Complement - pediagenosis
Article Update

Sunday, July 22, 2018


Fifteen or more serum components constitute the complement system, the sequential activation and assembly into functional units of which leads to three main effects: release of peptides active in inflammation (top right); deposition of C3b, a powerful attachment promoter (or ‘opsonin’) for phagocytosis, on cell membranes (bottom right); and membrane damage resulting in lysis (bottom left). Together these make it an important part of the defences against microorganisms. Deficiencies of some components can predispose to severe infections, particularly bacterial (see Fig. 33).


The upper half of the figure represents the serum, or ‘fluid’ phase, the lower half the cell surface, where activation (indicated by dotted haloes) and assembly largely occur. Activation of complement can be started either via adaptive or innate immune recognition. The former pathway is called ‘classic’ (because first described), and is initiated by the binding of specific antibody of the IgG or IgM class (see Fig. 14) to surface antigens (centre left); the innate, and probably earlier evolutionary pathways include the ‘alternative’ pathway, in which complement components are activated by direct interaction with polysaccharides on some microbial cell surfaces, or by a variety of pattern recognition receptors (PRRs; see Fig. 5) including ‘mannosebinding lectin (MBL) and C-reactive protein (CRP; centre left). Some of the steps are dependent on the divalent ions Ca2+ (shaded circles) or Mg2+ (black circles). A key feature of complement is that it functions via a biochemical cascade: a single activation event (whether by antibody or via innate pathways) leads to the production of many downstream events, such as deposition of C3b.
Activation is usually limited to the immediate vicinity  by  the very short life of the active products, and in some cases there are special inactivators (represented here by scissors). Nevertheless, excessive complement activation can cause unpleasant side-effects (see Fig. 36).
Note that, in the absence of antibody, many of the molecules that activate the complement system are carbohydrate or lipid in nature (e.g. lipopolysaccharides, mannose), suggesting that the system evolved mainly to recognize bacterial surfaces via their non-protein features. With the appearance of antibody in the vertebrates (see Fig. 46), it became possible for virtually any foreign molecule to activate the system.

Classic pathway
For many years this was the only way in which complement was known to be activated. The essential feature is the requirement for a specific antigen–antibody interaction, leading via components C1, C2 and C4 to the formation of a ‘convertase’ which splits C3.
Ig IgM and some subclasses of IgG (in the human, IgG1–IgG3), when bound to antigen are recognized by Clq to initiate the classic pathway.
C1 A Ca2+-dependent union of three components: Clq (MW 400 000), a curious protein with six valencies for Ig linked by collagen-like fibrils, which activates in turn Clr (MW 170 000) and C1s (MW 80 000), a serine proteinase that goes on to attack C2 and C4.
C2 (MW 120 000), split by C1s into small (C2b) and large (C2a) fragments.
C4 (MW 240 000), likewise split into C4a (small) and C4b (large). C4b then binds to C2, and also, via a very unusual type of reactive thioester bond, to any local macromolecule, such as the antigen– antibody complex itself, or to the membrane in the case of a cell-bound antigen. This tethers the C4bC2 complex forming a ‘C3 convertase’. Note that some complementologists prefer to reverse the names of C2a and b, so that for both C2 and C4 the ‘a’ peptide is the smaller one.

C3 (MW 180 000), the central component of all complement reac- tions, split by its convertase into a small (C3a) and a large (C3b) fragment. Some of the C3b is deposited on the membrane, where it serves as an attachment site for phagocytic polymorphs and macro- phages, which have receptors for it; some remains associated with C2a and C4b, forming a ‘C5 convertase’. Two ‘C3b inactivator’ enzymes rapidly inactivate C3b, releasing the fragment C3c and leaving membrane bound C3d.
C5 (MW 180 000), split by its convertase into C5a, a small peptide that, together with C3a (anaphylatoxins), acts on mast cells, polymorphs and smooth muscle to promote the inflammatory response, and C5b, which initiates the assembly of C6, 7, 8 and 9 into the membrane damaging or ‘lytic’ unit.
CR Complement receptor. Three types of molecule that bind different products of C3 breakdown are found on cell surfaces: CR1 is found on red cells, and is important for the removal of antibody–antigen complexes from blood; CR1 and CR3 on phagocytic cells, where they act as opsonins (see Fig. 9); and CR2 on B lymphocytes where it has a role in enhancing antibody production but is also, unfortunately, the receptor via which the Epstein–Barr virus (glandular fever) gains entry (see Fig. 27).
Alternative pathway
The principal features distinguishing this from the classic pathway are the lack of dependence on calcium ions and the lack of need for C1, C2 or C4, and therefore for specific antigen–antibody interaction. Instead, several different molecules can initiate C3 conversion, notably lipopolysaccharides (LPS) and other bacterial products, but also including aggregates of some types of antibody such as IgA (see Fig. 20). Essentially, the alternative pathway consists of a continuously ‘ticking over’ cycle, held in check by control molecules, the effects of which are counteracted by the various initiators. which are counteracted by the various initiators.
B  Factor B (MW 100 000), which complexes with C3b, whether produced via the classic pathway or the alternative pathway itself. It has both structural and functional similarities to C2, and both are coded for by genes within the very important major histocompatibility complex (see Fig. 11). In birds, which lack C2 and C4, C1 activates factor B.
D Factor D (MW 25 000), an enzyme that acts on the C3b–B complex to produce the active convertase, referred to in the language of com- plementologists as C3bBb.
Pr Properdin (MW 220 000), the first isolated component of the alter- native pathway, once thought to be the actual initiator but now known merely to stabilize the C3b–B complex so that it can act on further C3. Thus, more C3b is produced which, with factors B and D, leads in turn to further C3 conversion, a ‘positive feedback’ loop with great amplifying potential (but restrained by the C3b inactivators factor H and factor I).
MBL and other pathways
MBL Mannose-binding lectin (also variously referred to as mannose binding protein or mannan-binding protein), a C1q-like molecule that recognizes microbial components such as yeast mannan and activates C1r and C1s, and hence the rest of the classic pathway. MBL deficiency predisposes children to an increased incidence of some bacterial infections.
CRP C-reactive protein, produced in large amounts during ‘acute- phase’ responses (see Fig. 7), binds to bacterial phosphorylcholine and activates C1q.
Lytic pathway
Lysis of cells is probably the least vital of the complement reactions, but one of the easiest to study. It is initiated by the splitting of C5 by one of its two convertases: C3b–C2a–C4b (classic pathway) or C3b– Bb–Pr (alternative pathway). Thereafter the results are the same, however caused.
C6  (MW 150 000), C7 (MW 140 000) and C8 (MW 150 000) unite with C5b, one molecule of each, and with 10 or more molecules of C9 (MW 80 000). This ‘membrane attack complex’ is shaped some- what like a cylindrical tube and when inserted into the membrane of bacteria, red cells, etc. causes leakage of the contents and death by lysis. Needless to say, some bacteria have evolved various strategies for avoiding this (see Fig. 29).
Complement inhibitors
In order to prevent over-activation of the complement cascade, there are numerous inhibitory mechanisms regulating complement. Some of these, like C1q inhibitor, block the activity of complement proteinases. Others cleave active complement components into inactive fragments (factor I). Yet others destabilize the molecular complexes that build up during complement activation. Genetic manipulation has been used to make pigs carrying a transgene coding for the human version of one such important regulatory protein, DAF (decay accelerating factor); results suggest that tissues from such pigs are less rapidly rejected when transplanted into primates, increasing the chances of carrying out successful xenotransplantation (see Fig. 39).

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