Classical complement pathway

The classical complement pathway is one of three pathways which activate the complement
system, which is part of the immune system. The classical complement pathway is initiated by
antigen-antibody complexes with the antibody isotypes IgG and IgM.[1][2]

Classical and alternative pathways shown with

their corresponding proteins

Following activation, a series of proteins are recruited to generate C3 convertase (C4b2b,

historically referred C4b2a), which cleaves the C3 protein. The C3b component of the cleaved C3
binds to C3 convertase (C4b2b) to generate C5 convertase (C4b2b3b), which cleaves the C5
protein. The cleaved products attract phagocytes to the site of infection and tags target cells for
elimination by phagocytosis. In addition, the C5 convertase initiates the terminal phase of the
complement system, leading to the assembly of the membrane attack complex (MAC). The
membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and
death.[2][3]

The classical complement pathway can also be activated by apoptotic cells, necrotic cells, and
acute phase proteins.[1][3][4]
Complement cascade

The classical complement pathway leading

into a complement cascade that is shared with
the alternative pathway.

The classical pathway is distinct from the other complement pathways in its unique activation
triggers and cascade sequence. Activation of the complement pathway through the classical, lectin
or alternative complement pathway is followed by a cascade of reactions eventually leading to the
membrane attack complex.

Initiation

The classical complement pathway can be initiated by the binding of antigen-antibody complexes to
the C1q protein. The globular regions of C1q recognize and bind to the Fc region of antibody
isotypes IgG or IgM.[2] These globular regions of C1q can also bind to bacterial and viral surface
proteins, apoptotic cells, and acute phase proteins.[5] In the absence of these activation factors, C1q
is part of the inactive C1 complex which consists of six molecules of C1q, two molecules of C1r,
and two molecules of C1s.[1][4]

Formation of C4b convertase

The binding of C1q with pathogen surface or antigen-antibody immune complex leads to
conformational changes and the activation of the serine protease C1r. The activated C1r then
cleaves and activates the serine protease C1s.[3][4] Activated C1s cleaves C4 into C4a and C4b.

Regulation of C4b

The newly formed C4b cannot stay activated as a highly reactive thioester bond is revealed once C4
has been cleaved. The thioester bond is cleaved by water resulting in its cleavage permanently
deactivating the C4b molecule. As a result of this C4b is restricted to only bind to pathogen
surfaces. They would undergo rapid deactivation in the time it took to travel from the origin of
activation where C1q is complexed with an antigen-antibody immune complex(IC) or where C1q is
directly attached to the pathogens surface.[6]

Formation of C3-convertase.

Surface-bound C4b acts as a receptor for the binding of C2.[6] The binding of C2 and C4b results in
C2 being cleaved by C1s into C2a and C2b. C2b diffuses into the plasma as a protein inflammatory
mediator while C2a remains attached with C4b, forming the C3-convertase (C4b2a). The function of
the membrane-bound C3-convertase is the cleavage of many many molecules of C3 into C3a and
C3b. C3a is a smaller fragment of C3 is a potent inflammatory mediator.

C3b function and structure.

C3b can act as an opsonin. C3b is very similar to C4 in both structure and function also has a
thioester bond that forces it to attach to surface nucleophile of the activator(namely the pathogen
or IC). Phagocytes have receptors for C3b and as a result of receptor-ligand binding are able to
more easily recognize and engulf pathogen molecules. While the anaphylatoxin C3a interacts with
its C3a receptor (C3aR) to recruit leukocytes, C3b contributes to further downstream complement
activation.[1][3]

Formation of C5 convertase and MAC

C3b binds to the C3 convertase (C4b2a), to form C5 convertase (C4b2b3b). C5 convertase then
cleaves C5 into C5a and C5b.[3] Like C3a, C5a is also an anaphylatoxin that interacts with its
cognate C5a receptor (C5aR) to attract leukocytes.[1] Subsequent interactions between C5b and
other terminal components C6, C7, C8, and C9 form the membrane attack complex or the C5b-9
complex which forms pores on the target cell membranes to lysing.[7]
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.[8] 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.[8]

Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via
classical complement activation.[9] 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.[10] 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.[11] 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.

Lack of regulation of the classical complement pathway through the deficiency in C1-inhibitor
results in episodic angioedema.[1] C1-inhibitor defiency can be hereditary or acquired, resulting in
hereditary or acquired angioedema.[12] C1-inhibitor plays the role of inactivating C1r and C1s to
prevent further downstream classical complement activity.[13][12] C1-inhibitor controls the processes
involved in maintaining vascular permeability. As a result, C1-inhibitor levels of less than 50% of the
standard lead to increased vascular permeability, characteristic of angioedema.[12] Cinryze, a human
plasma derived C1-esterase inhibitor, has been approved for use in 2008 for the prevention of
hereditary angioedema attacks.[14][15]

Deficiency in the C1q protein of the classical complement pathway can lead to development of
systemic lupus erythematosus.[2][16] Among the many functions of C1q, C1q triggers clearance of
immune complexes and apoptotic cells by activating the classical pathway and binding directly onto
phagocytes.[1][17] Consequently, systemic lupus erythematosus from insufficient amounts of C1q is
characterized by the accumulation of autoantibodies and apoptotic cells.[4] Studies are being done
to look into antibodies against C1q as a diagnostic marker for systemic lupus erythematosus.[18][19]

See also

Alternative complement pathway

Lectin pathway

References

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