What is the Difference Between Classical Alternative and Lectin Pathway

The key difference between classical alternative and lectin pathway is that the initiation of the classical pathway takes place through the binding of antigen-antibody complexes to the C1q protein, and the alternative pathway initiation takes place through the binding of C3b onto foreign surfaces, while initiation of lectin pathway takes place through mannose-binding lectin.

The complement pathway or complement cascade is a part of the immune system that enhances the ability of phagocytic cells and antibodies to destroy and clear microbes and damaged cells from an organism, promote inflammation, and attack the cell membrane of the pathogen. The complement pathways are generated by the innate and adaptive immune systems. This system consists of small proteins which are synthesized by the liver and circulate in the blood in the inactive form. These proteins or precursors are activated in the complement pathways. There are three types of complement pathways: the classical pathway, the alternative pathway, and the lectin pathway.

CONTENTS

1. Overview and Key Difference
2. What is a Classical Pathway
3. What is an Alternative Pathway
4. What is a Lectin Pathway
5. Similarities – Classical Alternative and Lectin Pathway
6. Classical vs Alternative vs Lectin Pathway in Tabular Form
7. Summary – Classical vs Alternative vs Lectin Pathway

What is a Classical Pathway?

The classical pathway is one of the three pathways that activate the complement system. The complement system is a part of the immune system. The antigen-antibody complexes along with antibody isotypes IgG and IgM initiate the complement system. Apoptotic cells, necrotic cells, and acute-phase proteins also activate the classical pathway.

This pathway is initiated by the binding of antigen-antibody complexes to the C1q protein; the globular region of C1q recognizes and binds to the Fc region of the antibodies IgG and IgM isotypes. They also bind to the bacterial and viral surface proteins, apoptotic cells, and acute-phase proteins. During the absence of activation factors, C1q becomes a part of the inactive C1 complex, which consists of six molecules of C1q, two molecules of C1r, and two molecules of C1s. The binding of C1q leads to conformational changes and activation of serine protease C1r. This activates and cleaves serine protease C1s. C1s then cleave C4 into C4a and C4b and C2 into C2a and C2b. C4b aids in the formation of C3 convertase, C4bC2a. The C3 convertase has the ability to cleave c3 into C3a and C3b, which is an important factor for the next enzymatic reaction. C3v binds to C3 convertase to form C5 convertase, C4b2a3b, while C3a recruits inflammatory cells through. These are known as anaphylatoxins. C5 convertase cleaves C5 into C5 a and C5b. C5b combines with other terminal components to form the membrane attack complex (MAC). This leads to the lysis of invasive bacteria by insertion into target cell membranes, creating functional pores.

What is an Alternative Pathway?

The alternative pathway is one of the three pathways that opsonize and destroys pathogens. Virus, fungi, bacteria, parasites, immunoglobulin A and polysaccharides activate the alternative pathway and form an essential defense mechanism independent of the immune system. The C3b protein triggers this pathway, and this protein directly binds to a microbe. Foreign materials and damaged tissues also trigger the alternative pathway. Since C3b is free and abundant in plasma, it has the ability to bind to a host cell or pathogen surface. Different regulatory proteins take part in the prevention of complement activation on the host cell.

Complement receptor 1 (CR1) and decay-accelerating factor (DAF) compete with Factor B to bind with C3b on the cell’s surface and remove Bb from the C3bBb complex. Cleaving of C3b into the inactive form, iC3b, by plasma protease called complement factor 1 inhibits the formation of C3 convertase. Complement Factor 1 requires a C3b binding protein cofactor such as Factor H, Cr1, or membrane cofactor of proteolysis. Factor H inhibits the formation of C3 convertase by competing with Factor B to bind with C3b. This also accelerates the decay of the C3 convertase. CFHR5, which is the complement factor H related protein 5, has the ability to bind to act as a cofactor for factor 1 and accelerates the decaying activity, and binds to C3b at host cells.

What is a Lectin Pathway?

The lectin pathway is a type of cascade reaction in the complement system. After the activation of this pathway, the action of C4 and C2 produces activated complement proteins further down the cascade. This pathway does not recognize an antibody bound to its target and initiates with mannose-binding lectin (MBL) or ficolin binding to certain sugars. This MBL binds to sugars such as mannose and glucose with OH groups in terminal positions on carbohydrates or glycoproteins components of bacteria, fungi, and some viruses.

MBL, also known as mannose-binding protein, is capable of initiating the complement system by binding to pathogen surfaces. Multimers of MBL form complexes with serine proteases (mannose binding lectin associated serine protease: MASP1, MASP2 and MASP3) which are protein zymogens. They are similar to C1r and C1s in other pathways. MASP1 and MASP2 activate to cleave components C4 and C2 into C4a, C4b, C2a, and C2b. C4b tends to bind to bacterial cell membranes. If it does not activate, it combines with C2a to form classical C3 convertase opposing alternative C3 convertase. C4a and C2b act as potent cytokines. C4a causes degranulation of mast cells and basophils, and C2b increases vascular permeability.

What are the Similarities Between Classical Alternative and Lectin Pathway?

• Classical, alternative, and lectin pathways are activated by a cascade of reactions leading to the membrane attack complex.
• They are a part of the immune system.
• Each pathway has unique proteins for initiation.
• They are activated by certain isotypes of antibodies bound to antigens

What is the Difference Between Classical Alternative and Lectin Pathway?

The initiation of the classical pathway takes place through the binding of antigen-antibody complexes to the C1q protein. Alternative pathway initiation takes place through the binding of C3b onto foreign surfaces, while initiation of the lectin pathway takes place through mannose-binding lectin. Thus, this is the key difference between classical alternative and lectin pathway. The role of the classical pathway is that it acts as the effector arm of the adaptive immunity while alternative and lectin pathways function in innate immunity. Moreover, C4 and C2 activations in the classical pathway are C1s, and in lectin pathway is MASP-2, while there is no C4 and C2 activation in the alternative pathway.

The below infographic presents the differences between classical alternative and lectin pathway in tabular form for side by side comparison.

Summary – Classical vs Alternative vs Lectin Pathway

The initiation of the classical pathway takes place through the binding of antigen-antibody complexes to the C1q protein. Alternative pathway initiation takes place through the binding of C3b onto foreign surfaces while initiation of the lectin pathway takes place through mannose-binding lectin. So, this is the key difference between classical alternative and lectin pathway.

Reference:

1. “Classical Pathway.” Creative Biolabs.
2. Fujita, Teizo. “Evolution of the Lectin–Complement Pathway and Its Role in Innate Immunity.” Nature News, Nature Publishing Group.

Image Courtesy:

1. “Complement pathways.” By Tossh_eng – https://upload.wikimedia.org/wikipedia/commons/b/b0/Complement-pathways.png (CC BY-SA 4.0) via Commons Wikimedia
2. “Figure 1.4. Complement activation” By Hofman.martijn – Own work (CC BY-SA 4.0) via Commons Wikimedia