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 In vitro, classical complement activation differs by disease severity and between SARS-CoV-2 antigens

2021 ◽  
Author(s):  
Rachel E Lamerton ◽  
Edith Marcial Juarez ◽  
Sian E Faustini ◽  
Marisol E Perez-Toledo ◽  
Margaret Goodall ◽  
...  
Keyword(s):  
Complement Activation ◽  
Specific Antigen ◽  
Disease Status ◽  
Classical Pathway ◽  
Complement Protein ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Downstream Effects ◽  
Classical Complement

Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of anti-SARS-CoV-2 antibodies from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the antigen and subjects studied. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending on the specific antigen targeted and the disease status of the subject.

Activation of the Classical Pathway of Complement by Resting and Shear Stress-Stimulated Human Endothelial Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2664-2664
Author(s):  
Wei Yin ◽  
Babette Weksler ◽  
David Varon ◽  
Naphtali Savion ◽  
Berhane Ghebrehiwet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Complement Activation ◽  
Binding Domain ◽  
Complement Pathway ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Pathway Activation ◽  
Static Conditions ◽  
Classical Complement

Abstract Complement activation is associated with a variety of inflammatory conditions including atherosclerosis, but the mechanism of complement activation in these settings is poorly understood. Endothelial cells (EC) play an important role in vascular pathology and express a variety of complement receptors, including gC1qR/p33, recognizing the globular domain of the complement component C1q. In preliminary studies, purified recombinant gC1qR/p33 was found to support C1q-dependent C4 activation in vitro, comprising 19.5% ± 8.3% (mean ± S.D., n=5) of that produced by aggregated IgG. In contrast, a truncated form of gC1qR/p33, lacking the C1q binding domain, failed to support C4 activation. Additional studies were performed with immortalized bone marrow microvascular EC to investigate classical complement pathway activation and deposition. EC were exposed to anticoagulated (0.32 % sodium citrate) human plasma, diluted (1/10) in 0.01 M HEPES buffered modified Tyrode’s solution, pH 7.5, containing 2 mM Mg Cl2 and 1 mM CaCl2, for 60 min, 37°C. A solid phase ELISA approach was used to detect EC-associated C1q and C4 activation (C4d). Statistically significant deposition of C4d (0.72 ± 0.3. OD units (ODU), n=4)(p=0.04) and C1q (0.57 ± 0.19. ODU, n=4) (p=0.002) was observed on EC that had been immobilized on poly-L-lysine coated microtiter wells. Consistent with classical complement pathway activation, C4d deposition remained at baseline (0.23 ± 0.13, ODU, n=4) in the presence of 10 mM EDTA, but C1q deposition was unaffected. Moreover, no significant C1q or C4d deposition occurred when endothelial cells were exposed to C1q depleted serum. Similar studies were performed using EC grown to confluence on Type I collagen to examine the effect of shear stress (12 dynes/cm2 for 1 hour in a cone-and-plate shearing device), simulating flow conditions in coronary arteries, on classical complement pathway activation and deposition. Compared to static conditions, shear stress resulted in an approximately 50% increase in C1q and C4d deposition on EC. This was accompanied by an approximately 2-fold increase in EC binding of a monoclonal antibody, 60.11, recognizing the N-terminal C1q binding domain of gC1qR/p33. Taken together, these data present evidence for a potential paradigm shift, illustrating immune complex independent classical complement pathway activation by gC1qR/p33, and deposition of activated classical complement components on EC. The generation and deposition of active complement components on EC is likely to contribute directly to vascular inflammation and atherosclerotic changes.

scholarly journals Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway

2008 ◽  
Vol 76 (8) ◽  
pp. 3761-3770 ◽  
Author(s):  
Jose Yuste ◽  
Ashwin Sen ◽  
Lennart Truedsson ◽  
Göran Jönsson ◽  
Liang-Seah Tay ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Human Serum ◽  
Alternative Pathway ◽  
Antibody Activity ◽  
Classical Pathway ◽  
Complement Factor ◽  
Complement Pathway ◽  
Classical Complement Pathway ◽  
C2 Deficiency ◽  
Classical Complement

ABSTRACT Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2−/− subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.

scholarly journals Classical Pathway of Complement Activation in ITP: Inhibition By TNT003, a Novel C1s Inhibitor

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1453-1453
Author(s):  
Ellinor I.B. Peerschke ◽  
Sandip Panicker ◽  
Alexa M. Sughroue ◽  
James B. Bussel
Keyword(s):  
Complement Activation ◽  
In Vitro Assay ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Research Support ◽  
Vitro Assay ◽  
Classical Complement Pathway ◽  
Pathway Activation ◽  
Classical Complement

Abstract Background: Immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which antiplatelet antibodies mediate accelerated platelet clearance from circulation and also inhibit platelet production, resulting in thrombocytopenia. Activation of the classical pathway (CP) of complement is associated with a variety of immune disorders involving the presence of autoantibodies. The role of the complement system in ITP is poorly understood. Methods: Plasma samples (0.32% sodium citrate) from patients with chronic ITP (n=55) were evaluated for their ability to activate the CP of complement. The 55 patients consisted primarily of adult but also of pediatric patients with ITP, undergoing various treatment regimens. The most common included IVIG, rituximab, and especially thrombopoietic agents (eltrombopag, romiplostim). Almost all patients included in the analysis had chronic ITP, defined as ITP lasting > 12 months. The complement activating capacity (CAC) of patient plasma was evaluated with a previously described in vitro assay ( Peerschke et al., Brit J Haematol, 2009) that measures complement activation on immobilized, fixed heterologous platelets using an ELISA approach with monoclonal antibodies to C1q, C4d, iC3b, and C5b-9. CAC represents assay optical density readings normalized to reference normal plasma pool. A CAC of >1.5 was considered indicative of enhanced complement activation, based on reference ranges established for plasma from healthy volunteers. Patient CAC values were correlated with platelet count. The ability of TNT003 to block in vitro complement activation was assessed relative to an isotype matched control. TNT003 is a mouse monoclonal antibody (IgG2a) that targets the CP-serine protease C1s. Results: A statistically significant (p=0.042) inverse correlation was noted between C4d deposition and platelet count in the 55 ITP patient samples tested. Heightened classical complement pathway activation was demonstrated in 7 of 55 patients (~13%) with ITP as evidenced by increased C4d deposition. 6 of the 7 patients with increased C4d deposition had platelet counts <100k/mcL, and 5 patients had platelet counts <50K/mcL. There was a non-significant trend for higher C4d levels on platelets and lower AIPF (absolute immature platelet fraction, equivalent to platelet reticulocytes). TNT003 (100 mcg/ml) inhibited C4 activation by 44 + 43% in ITP plasma in vitro. Inhibition of downstream complement activation, iC3b and C5b-9 deposition, was 72% + 17 % and 82% + 14% (mean + S.D.), respectively. Similar results were obtained using 10 mM EDTA, a known inhibitor of complement activation. Conclusions: The heterogeneity of patient responses to different treatment modalities in ITP support the concept of different immune mechanisms contributing to thrombocytopenia. Our data demonstrate classical complement pathway activation in a subgroup of patients with ITP, and further present the first evidence of CP complement inhibition by a novel C1s inhibitor in this setting. Failure to completely block C4 activation in ITP plasma in vitro by either of TNT003 or EDTA, suggests the presence of preformed, circulating C4d containing complement complexes in patient plasma. The ability of TNT003 to more completely inhibit C3 activation and C5b-9 assembly downstream of C4 in the in vitro assay system is consistent with direct activation and inhibition of complement at the platelet surface. Thus, TNT003 may mitigate enhanced platelet clearance by RES via inhibition of complement mediated platelet opsonization by C3b and platelet lysis by C5b-9. Further studies are required to evaluate the impact of TNT003 on thrombocytopenia in ITP. Disclosures Peerschke: True North Therapeutics: Research Support Other. Panicker:True North Therapeutics: Employment. Bussel:True North Therapeutics: Research Support Other.

scholarly journals Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Lukas Muri ◽  
Emma Ispasanie ◽  
Anna Schubart ◽  
Christine Thorburn ◽  
Natasa Zamurovic ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Pneumococcal Infection ◽  
Alternative Complement Pathway ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Blood Leukocytes ◽  
Complement Components ◽  
Relative Contribution ◽  
Alternative Complement ◽  
Pathway Inhibition

To assess the relative contribution of opsonisation by antibodies, classical and alternative complement pathways to pneumococcal phagocytosis, we analyzed killing of pneumococci by human blood leukocytes collected from vaccine-naïve and PCV13-vaccinated subjects. With serotype 4 pneumococci as model, two different physiologic opsonophagocytosis assays based on either hirudin-anticoagulated whole blood or on washed cells from EDTA-anticoagulated blood reconstituted with active serum, were compared. Pneumococcal killing was measured in the presence of inhibitors targeting the complement components C3, C5, MASP-2, factor B or factor D. The two assay formats yielded highly consistent and comparable results. They highlighted the importance of alternative complement pathway activation for efficient opsonophagocytic killing in blood of vaccine-naïve subjects. In contrast, alternative complement pathway inhibition did not affect pneumococcal killing in PCV13-vaccinated individuals. Independent of amplification by the alternative pathway, even low capsule-specific antibody concentrations were sufficient to efficiently trigger classical pathway mediated opsonophagocytosis. In heat-inactivated or C3-inhibited serum, high concentrations of capsule-specific antibodies were required to trigger complement-independent opsonophagocytosis. Our findings suggest that treatment with alternative complement pathway inhibitors will increase susceptibility for invasive pneumococcal infection in non-immune subjects, but it will not impede pneumococcal clearance in vaccinated individuals.

scholarly journals Heptose I Glycan Substitutions on Neisseria gonorrhoeae Lipooligosaccharide Influence C4b-Binding Protein Binding and Serum Resistance

2007 ◽  
Vol 75 (8) ◽  
pp. 4071-4081 ◽  
Author(s):  
Sanjay Ram ◽  
Jutamas Ngampasutadol ◽  
Andrew D. Cox ◽  
Anna M. Blom ◽  
Lisa A. Lewis ◽  
...  
Keyword(s):  
Binding Protein ◽  
Alternative Pathway ◽  
Serum Resistance ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Pathway Activation ◽  
Normal Human ◽  
Classical Complement ◽  
Strain Background

ABSTRACT Lipooligosaccharide (LOS) heptose (Hep) glycan substitutions influence gonococcal serum resistance. Several gonococcal strains bind the classical complement pathway inhibitor, C4b-binding protein (C4BP), via their porin (Por) molecule to escape complement-dependent killing by normal human serum (NHS). We show that the proximal glucose (Glc) on HepI is required for C4BP binding to Por1B-bearing gonococcal strains MS11 and 1291 but not to FA19 (Por1A). The presence of only the proximal Glc on HepI (lgtE mutant) permitted maximal C4BP binding to MS11 but not to 1291. Replacing 1291 lgtE Por with MS11 Por increased C4BP binding to levels that paralleled MS11 lgtE, suggesting that replacement of the Por1B molecule dictated the effects of HepI glycans on C4BP binding. The remainder of the strain background did not affect C4BP binding; replacing the Por of strain F62 with MS11 Por (F62 PorMS11) and truncating HepI mirrored the findings in the MS11 background. C4BP binding correlated with resistance to killing by NHS in most instances. F62 PorMS11 and its lgtE mutant were sensitive to NHS despite binding C4BP, secondary to kinetically overwhelming classical pathway activation and possibly increased alternative pathway activation (measured by factor Bb binding) by the F62 background. FA19 lgtF (HepI unsubstituted) resisted killing by only 10% NHS, not 50% NHS, despite binding levels of C4BP similar to those of FA19 and FA19 lgtE (both resistant to 50% serum), suggesting a role for the proximal Glc in serum resistance independently of C4BP binding. This study provides mechanistic insights into how HepI LOS substitutions affect the serum resistance of N. gonorrhoeae.

In vivo pharmacokinetics of calreticulin S-domain, an inhibitor of the classical complement pathway

2002 ◽  
Vol 2 (4) ◽  
pp. 415-422 ◽  
Author(s):  
Nicholas J. Lynch ◽  
Heiko Schneider ◽  
Robert B. Sim ◽  
Ulrich Bickel ◽  
Wilhelm J. Schwaeble
Keyword(s):  
Complement Pathway ◽  
Classical Complement Pathway ◽  
In Vivo Pharmacokinetics ◽  
Classical Complement

scholarly journals In vitro complement binding on cytoplasmic structures in normal human skin: immunoelectronmicroscopic studies.

1982 ◽  
Vol 95 (2) ◽  
pp. 543-551 ◽  
Author(s):  
G Schuler ◽  
H Hintner ◽  
K Wolff ◽  
P Fritsch ◽  
G Stingl
Keyword(s):  
Cell Types ◽  
Exact Nature ◽  
Complement Pathway ◽  
Experimental Conditions ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Pathway Activation ◽  
Normal Human ◽  
Cytoplasmic Structures ◽  
Classical Complement

We have previously provided evidence that suggests that exposure of cryostat skin sections to normal human serum (NHS) results in the antibody-independent Clq binding to cytoplasmic structures of various cell types, leading to classical complement pathway activation as evidenced by cytoplasmic C3 deposition. In the present study, we have employed immunoelectronmicroscopic methods to clarify the exact nature of cytoplasmic C3 binding structures. Incubation of cryostat skin sections with NHS followed by peroxidase-labeled rabbit anti-human C3 serum (HRP-R/Hu C3) revealed that intracytoplasmic binding of C3 occurred in suprabasal keratinocytes, melanocytes, fibroblasts, smooth muscle cells, endothelial cells, pericytes, Schwann cells, and nerve axons, but not in basal keratinocytes, Langerhans cells, and other cellular constituents of the skin. C3 binding, as revealed by the deposition of HRP reaction product, was exclusively confined to intermediate-sized filaments (ISF), which can therefore be considered to represent the subcellular site for classical complement pathway activation. Under experimental conditions that do not allow classical complement pathway activation, ISF were not decorated. Our observation that ISF of ontogenetically different cell types share the capacity of complement fixation is in accordance with the recent finding that different ISF types, despite their biochemical and antigenic heterogeneity, have common alpha-helical domains and may provide a clue to the mechanism and site of interaction between complement components and ISF.

scholarly journals Evidence of Classical Complement Pathway Involvement in a Subset of Patients with Warm Autoimmune Hemolytic Anemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2001-2001
Author(s):  
Jeffrey Teigler ◽  
Julian Low ◽  
Shawn Rose ◽  
Ellen Cahir-Mcfarland ◽  
Ted Yednock ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Publicly Traded ◽  
Inhibitory Antibody ◽  
Advisory Committees ◽  
Classical Complement Pathway ◽  
Complement Deposition ◽  
Classical Complement

Abstract Introduction: Autoimmune Hemolytic Anemia (AIHA) is caused by autoantibodies that react with red blood cells (RBCs) resulting in predominantly extravascular hemolysis in an FcR and/or complement-dependent manner. In warm AIHA (wAIHA), autoantibodies are generally of the IgG isotype, while in cold agglutinin disease (CAD) they are predominantly of the IgM isotype. It is well established that the classical complement cascade is critical for the pathogenesis of CAD based on therapeutic clinical studies. Published data also suggest that complement activation plays a role in wAIHA, although it is not clear which patients would most benefit from complement-based therapy. To help address this question, we utilized an assay that measures the ability of autoantibodies in patient sera to induce complement deposition on the surface of donor RBCs (based on Meulenbroek, et al., 2015). Methods: Sera were collected retrospectively from 12 wAIHA patients whose direct antiglobulin tests (DAT) were either IgG+/C3+ or IgG+/C3-. Sera retrospectively collected from two CAD patients were used as positive controls. Individual patient sera were examined in the in vitro complement deposition assay using RBCs from type O+ healthy donors. RBCs and sera were incubated at 37 oC in the presence of either EDTA or an inhibitory antibody against C1q as inhibitors of the classical pathway. RBCs were then stained and processed by flow cytometry to determine the level of C4 deposition. Results: Sera from both CAD patients deposited C4 on the surface of ~70% of healthy human RBCs in vitro. Four out of twelve (33%) sera from wAIHA patients displayed this activity, and all four of these patients were identified as IgG+/C3+ on DAT. Complement deposition ranged from ~10-60% of the RBCs in wAIHA, suggesting heterogeneity in antibody activity for complement deposition in sera from wAIHA patients. Addition of EDTA or an inhibitory antibody against C1q fully blocked deposition of C4 on RBCs by wAIHA sera, indicating dependence of the classical complement pathway. These results indicate differences in the frequency of classical pathway involvement in CAD versus wAIHA and may help identify a subset of wAIHA patients most likely to respond to anti-C1q therapy. Conclusions: The hypothesis of classical complement cascade involvement in wAIHA disease in a subset of patients is supported by our results. Critically, complement deposition on the surface of cells by anti-C1q prevented the deposition of a downstream complement marker, C4. Inhibition of C1q has been shown to block activation of all downstream classical complement components, including C3b and C4b involved in extravascular hemolysis and C5b involved in direct cell lysis. The therapeutic potential of blocking classical complement pathway activity in wAIHA is currently being evaluated in an ongoing Phase 2 interventional trial (NCT04691570) assessing efficacy of an anti-C1q drug candidate in wAIHA patients, focusing on those with evidence of classical complement pathway activity. Disclosures Teigler: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Low: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Rose: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Cahir-Mcfarland: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Yednock: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Kroon: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Keswani: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Barcellini: Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees.

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.

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