Most of the
proteins and
glycoproteins that constitute the complement system are synthesized by
hepatocytes. But significant amounts are also produced by tissue
macrophages, blood
monocytes, and
epithelial cells of the
genitourinary system and
gastrointestinal tract. The three pathways of activation all generate homologous variants of the
protease C3-convertase. The classical complement pathway typically requires
antigen-antibody complexes for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous
complement component 3 (C3) hydrolysis, foreign material, pathogens, or damaged cells. The
mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by
phagocytic cells by
opsonization. In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a.
C5 convertase is also formed by the classical pathway when C3b binds C4b and C2b.
C5a is an important
chemotactic protein, helping recruit inflammatory cells. C3a is the precursor of an important
cytokine (
adipokine) named
ASP (although this is not universally accepted ) and is usually rapidly cleaved by
carboxypeptidase B. Both C3a and C5a have
anaphylatoxin activity, directly triggering
degranulation of
mast cells as well as increasing vascular permeability and
smooth muscle contraction. MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes
osmotic lysis of the target cell.
Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the
protostome horseshoe crab species, putting the origins of the system back further than was previously thought.
Classical pathway The
classical pathway is triggered by activation of the C1-complex. The
C1-complex is composed of 1 molecule of
C1q, 2 molecules of C1r and 2 molecules of C1s, or
C1qr2s2. This occurs when C1q binds to
IgM or
IgG complexed with
antigens. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when
C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two
C1r molecules. C1r is a serine protease. They then cleave
C1s (another serine protease). The C1r2s2 component now splits
C4 and then
C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).
Alternative pathway The
alternative pathway is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous
C3 hydrolysis due to the breakdown of the internal
thioester bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways. The C3bBb complex is stabilized by binding oligomers of
factor P (properdin). The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b. This newly bound C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include
CD35,
CD46,
CD55 and
CD59, depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of
innate immunity. Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent
anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the
membrane attack complex. This creates a hole or pore in the membrane that can kill or damage the pathogen or cell. In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.
Complement protein fragment nomenclature Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b. However, this was amplified in their 1999 4th edition, to say that: "It is also useful to be aware that the larger active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers. Here, for consistency, we shall call all large fragments of complement
b, so the larger fragment of C2 will be designated C2b. In the classical and lectin pathways the C3 convertase enzyme is formed from membrane-bound C4b with C2b." The assignment is mixed in the latter literature, though. Some sources designate the larger and smaller fragments as C2a and C2b respectively while other sources apply the converse. However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition
Review == Activation of complements by antigen-associated antibody ==