scholarly journals Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

2020 ◽  
Vol 117 (40) ◽  
pp. 25018-25025 ◽  
Author(s):  
Jan C. Holter ◽  
Soeren E. Pischke ◽  
Eline de Boer ◽  
Andreas Lind ◽  
Synne Jenum ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Failure ◽  
Complement Activation ◽  
Blood Donors ◽  
Innate Immune ◽  
Lectin Pathway ◽  
Complement Inhibitors ◽  
Activation Products ◽  
The Complement System ◽  
Recognition Molecule

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

scholarly journals Structure and activation of C1, the complex initiating the classical pathway of the complement cascade

2017 ◽  
Vol 114 (5) ◽  
pp. 986-991 ◽  
Author(s):  
Simon A. Mortensen ◽  
Bjoern Sander ◽  
Rasmus K. Jensen ◽  
Jan Skov Pedersen ◽  
Monika M. Golas ◽  
...  
Keyword(s):  
Serine Protease ◽  
Innate Immune System ◽  
Innate Immune ◽  
Lectin Pathway ◽  
Classical Pathway ◽  
Structural Studies ◽  
Proteolytic Activation ◽  
Molecular Patterns ◽  
The Complement System ◽  
Recognition Molecule

The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r2s2, to a variety of activators presenting specific molecular patterns such as IgG- and IgM-containing immune complexes. A canonical model entails a C1r2s2with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator. Here, we show that the serine protease domains of C1r and C1s are located at the periphery of the C1r2s2tetramer both when alone or within the nonactivated C1 complex. Our structural studies indicate that the C1 complex adopts a conformation incompatible with intramolecular activation of C1, suggesting instead that intermolecular proteolytic activation between neighboring C1 complexes bound to a complement activating surface occurs. Our results rationalize how a multitude of structurally unrelated molecular patterns can activate C1 and suggests a conserved mechanism for complement activation through the classical and the related lectin pathway.

Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond

Blood ◽  
2021 ◽  
Author(s):  
Eleni Gavriilaki ◽  
Régis Peffault de Latour ◽  
Antonio Maria Risitano
Keyword(s):  
Complement Activation ◽  
Lectin Pathway ◽  
Prototype Model ◽  
Complement Inhibition ◽  
Hematologic Diseases ◽  
Classical Complement Pathway ◽  
Complement Inhibitors ◽  
Hemolytic Transfusion Reaction ◽  
Personalized Approach ◽  
Long Acting

Complement is an elaborate system of the innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototype model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan have been also now approved with PNH. Novel agents, such as factor B and factor D inhibitors, are under study with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug needs to be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease (CAD), primarily with the C1s inhibitor of the classical complement pathway, sutimlimab, but also with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, are investigated in transplant-associated thrombotic microangiopathy (TA-TMA). With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction (DHTR) or immune thrombocytopenia (ITP), might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases focusing on: a) complement biology for the clinician, b) complement activation and therapeutic inhibition in prototypical complement-mediated hematologic diseases, c) hematologic entities under investigation for complement inhibition, and d) other complement-related disorders of potential interest to hematologists.

scholarly journals A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6043-6051 ◽  
Author(s):  
Michelle Elvington ◽  
Yuxiang Huang ◽  
B. Paul Morgan ◽  
Fei Qiao ◽  
Nico van Rooijen ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cell ◽  
Complement Activation ◽  
Metastatic Cancer ◽  
Protein Targets ◽  
Complement Inhibitors ◽  
Activation Products ◽  
Cellular Immune

Abstract Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer.

scholarly journals The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection

2012 ◽  
Vol 8 (7) ◽  
pp. e1002793 ◽  
Author(s):  
Youssif M. Ali ◽  
Nicholas J. Lynch ◽  
Kashif S. Haleem ◽  
Teizo Fujita ◽  
Yuichi Endo ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Complement Activation ◽  
Pneumococcal Infection ◽  
Innate Immune ◽  
Lectin Pathway ◽  
Critical Component

Complement activation by salivary agglutinin is secretor status dependent

2015 ◽  
Vol 396 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Sabrina T.G. Gunput ◽  
Antoon J.M. Ligtenberg ◽  
Bas Terlouw ◽  
Mieke Brouwer ◽  
Enno C.I. Veerman ◽  
...  
Keyword(s):  
Blood Group ◽  
Complement Activation ◽  
Anguilla Anguilla ◽  
Mucosal Damage ◽  
Lectin Pathway ◽  
Blood Group System ◽  
Group Status ◽  
Chemical Structures ◽  
The Complement System ◽  
Binding Lectin

Abstract After mucosal damage or gingival inflammation, complement proteins leak into the oral cavity and mix with salivary proteins such as salivary agglutinin (SAG/gp-340/DMBT1). This protein is encoded by the gene Deleted in Malignant Brain Tumors 1 (DMBT1), and it aggregates bacteria, viruses and fungi, and activates the lectin pathway of the complement system. In the lectin pathway, carbohydrate structures on pathogens or altered self cells are recognized. SAG is highly glycosylated, partly on the basis of the donor’s blood group status. Whereas secretors express Lewis b, Lewis y, and antigens from the ABO-blood group system on SAG, non-secretors do not. Through mannose-binding lectin (MBL) binding and C4 deposition assays, we aimed to identify the chemical structures on SAG that are responsible for complement activation. The complement-activating properties of SAG were completely abolished by oxidation of its carbohydrate moiety. SAG-mediated activation of complement was also inhibited in the presence of saccharides such as fucose and Lewis b carbohydrates, and also after pretreatment with the fucose-binding lectin, Anguilla anguilla agglutinin. Complement activation was significantly (p<0.01) higher in secretors than in non-secretors. Our results suggest that fucose-rich oligosaccharide sidechains, such as Lewis b antigens, are involved in the activation of complement by SAG.

scholarly journals MAp44, a Human Protein Associated with Pattern Recognition Molecules of the Complement System and Regulating the Lectin Pathway of Complement Activation

2009 ◽  
Vol 183 (11) ◽  
pp. 7371-7378 ◽  
Author(s):  
Søren E. Degn ◽  
Annette G. Hansen ◽  
Rudi Steffensen ◽  
Christian Jacobsen ◽  
Jens C. Jensenius ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Complement System ◽  
Complement Activation ◽  
Human Protein ◽  
Lectin Pathway ◽  
The Complement System

scholarly journals A Plausible Role for Collectins in Skin Immune Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Tian Wang ◽  
Ke Li ◽  
Shengxiang Xiao ◽  
Yumin Xia
Keyword(s):  
Complement System ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Lectin Pathway ◽  
Immune Homeostasis ◽  
Innate Immune Responses ◽  
Mannose Binding ◽  
The Complement System ◽  
Complex Organ

The skin is a complex organ that faces the external environment and participates in the innate immune system. Skin immune homeostasis is necessary to defend against external microorganisms and to recover from stress to the skin. This homeostasis depends on interactions among a variety of cells, cytokines, and the complement system. Collectins belong to the lectin pathway of the complement system, and have various roles in innate immune responses. Mannose-binding lectin (MBL), collectin kidney 1, and liver (CL-K1, CL-L1) activate the lectin pathway, while all have multiple functions, including recognition of pathogens, opsonization of phagocytosis, and modulation of cytokine-mediated inflammatory responses. Certain collectins are localized in the skin, and their expressions change during skin diseases. In this review, we summarize important advances in our understanding of how MBL, surfactant proteins A and D, CL-L1, and CL-K1 function in skin immune homeostasis. Based on the potential roles of collectins in skin diseases, we suggest therapeutic strategies for skin diseases through the targeting of collectins and relevant regulators.

scholarly journals A Review of Complement Activation in SLE

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Arthur Weinstein ◽  
Roberta V. Alexander ◽  
Debra J. Zack
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Adverse Outcomes ◽  
Pathogenetic Mechanism ◽  
Activation Products ◽  
The Complement System ◽  
Anti Phospholipid Syndrome ◽  
Lupus Disease Activity

Abstract Purpose of Review Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis. Recent Findings Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Summary Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.

Changes in complement activation products after anti-VEGF injection for choroidal neovascularization in age-related macular degeneration and pachychoroid disease

2020 ◽  
Author(s):  
Keiichiro Tanaka ◽  
Yasuharu Oguchi ◽  
Tomoko Oomori ◽  
Yumi Ishida ◽  
Hiroaki Shintake ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Complement System ◽  
Complement Activation ◽  
Age Related Macular Degeneration ◽  
Anti Vegf ◽  
Age Related ◽  
Activation Products ◽  
The Complement System ◽  
Vegf Level

Abstract We evaluated changes in the complement system resulting from anti-vascular endothelial growth factor (VEGF) in eyes with age-related choroidal neovascularization (CNV) including neovascular age-related macular degeneration, pachychoroid neovasculopathy, and polypoidal choroidal neovasculopathy. We measured the concentrations of the complement activation products (C3a, C4a), VEGF, and monocyte chemotactic protein-1 in the aqueous humor during intravitreal anti-VEGF injections for CNV. The VEGF level decreased significantly (P < 0.001), while the C3a and C4a levels increased significantly (P < 0.001 for both comparisons) 1 month after two monthly anti-VEGF injections. The VEGF level was correlated with the C3a (R = 0.328, P = 0.007) and C4a (R = -0.237, P = 0.055) levels at baseline, but the correlation between the VEGF and C3a levels (R = -0.148, P = 0.242) changed significantly (P = 0.028 by analysis of covariance) after anti-VEGF treatment. The C3a increase after anti-VEGF therapy did not change the visual outcomes in eyes with CNV for 1 year. Dysregulation of the complement system can be induced by excessive reduction of intraocular VEGF after anti-VEGF therapy.

scholarly journals Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

2021 ◽  
Vol 12 ◽  
Author(s):  
Youssif M. Ali ◽  
Matteo Ferrari ◽  
Nicholas J. Lynch ◽  
Sadam Yaseen ◽  
Thomas Dudler ◽  
...  
Keyword(s):  
Complement Activation ◽  
Lectin Pathway ◽  
Inhibitory Antibody ◽  
Hek 293 ◽  
N Protein ◽  
293 Cells ◽  
Activation Products ◽  
Inflammatory Phenotype ◽  
Subsequent Activation ◽  
Cellular Immune

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.

Sign in / Sign up

Export Citation Format

Share Document