scholarly journals Multi-organ complement deposition in COVID-19 patients

2021 ◽  
Author(s):  
Paolo Macor ◽  
Paolo Durigutto ◽  
Alessandro Mangogna ◽  
Rossana Bussani ◽  
Stefano D'Errico ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Tissue Level ◽  
Spike Protein ◽  
Classical Pathway ◽  
Limited Information ◽  
Alveolar Cells ◽  
Complement Components ◽  
Alternative Pathways ◽  
Activation Products

Background: Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear. Methods: We performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein of SARS-CoV-2. Findings: Lung deposits of C1q, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver. Interpretation. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.

scholarly journals Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1003
Author(s):  
Paolo Macor ◽  
Paolo Durigutto ◽  
Alessandro Mangogna ◽  
Rossana Bussani ◽  
Luca De Maso ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Tissue Level ◽  
Multiple Organ ◽  
Spike Protein ◽  
Classical Pathway ◽  
Limited Information ◽  
Alveolar Cells ◽  
Complement Components ◽  
Activation Products

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage.

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.

scholarly journals Complement-dependent Clearance of Apoptotic Cells by Human Macrophages

1998 ◽  
Vol 188 (12) ◽  
pp. 2313-2320 ◽  
Author(s):  
Dror Mevorach ◽  
John O. Mascarenhas ◽  
Debra Gershov ◽  
Keith B. Elkon
Keyword(s):  
Cell Surface ◽  
Complement Activation ◽  
Apoptotic Cell ◽  
Alternative Pathway ◽  
Systemic Circulation ◽  
Classical Pathway ◽  
Apoptotic Cells ◽  
Complement Components ◽  
Serum Factors ◽  
Systemic Autoimmunity

Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.

scholarly journals Continual Low-Level Activation of the Classical Complement Pathway

2001 ◽  
Vol 194 (6) ◽  
pp. 747-756 ◽  
Author(s):  
Anthony P. Manderson ◽  
Matthew C. Pickering ◽  
Marina Botto ◽  
Mark J. Walport ◽  
Christopher R. Parish
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Blood Stasis ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Alternative Complement ◽  
Classical Complement

There is evidence that the classical complement pathway may be activated via a “C1-tickover” mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.

scholarly journals Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010 ◽  
Vol 23 (4) ◽  
pp. 740-780 ◽  
Author(s):  
Sanjay Ram ◽  
Lisa A. Lewis ◽  
Peter A. Rice
Keyword(s):  
Complement Activation ◽  
Antigen Processing ◽  
Respiratory Infections ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Host Cells ◽  
Medical Attention ◽  
Classical Pathway ◽  
Complement Components ◽  
Complement Pathways

SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

scholarly journals Loss of Complement Activation and Leukocyte Adherence as Nippostrongylus brasiliensis Develops within the Murine Host

2005 ◽  
Vol 73 (11) ◽  
pp. 7442-7449 ◽  
Author(s):  
Paul R. Giacomin ◽  
Hui Wang ◽  
David L. Gordon ◽  
Marina Botto ◽  
Lindsay A. Dent
Keyword(s):  
Complement Activation ◽  
Ex Vivo ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Nippostrongylus Brasiliensis ◽  
Infective Stage ◽  
Leukocyte Adherence ◽  
Factor B ◽  
Alternative Pathways ◽  
Parasitic Helminths

ABSTRACTComplement activation and C3 deposition on the surface of parasitic helminths may be important for recruitment of leukocytes and for damage to the target organism via cell-mediated mechanisms. Inhibition of complement activation would therefore be advantageous to parasites, minimizing damage and enhancing migration through tissues. The aim of this study was to determine ex vivo if complement activation by, and leukocyte adherence to, the nematodeNippostrongylus brasiliensischange as the parasite matures and migrates through the murine host. Pathways of activation of complement and the mechanism of adherence of leukocytes were also defined using sera from mice genetically deficient in either C1q, factor B, C1q and factor B, C3, or C4. Substantive deposition of C3 and adherence of eosinophil-rich leukocytes were seen with infective-stage (L3) but not with lung-stage (L4) larvae. Adult intestinal worms had low to intermediate levels of both C3 and leukocyte binding. For L3 and adult worms, complement deposition was principally dependent on the alternative pathway. For lung-stage larvae, the small amount of C3 detected was dependent to similar degrees on both the lectin and alternative pathways. The classical pathway was not involved for any of the life stages of the parasite. These results suggest that in primary infections, the infective stage ofN. brasiliensisis vulnerable to complement-dependent attack by leukocytes. However, within the first 24 h of infection,N. brasiliensisacquires the ability to largely avoid complement-dependent immune responses.

scholarly journals Complement Activation in Chromosome 13 Dementias

2002 ◽  
Vol 277 (51) ◽  
pp. 49782-49790 ◽  
Author(s):  
Agueda Rostagno ◽  
Tamas Revesz ◽  
Tammaryn Lashley ◽  
Yasushi Tomidokoro ◽  
Laura Magnotti ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Classical Pathway ◽  
Chromosome 13 ◽  
Chronic Inflammatory Response ◽  
General Terms ◽  
Familial Danish Dementia ◽  
Activation Products

Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimer's disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Aβ in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Aβ1–42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds ∼70–75% through the classical pathway while only ∼25–30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptidesin vivomight be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions.

Complement in the Newborn Infant

PEDIATRICS ◽  
1979 ◽  
Vol 64 (5) ◽  
pp. 781-786
Author(s):  
Richard B. Johnston ◽  
Karl M. Altenburger ◽  
Alva W. Atkinson ◽  
Robert H. Curry
Keyword(s):  
Newborn Infant ◽  
Gestational Age ◽  
Hemolytic Activity ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Term Infants ◽  
Complement Components ◽  
Factor B ◽  
Serious Infection ◽  
Dual Pathway

Classical pathway activities and component concentrations in sera from newborns can be compared more realistically to normal adult values than to maternal values since activities and components are increased in maternal sera. Whole complement hemolytic activity appears to be subnormal in approximately half of term infants, with mean activity being about 70% to 90% of normal. Concentrations of Clq, C4, C2, C3, and C7 have been 60% to 100% of adult concentrations in term infants and somewhat less in preterm infants. Younger gestational age has been correlated with lower levels of total hemolytic activity, Clq, C4, and C3. Activity of the alternative pathway appears to be more frequently subnormal in newborn sera than does activity of the classical pathway. Factor B and properdin concentrations have varied from about 35% to 60% and 35% to 70% of adult values, respectively. Opsonization and hemolysis mediated by the alternative pathway have been subnormal in 15% to 75% of term infants, depending upon the assay. Gestational age appears to correlate with alternative pathway hernobytic activity and properdin concentration but not with concentration of factor B. Reductions such as these in single complement components and functions probably would not predispose an otherwise normal individual to infection. However, it seems likely that the multicomponent and dual pathway deficiencies found in neonates, especially in conjunction with the decreased phagocyte function known to exist in that population, could increase the likelihood of serious infection. Predicted infections with this configuration of abnormalities would be extracellular bacterial. Whether the newborn infant is actually predisposed to infection because of the complement deficiencies summarized here remains to be proved. This and other unanswered questions lead us to conclude that understanding of the complement system in the newborn is, pardon the expression, still in its infancy.

The Studies in Various Murine Strains with Defects in Activation of Complement Cascade (CC) Reveal Both Pivotal and Pleiotropic Role of CC in Mobilization of Hematopoietic Stem/Progenitor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 774-774
Author(s):  
Marcin Wysoczynski ◽  
Ryan Reca ◽  
Wu Wan ◽  
Magda Kucia ◽  
Marina Botto ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Molecular Level ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Complement Cascade ◽  
Hematopoietic Stem ◽  
Alternative Pathways ◽  
Dependent Pathway ◽  
Poor Mobilizers

Abstract We reported that complement cascade (CC) becomes activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPC) by i) immunoglobulin (Ig)-dependent pathway and/or by ii) alternative Ig-independent pathway and, as result of this, iii) several potent bioactive CC anaphylatoxins (C3a, desArgC3a, C5a and desArgC5a) are released (Blood2003;101,3784; Blood2004;103,2071; Blood2005;105,40). To learn more on the role of CC and innate immunity in this process, we compared mobilization in mice that possess defects in CC activation by i) classical pathway (C1q−/−, Ig-deficient), ii) both classical and alternative pathway (C2fB−/−) and in animals iii) that do not generate CC-derived anaphylatoxins (C3−/−, C5−/−). For mobilization, we employed G-CSF and zymosan that activate classical and alternative pathways of CC, respectively. First, we found by ELISA that CC activation in fact correlates with the level of HSPC mobilization. Next, studies in mice deficient in CC activation revealed that CC plays both pivotal and pleiotropic roles in this process. Accordingly, while C1q−/− and C3−/− mice turned out to be easy mobilizers, mobilization was very poor in Ig-deficient, C2fB−/− and C5−/− mice that demonstrate that C3 and C5 cleavage fragments differently control the mobilization of HSPC. To explain this at molecular level, we found that C3 cleavage fragments (C3a, desArgC3a) directly interact with HSPC and increase their responsiveness to SDF-1 gradient and thus prevent uncontrolled egress of HSPC from BM. It explains why C1q−/− and C3−/− mice that do not generate C3 cleavage fragments in BM release easily HSPC into circulation. In contrast, C5 cleavage fragments (C5a, desArgC5a) increase permeability of BM-endothelium and thus are crucial for the egress of HSPC from BM to occur. This explains why mice that do not activate efficient CC such as Ig-deficient, C2fB−/− and C5−/− animals are poor mobilizers. We conclude that the mobilization of HSPC is i) dependent on C activation by the classical or alternative pathway and balanced differently by C3 and C5 cleavage fragments that enhance retention or promote egress of HSPC respectively. Thus, modulation of C activation in BM may help to develop new more efficient strategies for both HSPC mobilization and their homing/engraftment.

scholarly journals Infectious diseases associated with complement deficiencies.

1991 ◽  
Vol 4 (3) ◽  
pp. 359-395 ◽  
Author(s):  
J E Figueroa ◽  
P Densen
Keyword(s):  
Infectious Diseases ◽  
Host Defense ◽  
Complement Activation ◽  
Immune Modulation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Classical Pathway ◽  
Cellular Effects

The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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