Classical Complement Pathway

Complement Activation Classical Pathway Background

Although at least 21 different serum proteins have thus far been identified as part of the classical complement pathway, one can look at it as a pathway that is primarily activated by either IgG or IgM binding to an antigen and involves 11 major serum protein components.

IgG and IgM are classes of antibody molecules, one of the major defenses against microbes is the immune defenses' production of antibody molecules against that microbe. The "tips" of the antibody (the Fab portion have shapes that are complementary to epitopes - portions of microbial proteins and glycoproteins found on the surface of the microbe. The Fc portion of IgG and IgM can activate the classical complement pathway by enabling the first enzyme in the pathway, C1, to assemble.

Complement Activation Classical Pathway Steps

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 Classical Pathway Clinical Significance

Because of its role in the innate immune system classical complement has been implicated in a number of pathogen related disorders. Complement is responsible for immune inflammatory response in adipose tissues which has been implicated in the development of obesity. Obesity in turn results in an abnormally high level of complement activation via production of the C1 component of the classical pathway, which can lead to tissue inflammation and eventually insulin resistance, however the exact mechanisms that causes this is yet unknown.

Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via classical complement activation. This process involves creating synthetic peptides that target conserved regions in HIV specific proteins and induce an antibody specific immune response through IgG antibodies. This is important for targeting the virus in its intracellular phase because the antibodies specific to the synthetic peptides can trigger the classical complement pathway and induce the death of HIV infected cells.

Classical complement activation has also been shown to combat Methicillin-resistant Staphylococcus aureus. Certain variants of the IgM antibody were found to bind the Methicillin-resistant Staphylococcus aureus these IgM were found to be critical in complement activation through the classical pathway and subsequent destruction of the bacteria. Therapies that utilize classical complement activation have been shown to be effective in targeting and killing cancer cells and destroying tumors. Tachyplesin, a small peptide, has been shown to exhibit these effects. When injected into target tissue encourages recruitment of c1q and activates downstream events, eventually leading to the formation of the c5b-9 complex which damages tumor cells, killing them.


Nesargikar P, et al. (2012). The complement system: history, pathways, cascade and inhibitors. European Journal of Microbiology and Immunology, 2(2), 103-111.