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Complement System

The complement system is part of the innate immune system and plays an important role in the host defense, inflammation, tissue regeneration and other physiological processes. Complement activation results in opsonization of pathogens and their removal by phagocytes. It also causes chemotactic attraction of phagocytes and macrophages. Furthermore, the complement system forms the terminal attack complex (MAC), a membrane channel causing osmotic lysis of the respective pathogen. While complement is not adaptable it does complement the adaptive immune system and it is also involved in B and T cell response regulation.

Activation of complement unfolds along three different complement activation pathways depending on the nature of the pathogen: the classical pathway, the lectin pathway, and the alternative pathway. All three converge into the common terminal pathway that leads to the formation of the MAC. In addition, anaphylatoxins C3a and C5a elicit a plethora of physiological responses that range from chemoattraction to apoptosis. The complement system consists of more than 30 proteins that are either present as soluble proteins in the blood or as membrane-associated proteins. Most exist as inactive zymogens that are then sequentially cleaved and activated. The central component in all three pathways is component C3, the most abundant complement protein found in the blood. Its activation induces the formation of the activation products C3a, C3b, and C5a and ultimately the MAC.

In addition to these three established pathways, it has been shown that factors such as kallikrein, plasmin, thrombin, and factor XIIa activate the complement system independently of the C3 protein.

In COVID-19, the SARS-CoV-2 nucleocapsid protein protein triggers activation of the lectin pathway of the complement system through interaction with mannose binding lectin (MBL)-associated serine protease (MASP)2. Released soluble N protein dimers interact with MASP-2, further accelerating MASP-2 activation and activation of the complements system. The positive feedback through cell lysis and release of N-protein leads to elevation of pro-inflammatory cytokines, characterized as cytokine storm.

N-protein neutralization is a promising avenue for a COVID-19 therapy, as well as the targeted inhibition of MASP-2. Suppressive effects could also be observed with anti-C5a antibody treatment.

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References:

Gao T, et al. (2020): "Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation" medRxiv, [DOI: 10.1101/2020.03.29.20041962v2]
Risitano AM, et al., (2020): “Complement as a target in COVID-19?” Nature Reviews Immunology, 65(12): 1337-45 [DOI: 10.1038/s41577-020-0320-7]

Classical Pathway

C1QA (Complement Component 1, Q Subcomponent, A Chain):

C1QB (Complement Component 1, Q Subcomponent, B Chain):

C1QC (Complement Component 1, Q Subcomponent, C Chain):

C1QC Antibody (Center) (ABIN655873) flow cytometric analysis of HL-60 cells (right histogram) compared to a negative control cell (left histogram).FITC-conjugated goat-anti-rabbit secondary antibodies were used for the analysis.

C1R (Complement Component 1, R Subcomponent):

Human Tonsil: Formalin-Fixed, Paraffin-Embedded (FFPE)

C1S (Complement Component 1, S Subcomponent):

C4a - C4A:

C4 - Complement 4:

C4b - C4B:

Lectin Pathway

MASP2 (Mannan-Binding Lectin serine Peptidase 2):

The Ra-reactive factor (RARF) is a complement-dependent bactericidal factor that binds to the Ra and R2 polysaccharides expressed by certain enterobacteria. Alternate splicing of this gene results in two transcript variants encoding two RARF components that are involved in the mannan-binding lectin pathway of complement activation. The longer isoform is cleaved into two chains which form a... More...

MASP1 (Mannan-Binding Lectin serine Peptidase 1 (C4/C2 Activating Component of Ra-Reactive Factor)):

MBL2 (Mannose-Binding Lectin (Protein C) 2, Soluble):

FCN1 (Ficolin (Collagen/fibrinogen Domain Containing) 1):

FCN2 (Ficolin (Collagen/fibrinogen Domain Containing Lectin) 2 (Hucolin)):

FCN3 (Ficolin (Collagen/fibrinogen Domain Containing) 3 (Hakata Antigen)):

Alternative Pathway

CFB - Complement Factor B

Immunohistochemistry of paraffin-embedded mouse kidney using CFB antibody at dilution of 1:200 (x400 lens)

CFD - Adipsin

CFD Antibody (N-term) western blot analysis in A549 cell line lysates (35ug/lane).This demonstrates the CFD antibody detected the CFD protein (arrow).

C3 (Complement Component 3):

C3b - Complement Fragment 3b:

CFH - Complement Factor H:

Terminal Pathway

C5 (Complement Component 5):

Flow cytometric analysis of MDA-231 cells using C5 Antibody (N-term)(bottom histogram) compared to a negative control cell (top histogram). FITC-conjugated goat-anti-rabbit secondary antibodies were used for the analysis.

The protein encoded by this gene is the fifth component of complement, which plays an important role in inflammatory and cell killing processes. This protein is comprised of alpha and beta polypeptide chains that are linked by a disulfide bridge. An activation peptide, C5a, which is an anaphylatoxin that possesses potent spasmogenic and chemotactic activity, is derived from the alpha... More...

C5a - C5A:

C7 (Complement Component C7):

C8A (Complement Component 8, alpha Polypeptide):

C8B (Complement Component 8, beta Polypeptide):

C8G (Complement Component 8, gamma Polypeptide):

C9 (Complement Component C9):

Regulators

CD55 (Complement Decay-Accelerating Factor):

Formalin-fixed and paraffin embedded human lung carcinoma labeled with Anti-CD55/DAF Polyclonal Antibody, Unconjugated at 1:200 followed by conjugation to the secondary antibody and DAB staining.

CD59 (CD59):

Western blot analysis using CD59 antibody against human CD59 recombinant protein. (Expected MW is 34.7 kDa).

SERPING1 (Serpin Peptidase Inhibitor, Clade G (C1 Inhibitor), Member 1):

CFI - Complement Factor I:

CR1 (Complement Component Receptor 1 (CD35)):

CFP (Complement Factor P):

C4BPA (Complement Component 4 Binding Protein, alpha):

C4BPB (Complement Component 4 Binding Protein, beta):

Extrinsic Pathway

F2 - Prothrombin

Western blot (WB) analysis of Prothrombin polyclonal antibody at 1:500 dilution Lane1:K562 whole cell lysate(40ug) Lane2:A549 whole cell lysate(40ug) Lane3:L02 whole cell lysate(40ug) Lane4:The Liver tissue lysate of Rat(40ug) Lane5:The Liver tissue lysate of Mouse(40ug)

Coagulation factor II is proteolytically cleaved to form thrombin in the first step of the coagulation cascade which ultimately results in the stemming of blood loss. F2 also plays a role in maintaining vascular integrity during development and postnatal life. Mutations in F2 leads to various forms of thrombosis and dysprothrombinemia. [provided by RefSeq, Jul 2008]. More...

References:

Classical Pathway

C1QA (Complement Component 1, Q Subcomponent, A Chain):

C1QB (Complement Component 1, Q Subcomponent, B Chain):

C1QC (Complement Component 1, Q Subcomponent, C Chain):

C1R (Complement Component 1, R Subcomponent):

C1S (Complement Component 1, S Subcomponent):

C4a - C4A:

C4 - Complement 4:

C4b - C4B:

Lectin Pathway

MASP2 (Mannan-Binding Lectin serine Peptidase 2):

MASP1 (Mannan-Binding Lectin serine Peptidase 1 (C4/C2 Activating Component of Ra-Reactive Factor)):

MBL2 (Mannose-Binding Lectin (Protein C) 2, Soluble):

FCN1 (Ficolin (Collagen/fibrinogen Domain Containing) 1):

FCN2 (Ficolin (Collagen/fibrinogen Domain Containing Lectin) 2 (Hucolin)):

FCN3 (Ficolin (Collagen/fibrinogen Domain Containing) 3 (Hakata Antigen)):

Alternative Pathway

CFB - Complement Factor B

CFD - Adipsin

C3 (Complement Component 3):

C3b - Complement Fragment 3b:

CFH - Complement Factor H:

Terminal Pathway

C5 (Complement Component 5):

C5a - C5A:

C7 (Complement Component C7):

C8A (Complement Component 8, alpha Polypeptide):

C8B (Complement Component 8, beta Polypeptide):

C8G (Complement Component 8, gamma Polypeptide):

C9 (Complement Component C9):

Regulators

CD55 (Complement Decay-Accelerating Factor):

CD59 (CD59):

SERPING1 (Serpin Peptidase Inhibitor, Clade G (C1 Inhibitor), Member 1):

CFI - Complement Factor I:

CR1 (Complement Component Receptor 1 (CD35)):

CFP (Complement Factor P):

C4BPA (Complement Component 4 Binding Protein, alpha):

C4BPB (Complement Component 4 Binding Protein, beta):

Extrinsic Pathway

F2 - Prothrombin

PLG (Plasminogen):

KLK1 - Kallikrein 1:

KLK2 - Kallikrein 2:

PSA - Prostate Specific Antigen:

KLKB1 (Kallikrein B, Plasma (Fletcher Factor) 1):

KLK4 - Kallikrein 4:

KLK5 - Kallikrein 5:

KLK6 - Kallikrein 6:

KLK7 - Kallikrein 7:

KLK8 - Kallikrein 8:

KLK9 - Kallikrein 9:

KLK10 - Kallikrein 10:

PRSS57 (Protease, Serine, 57):

KLK11 - Kallikrein 11:

KLK12 - Kallikrein 12:

KLK13 - Kallikrein 13:

KLK14 - Kallikrein 14:

KLK15 - Kallikrein 15:

F12 - Coagulation Factor XII:

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