scholarly journals Involvement of the Lectin Pathway of Complement Activation in Antimicrobial Immune Defense during Experimental Septic Peritonitis

2004 ◽  
Vol 72 (9) ◽  
pp. 5247-5252 ◽  
Author(s):  
Michaela Windbichler ◽  
Bernd Echtenacher ◽  
Thomas Hehlgans ◽  
Jens C. Jensenius ◽  
Wilhelm Schwaeble ◽  
...  
Keyword(s):  
Complement Activation ◽  
Expression Profiles ◽  
Alternative Pathway ◽  
Immune Defense ◽  
Lectin Pathway ◽  
Alternative Pathways ◽  
Activation Pathway ◽  
Deficient Mice ◽  
Complement Activation Pathway ◽  
Classical Complement

ABSTRACT A critical first line of defense against infection is constituted by the binding of natural antibodies to microbial surfaces, activating the complement system via the classical complement activation pathway. In this function, the classical activation pathway is supported and amplified by two antibody-independent complement activation routes, i.e., the lectin pathway and the alternative pathway. We studied the contribution of the different complement activation pathways in the host defense against experimental polymicrobial peritonitis induced by cecal ligation and puncture by using mice deficient in either C1q or factors B and C2. The C1q-deficient mice lack the classical complement activation pathway. While infection-induced mortality of wild-type mice was 27%, mortality of C1q-deficient mice was increased to 60%. Mice with a deficiency of both factors B and C2 lack complement activation via the classical, the alternative, and the lectin pathways and exhibit a mortality of 92%, indicating a significant contribution of the lectin and alternative pathways of complement activation to survival. For 14 days after infection, mannan-binding lectin (MBL)-dependent activation of C4 was compromised. Serum MBL-A and MBL-C levels were significantly reduced for 1 week, possibly due to consumption. mRNA expression profiles did not lend support for either of the two MBL genes to respond as typical acute-phase genes. Our results demonstrate a long-lasting depletion of MBL-A and MBL-C from serum during microbial infection and underline the importance of both the lectin and the alternative pathways for antimicrobial immune defense.

scholarly journals Distinct Different Contributions of the Alternative and Classical Complement Activation Pathway for the Innate Host Response during Sepsis

2011 ◽  
Vol 186 (5) ◽  
pp. 3066-3075 ◽  
Author(s):  
Katja Dahlke ◽  
Christiane D. Wrann ◽  
Oliver Sommerfeld ◽  
Maik Soßdorf ◽  
Peter Recknagel ◽  
...  
Keyword(s):  
Complement Activation ◽  
Host Response ◽  
Activation Pathway ◽  
Complement Activation Pathway ◽  
Classical Complement

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.

Antiphospholipid Syndrome (APS) Patient Plasmas Consistently Activate Complement: A Novel Approach to Detecting a Pathogenic Mechanism for APS

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 719-719
Author(s):  
Jacob H. Rand ◽  
Xiao-Xuan Wu ◽  
Lucia R Wolgast ◽  
Victor Lei ◽  
Edward M. Conway
Keyword(s):  
Antiphospholipid Syndrome ◽  
Complement Activation ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
Disease Process ◽  
Pathogenic Mechanism ◽  
Phospholipid Vesicles ◽  
Lectin Pathway ◽  
Activation Markers ◽  
Novel Approach

Abstract INTRODUCTION: The antiphospholipid syndrome (APS) has remained an enigmatic condition for over 3 decades. Pathogenic mechanism(s) have not been established, and the disorder has therefore continued to be defined by non-mechanistic assays such as the lupus anticoagulant and antiphospholipid immunoassays. Although evidence from animal models has indicated a role for complement activation in the disease process, it is has been remarkable that activation markers are not consistently detected in human APS plasmas. We hypothesized that this might be due to rapid clearance of activation products and that we might be better able to detect a role for complement in APS through a 2 stage system - i.e. by first allowing APS immune complexes to form on phospholipid vesicles and then measuring whether those vesicles might activate complement in normal serum. METHODS : Complement activation markers - specifically C5a and the C5b-9 membrane attack complex - were measured in plasmas of 5 groups of plasmas (n= 10 for each group): normal healthy controls, APS with clinical histories for thrombosis (8 with venous thromboembolism (VTE), 1 venous stroke, and 1 arterial stroke), cancer patients without thrombosis, systemic lupus erythematosus (SLE) without APS, and VTE without APS. These were compared to measurements of complement activation induced by phospholipid vesicles that were pre-incubated with the same plasmas. Additional experiments were then done to: 1) characterize whether the effects could be reproduced with purified APS vs control IgGs and β2-glycoprotein I (β2GPI), 2) define the complement activation pathways involved with factor B and C2 deficient sera and with serum in the presence of EGTA and MgCl2, and 3) determine whether the activation could be inhibited by the monoclonal anti-C5 antibody, eculizimab. RESULTS: When the plasmas themselves were assayed, we found no significant differences in the plasmas levels of C5a or C5b-9 between APS and controls or among the 5 groups (Fig 1 A, B). In contrast, preincubation of phospholipid vesicles with plasmas resulted in significant elevations of both C5a (Fig 1C) and C5b-9 (Fig 1D) in APS compared to controls. Also, C5a levels in cancer, SLE and VTE were significantly lower than in APS, but above the controls. C5b-9 levels were elevated in APS and the other disease groups compared to controls, with the APS levels that were significantly higher than only the cancer group. The results were confirmed using purified IgGs and β2GPI in place of the whole plasmas. In addition, we found that APS-treated vesicles triggered complement activation via both the classical/lectin pathway and the alternative pathway. Eculizimab completely abrogated the complement activation. CONCLUSIONS: To our knowledge, this is the first demonstration that APS patient plasmas clearly and consistently activate complement. This was achieved through the novel approach of first incubating the plasmas with phospholipid vesicles which serve as platforms for the assembly of APS plasma-derived protein complexes that, in turn, activate complement. In addition, these findings may provide the basis for a mechanistic biomarker for disease activity in APS, by detecting complement activation at the site of injury. * P<0.05 vs Controls. # P<0.05 vs APS Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis

2001 ◽  
Vol 69 (12) ◽  
pp. 7304-7309 ◽  
Author(s):  
Ilhan Celik ◽  
Cordula Stover ◽  
Marina Botto ◽  
Steffen Thiel ◽  
Sotiria Tzima ◽  
...  
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Immune Defense ◽  
Classical Pathway ◽  
Complement Factor ◽  
Wild Type ◽  
Factor B ◽  
The Complement System ◽  
Deficient Mice

ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

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