ◽  
Serum Factors ◽  
Relative Contribution ◽  
Normal Human ◽  
The Complement System

We studied the generation of CD11b/CD18 mobilizing factors in serum after incubation with dialysis membrane fragments of different chemical composition. We also evaluated the relative importance of the alternative and classical pathways of the complement system in the generation of such factors. Monocytes and granulocytes from healthy blood donors were incubated in normal human serum (NHS) and in NHS that had been preincubated with Cuprophan (CU) membrane (NHS-CU), Hemophan (HE) (NHS-HE) or polysulfone (PS) (NHS-PS). NHS-CU caused the highest up-regulation of the CD11b/CD18 receptor on monocytes and granulocytes. The rank in capacity to mobilize CD11b/CD18 on granulocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.001). The rank in capacity to mobilize CD11b/CD18 on monocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.01). NHS-PS induced a lower up-regulation of CD11b/CD18 compared to NHS which indicates that serum factors with the ability to mobilize the CD11b/CD18 receptor on monocytes and granulocytes are deposited on or adsorbed by PS. In order to study the relative contribution of the alternative and classical pathways of the complement system in the generation of CD11b/CD18 mobilizing factors in serum, three different serum preparations (1. both pathways intact. 2. only the alternative intact and 3. only the classical pathway intact) were used. The CU membrane activated the classical pathway to a larger extent than the PS membrane (p<0.01). When only the alternative pathway was intact no difference in the generation of CD11b/CD18 mobilizing factors between the CU and PS membranes was observed. These studies show that CD11b/CD18 mobilizing serum factors are generated after incubation with CU membranes and that such factors are probably adsorbed by PS. The classical pathway of complement activation seems to contribute to the generation of CD11b/CD18 mobilizing factors in serum.

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.

The Complement System

1992 ◽  
Vol 5 (2) ◽  
pp. 123-130 ◽  
Author(s):  
A. Agostoni ◽  
M. Cicardi ◽  
M. Gardinali ◽  
L. Bergamaschini
Keyword(s):  
Cell Membrane ◽  
Complement System ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Enzyme Complex ◽  
Common Pathway ◽  
Complex Figure ◽  
The Common ◽  
Membrane Components ◽  
The Complement System

The human complement system (C) acts to lyse susceptible cells, to promote phagocytosis of target particles, and to solubilize immune-complexes, its activation generates peptides that mediate features of the inflammatory response. It is comprised of a series of plasma zymogens, activated by proteolytic cleavage in a cascade manner, and of plasma and cell membrane control proteins. Activation is achieved by two independent routes: the classical pathway, started by immunoglobulins, and the alternative pathway, started by cell membrane components. Both of them promote the generation of an enzyme-complex (C3 convertase) able to cleave the pivotal protein of the complement system, C3, thus initiating the common pathway with the formation of the lytic complex (Figure 1). In this paper we will briefly review the physiologic phenomena related to the complement activation and its role in pathogenesis of illness particularly focusing on the studies carried out in our laboratory.

scholarly journals In vitro and in situ activation of the complement system by the fungus Lacazia loboi

2007 ◽  
Vol 49 (2) ◽  
pp. 97-101 ◽  
Author(s):  
Fátima Regina Vilani-Moreno ◽  
Érika Mozer ◽  
Ana Márcia Guedes de Sene ◽  
Margarete de Oliveira Ferasçoli ◽  
Tânia Cristina Pereira ◽  
...  
Keyword(s):  
Complement System ◽  
Alternative Pathway ◽  
Immunofluorescence Staining ◽  
Sterile Saline ◽  
In Situ Activation ◽  
Significant Difference ◽  
Lacazia Loboi ◽  
Lacazia Loboï ◽  
The Complement System

Since there are no studies evaluating the participation of the complement system (CS) in Jorge Lobo's disease and its activity on the fungus Lacazia loboi, we carried out the present investigation. Fungal cells with a viability index of 48% were obtained from the footpads of BALB/c mice and incubated with a pool of inactivated serum from patients with the mycosis or with sterile saline for 30 min at 37 ºC. Next, the tubes were incubated for 2 h with a pool of noninactivated AB+ serum, inactivated serum, serum diluted in EGTA-MgCl2, and serum diluted in EDTA. The viability of L. loboi was evaluated and the fungal suspension was cytocentrifuged. The slides were submitted to immunofluorescence staining using human anti-C3 antibody. The results revealed that 98% of the fungi activated the CS by the alternative pathway and no significant difference in L. loboi viability was observed after CS activation. In parallel, frozen histological sections from 11 patients were analyzed regarding the presence of C3 and IgG by immunofluorescence staining. C3 and IgG deposits were observed in the fungal wall of 100% and 91% of the lesions evaluated, respectively. The results suggest that the CS and immunoglobulins may contribute to the defense mechanisms of the host against L. loboi.

scholarly journals Two New Compounds and Anti-complementary Constituents from Amomum tsao-ko

2013 ◽  
Vol 8 (12) ◽  
pp. 1934578X1300801
Author(s):  
Jiahong Jin ◽  
Zhihong Cheng ◽  
Daofeng Chen
Keyword(s):  
Phenolic Compounds ◽  
High Resolution ◽  
Complement System ◽  
Alternative Pathway ◽  
2D Nmr ◽  
Classical Pathway ◽  
Ms Analysis ◽  
New Compounds ◽  
The Complement System

Two new compounds, (2 R,3 R,4 R)–3′,5′-dimethoxy-3,4,7,4′-tetrahydroxy-flavan (1) and 2-(4-hydroxy-3-methoxybenzoyl)-4-methoxy-benzaldehyde (2), together with 35 known phenolic compounds were obtained from the fruits of Amomum tsao-ko. Structures of the new compounds were elucidated on the basis of spectroscopic means, including 2D NMR, and high-resolution MS analysis. The isolated compounds were tested in vitro for their complement-inhibitory properties against the classical pathway (CP) and alternative pathway (AP). The results showed that 14 compounds exhibited anti-complementary activities against the CP and AP with CH50 values of 0.42 - 4.43 mM and AP50 values of 0.53 −1.51 mM. Preliminary mechanism studies showed that 1,7-bis(4-hydroxyphenyl)–4( E)-hepten-3-one (8) blocked C1q, C2, C3, C4, C5 and C9 components of the complement system, and hydroquinone (15) acted on C1q, C2, C3, C5 and C9 components.

scholarly journals The Role of Complement System and the Immune Response to Tuberculosis Infection

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 84
Author(s):  
Heena Jagatia ◽  
Anthony G. Tsolaki
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Cell Surface ◽  
Complement System ◽  
Bacterial Cell ◽  
Lectin Binding ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Bacterial Cell Surface ◽  
The Complement System

The complement system orchestrates a multi-faceted immune response to the invading pathogen, Mycobacterium tuberculosis. Macrophages engulf the mycobacterial bacilli through bacterial cell surface proteins or secrete proteins, which activate the complement pathway. The classical pathway is activated by C1q, which binds to antibody antigen complexes. While the alternative pathway is constitutively active and regulated by properdin, the direct interaction of properdin is capable of complement activation. The lectin-binding pathway is activated in response to bacterial cell surface carbohydrates such as mannose, fucose, and N-acetyl-d-glucosamine. All three pathways contribute to mounting an immune response for the clearance of mycobacteria. However, the bacilli can reside, persist, and evade clearance by the immune system once inside the macrophages using a number of mechanisms. The immune system can compartmentalise the infection into a granulomatous structure, which contains heterogenous sub-populations of M. tuberculosis. The granuloma consists of many types of immune cells, which aim to clear and contain the infection whilst sacrificing the affected host tissue. The full extent of the involvement of the complement system during infection with M. tuberculosis is not fully understood. Therefore, we reviewed the available literature on M. tuberculosis and other mycobacterial literature to understand the contribution of the complement system during infection.

scholarly journals Prognostic Value of Complement Properdin in Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandro Mangogna ◽  
Praveen M. Varghese ◽  
Chiara Agostinis ◽  
Salman H. Alrokayan ◽  
Haseeb A. Khan ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Prognostic Marker ◽  
Immune Cells ◽  
Complement System ◽  
Alternative Pathway ◽  
Complement Protein ◽  
Significant Difference ◽  
The Complement System

The complement system is readily triggered by the presence of damage-associated molecular patterns on the surface of tumor cells. The complement alternative pathway provides rapid amplification of the molecular stress signal, leading to complement cascade activation to deal with pathogens or malignant cells. Properdin is the only known positive regulator of the alternative pathway. In addition, properdin promotes the phagocytic uptake of apoptotic T cells by macrophages and dendritic cells without activating the complement system, thus, establishing its ability to recognize “altered-self”. Dysregulation of properdin has been implicated in substantial tissue damage in the host, and in some cases, chronic unresolved inflammation. A corollary of this may be the development of cancer. Hence, to establish a correlation between properdin presence/levels in normal and cancer tissues, we performed bioinformatics analysis, using Oncomine and UALCAN. Survival analyses were performed using UALCAN and PROGgeneV2 to assess if properdin can serve as a potential prognostic marker for human lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma (CESC), and pancreatic adenocarcinoma (PAAD). We also analyzed levels of tumor-infiltrating immune cells using TIMER, a tool for characterizing immune cell composition in cancers. We found that in LUAD and LIHC, there was a lower expression of properdin in the tumors compared to normal tissues, while no significant difference was observed in CESC and PAAD. Survival analysis demonstrated a positive association between properdin mRNA expression and overall survival in all 4 types of cancers. TIMER analysis revealed that properdin expression correlated negatively with tumor purity and positively with levels of infiltrating B cells, cytotoxic CD8+ T cells, CD4+ helper T cells, macrophages, neutrophils and dendritic cells in LUAD, CESC and PAAD, and with levels of B cells, CD8+ T cells and dendritic cells in LIHC. Immunohistochemical analysis revealed that infiltrating immune cells were the most likely source of properdin in the tumor microenvironment. Thus, complement protein properdin shows promise as a prognostic marker in cancer and warrants further study.

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