Complement Activation Pathways

Complement Activation Classical Pathway(Proteins | Antibodies | Genes | ELISA Kits)

Complement Activation Lectin Pathway (Proteins | Antibodies | Genes | ELISA Kits)

Complement Activation Alternative Pathway (Proteins | Antibodies | Genes | ELISA Kits)

Serine Proteases of Complement Activation Pathway (Proteins | Antibodies | Genes | ELISA Kits)

Complement Activation Pathways Background

Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage.

Complement Activation Classical Pathway

The classical pathway is initiated by IgM or IgG antigen/antibody complexes binding to C1q (first protein of the cascade) leading to activation of C1r, which in turn cleaves C1s. This in turn activates the serine proteases that lead to cleaving of C4 and C2, leading to formation of C4b2a (C3 convertase), which in turn cleaves C3 into C3a and C3b. While C3a acts as a recruiter of inflammatory cells (anaphylatoxin), C3b binds to the C4b2a complex to form C5 convertase (C4b2a3b). The C5 convertase initiates the formation of the Membrane Attack Complex (MAC), that inserts into membrane creating functional pores in bacterial membranes leading to its lysis. The classical pathway can also be activated by other danger signals like C-reactive protein, viral proteins, polyanions, apoptotic cells and amyloid, thus providing evidence that classical pathway could be activated independent of antibodies.

Complement Activation Alternative Pathway

Complement activation alternative pathway was discovered by Pillemer and colleagues in 1954 but was recognized universally some years later. The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections. The alternative pathway is one of three complement pathways that opsonize and kill pathogens.This pathway is activated by viruses, fungi, bacteria, parasites, cobra venom, immunoglobulin A, and polysaccharides and forms an important part of the defense mechanism independent of the immune response. Here, C3b binds to factor B that is cleaved by factor D to Bb. C3bBb complex then acts as the C3 convertase and generates more C3b through an amplification loop. Binding of factor H to C3b increases its inactivation by factor I. Properdin stabilizes it, preventing its inactivation by factors H and factor I. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. It simply does not require specific antigen-antibody interactions for initiation.

Complement Activation Lectin Pathway

The lectin pathway is very similar to the classical pathway. It is initiated by the binding of mannose-binding lectin (MBL) to bacterial surfaces with mannose-containing polysaccharides (mannans). Binding of MBL to a pathogen results in the association of two serine proteases, MASP-1 and MASP-2 (MBL-associated serine proteases). MASP-1 and MASP-2 are similar to C1r and C1s, respectively and MBL is similar to C1q. Formation of the MBL/MASP-1/MASP-2 tri-molecular complex results in the activation of the MASPs and subsequent cleavage of C4 into C4a and C4b. The C4b fragment binds to the membrane and the C4a fragment is released into the microenvironment. Activated MASPs also cleave C2 into C2a and C2b. C2a binds to the membrane in association with C4b and C2b is released into the microenvironment. The resulting C4bC2a complex is a C3 convertase, which cleaves C3 into C3a and C3b. C3b binds to the membrane in association with C4b and C2a and C3a is released into the microenvironment. The resulting C4bC2aC3b is a C5 convertase. The generation of C5 convertase is the end of the lectin pathway. The biological activities and the regulatory proteins of the lectin pathway are the same as those of the classical pathway.

Complement Activation Pathways References

1. Nesargikar P, et al. (2012). The complement system: history, pathways, cascade and inhibitors. European Journal of Microbiology and Immunology, 2(2), 103-111.
2. Thurman, J M, et al. (2006). The central role of the alternative complement pathway in human disease. The Journal of Immunology, 176(3), 1305-1310.

Complement System
Complement System Overview
What is Complement System
How Does Complement System Work
Complement Protein Fragment Nomenclature
Complement System Component / Protein Regulator and Receptor
Complement Component / Protein of Complement System
Complement Regulator of Complement System: RCA/CCP family
Complement Regulator of Complement System: Others
Complement Receptors of Complement System
Complement Genetic Feature
Regulator of complement activation / RCA Gene Cluster
Complement MAC Gene Cluster
Complement MHC Class III Gene Cluster
Complement Activation Pathways
Complement Activation Definition
Complement Activation Classical Pathway
Complement Activation Alternative Pathway
Complement Activation Lectin Pathway
Serine Proteases of Complement Activation Pathway
Complement System Role
Complement System and Direct Interactions
Complement System Function in Immune System
Complement-Dependent Cytotoxicity/CDC
Therapeutic Target of Complement System
Complement System and Toll-like Receptors / TLRs
Complement System and Coagulation
Complement Cascade and Inhibitors
Complement Evasion of Pathogens
Complement System and Antimicrobial Peptides/AMPs
Complement System and Diseases
Complement System and Cancer
Complement System and Rheumatic Diseases
Complement Receptor 1 / CR1 and Alzheimer's Disease / AD
Complement System and Autoimmune Diseases
Complement System and Age-Related Macular Degeneration/AMD
Complement System and Schizophrenia
Complement System Deficiency Diseases
Classical Pathway Deficiency
Alternative Pathway Deficiency
Complement Receptor Deficiency
Mannose-Binding Lectin / MBL Pathway Deficiency
Membrane Attack Complex/MAC Deficiency
Total Complement Activity / CH50 / CH100
Complement System Structure
Complement Membrane Attack Complex/MAC
Complement Component / Protein Structure
Complement Regulator Structure
Complement Receptor Structure
Collectins and Ficolins: Humoral Lectins of the Innate Immune System
Complement System Effector Functions
Complement Mediated Opsonization
Complement Mediated Cell Lysis
Complement Mediated Phagocytosis
Complement Mediated Inflammation
Complement Mediated Chemotaxis
Complement Mediated Antibody Formation
Anti-Complement Antibody Products