Complement Pathways

See also complement system generally and regulation of the complement system

There are 3 distinct pathways of complement activation. The classical system is antibody dependent whereas the other 2 pathways, lectin and alternative, are antibody independent and are initiated by reaction of complement proteins with surface molecules of microorganisms rather than antibody. All 3 pathways generate C3, and C5 convertases and bound C5b, which is converted into a membrane attack complex (MAC). The MAC complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane. Hydrolysis of C3 by C3 convertase enzymes of the classical, lectin and alternative pathways is the major amplification step, generating large amounts of C3b, which forms part of the C5 convertase. C3b also can diffuse away from the activating surface and bind to immune complexes of foreign cell surfaces, where it functions as an opsonin by phagocytic cells bearing C3b receptors.

Cleavage fragments are designated with a small letter following the designation of the component (e.g., C3a and C3b are fragments of C3). Inactive C3b is designated iC3b. Polypeptide chains of complement proteins are designated with a Greek letter after the component (e.g., C3alpha and C3beta are the alpha and beta chains of C3. Cell membrane receptors for C3 are abbreviated CR1, CR2, CR3, and CR4.

(1) classical pathway is activated by IgG or IgM isotypes when they bind antigen, resulting in increased affinity of the Fc domains for the first component of complement C1q. Since IgM is a pentamer whereas IgG is a monomer, IgM is a better activator since there are more regions for the complement to bind. Classical pathway components are labeled with a C and a number (e.g., C1, C3) Because of the sequence in which they were identified, the first four components are numbered C1, C4, C2, and C3.
(2) lectin pathway is initiated by mannan-binding lectin (MBL) which is a protein that binds specifically to mannose residues in bacterial cell walls. It is a phylogenetically ancient mechanisms which was first shown to be activated by MBL when it interacts with repeating mannose residues on the surface of pathogens. Once MBL is bound to its target, MBL-associated proteins 1, 2, and 3 (MASP-1, MASP-2, and MASP-3) are activated, resulting in the cleavage of C4 and C2, which is then followed by the assembly of the remainder of the complement pathway. The lectin pathway is particularly important in the recognition and clearance of pathogens, as deficiencies are strongly associated with recurrent infections and earlier death in patients with cystic fibrosis and recurrent pulmonary infection. Alternative pathway components are lettered (e.g., B, P, D).

(3) alternative pathway (AP): The AP is responsible for 80-95% of total complement activity. The AP is a complement activation pathway which is triggered by artificial surfaces such as LPS from Gram negative outer membranes and rabbit erythrocytes, zymosan from fungal and yeast cell walls, as well as from many pure polysaccharides, viruses, bacterial, animal tumor cells, parasites and damaged cells. The pathway is initiated mainly by cell surface constituents that are foreign to the host like gram negative and positive bacteria. The alternative pathway generates bound C5b, the same product that the classical pathway generates but it does so without the need for antigen-antibody complexes for initiation. Because no antibody is required, it is a component of the innate immune system. This pathway involves 4 serum proteins like factor B and D. The alternative pathway is also an ancient immune mechanism that is primarily activated onto the surface of pathogens by a process called "tickover". Tickover is facilitated by the presence of surfaces that lack complement regulatory proteins and which support the binding of activated C3. Potential therapeutic targets specific to the alternative pathway include factor B, factor D, and properdin.

Activation of the alternative complement pathway begins when C3b binds to the cell wall and other cell components of the pathogens and/or to IgG antibodies. Factor B then combines with cell bound c3b and forms c3bB. C3bB is then split into Bb and Ba by factor B, forming the alternative pathway C3 convertase, C3bBb. Properdin, a serum protein, then binds C3bBb and forms C3bBbP that functions as a C3 convertase, which enzymatically splits C3 molecules into C3a and C3b. At this point, the alternative complement pathway is activated. The rate limiting step of activation of the alternative pathway in humans is the enzymatic action of factor D on the cleavage of factor B to form the alternative pathway C3 convertase.

Factor B is a tightly regulated, highly specific serine protease. It is the zymogen of the alternative pathway C3/C5 convertase, and is activated when it is split by factor D into two fragments, Ba and Bb, after it has formed a complex with C3b.The interaction between factor B and surface-bound C3b triggers a conformational change in factor B that ultimately creates the “C3 convertase” (PC3bBb) of the alternative complement pathway. The activation of the AP hinges on a Mg ion-enhanced interaction between factor B and C3b. Upon binding, factor B is rendered susceptible to proteolytic cleavage by factor D, forming fragments Ba and Bb. Bb, in associates with C3b, comprises the AP C3 convertase. This complex has serine protease activity and functions to cleave native C3 in C3a and C3b. 

 

See Complement System Generally and Functions