Complement Activation Pathways Overview

The classical pathway of complement activation is triggered by the binding of C1 to antibody-antigen (Ab:Ag) complexes, typically IgM or IgG.

C1 is a protein complex composed of three subunits: C1q, C1r, and C1s.

One C1q molecule binds to two molecules each of C1r and C1s, forming a larger complex.

C1q binds to IgM or IgG antibodies that have attached to a pathogen, triggering the activation cascade.

The binding of C1 to an antibody-antigen complex activates the protease activity of C1r and C1s, leading to the cleavage of C2 and C4.

C2 and C4 are cleaved by C1s into smaller fragments, leading to the formation of the C3 convertase, a key enzyme in the complement cascade.

The C3 convertase in the classical pathway is formed from the complex of C4b and C2a, which together act as a protease.

The formation of C3 convertase marks the convergence of the classical, lectin, and alternative pathways, as this enzyme is common to all three pathways.

The classical pathway of complement activation is initiated by the binding of C1q to antibody-antigen complexes.

The classical pathway activates C1r, which in turn cleaves C1s.

Activated C1s cleaves C4, generating C4b and C4a. C4b covalently binds to the pathogen surface.

Bound C4b attracts C2, which is cleaved by C1s to form C2a.

The complex C4b2a is formed, which acts as the C3 convertase of the classical pathway.

C3b binds to the C3 convertase, creating C5 convertases: C4b2a3b and C3bBb3b.

C5b initiates the assembly of the membrane attack complex (MAC), which forms pores in cell membranes.

The MAC allows ions and small molecules to freely pass through the cell membrane, resulting in cell lysis.

A system of proteins in the blood that helps to fight off infections. It can be activated by three pathways: the classical, lectin, and alternative pathways.

The pathway of complement activation that is triggered by the binding of mannose-binding lectin (MBL) to mannose residues on the surface of pathogens. It resembles the classical pathway, but uses MBL instead of antibodies.

The pathway of complement activation that is initiated by the direct interaction of C3 with the surface of pathogens. It is a self-amplifying loop that does not require antibodies or lectins.

A key enzyme in the complement cascade that cleaves C3, generating C3a and C3b. C3a is involved in inflammation, while C3b opsonizes pathogens and activates further complement components.

A complex of complement proteins that forms a pore in the membrane of pathogens, leading to their lysis. It is the final step in the complement cascade.

Proteins that regulate the activity of the complement system. They prevent excessive or uncontrolled activation of complement, protecting host cells and tissues from damage.

A serpin (serine protease inhibitor) that regulates the classical pathway by binding to and inactivating the C1r2s2 complex. It is a soluble inhibitor found in plasma.

C1 inhibitor (C1INH) is a protein that regulates the classical complement pathway by limiting the activity of the C1 complex, which consists of C1q, C1r, and C1s. C1INH binds to and inactivates the activated forms of C1r and C1s, preventing them from cleaving C4 and C2, which are crucial components of the classical pathway.

The C3 convertase (C4b2b) is a key enzyme in the classical complement pathway. It is formed when C4b, a cleavage product of C4, binds to C2b, a cleavage product of C2. The C3 convertase then cleaves C3, initiating the formation of the membrane attack complex (MAC), which ultimately leads to lysis of the target cell.

Three regulators bind to C4b to control the classical pathway: C4 binding protein (C4BP), complement receptor 1 (CR1), and decay accelerating factor (DAF). They bind to C4b and facilitate the dissociation of C2a, preventing further activation of the C3 convertase. DAF is a membrane-bound protein, while C4BP and CR1 are often found in the fluid phase.

C1INH deficiency is a genetic disorder that can lead to hereditary angioedema (HAE), a disease characterized by swelling of the skin, airways, and gastrointestinal tract. The deficiency in C1INH leads to uncontrolled activation of the classical complement pathway.

C1 inhibitor (C1INH) limits the time in which active C1 can cleave C4 and C2. Factors I and C4BP/CR1/MCP, as well as C4c and C4d help to control the classical pathway, and also play a role in the mannose-binding lectin (MBL) pathway.

C4b bound to C4BP, membrane cofactor protein (MCP), or CR1 can be cleaved by Factor I, generating inactive C4c and C4d.

C3b bound to Factor H, DAF, or CR1 is inactivated by Factor I, resulting in iC3b.

CD59 (protectin) prevents the formation of the membrane attack complex (MAC) by inhibiting the binding of C9 to the C5b678 complex.

The complement system encompasses the classical, lectin, and alternative pathways. Each pathway is initiated by distinct triggers, involving specific components.

The classical pathway is triggered by the binding of C1 to antigen-antibody complexes, typically IgM or IgG, while the lectin pathway is activated by the binding of lectins to carbohydrates on pathogen surfaces.

The alternative pathway is a spontaneous activation pathway that's triggered by the initial binding of C3b to microbial surfaces. This pathway is regulated by factors like Factor H and DAF.

Both the classical and lectin pathways involve the formation of a C3 convertase which then produces C3b. The C3b further amplifies the complement cascade by activating the alternative pathway.

Host cells express inhibitors like DAF, MCP, and CD59 (membrane-bound), while serum proteins like Factor H and Factor I also act as inhibitors.