Control of the complement system is required to prevent the consumption of components through unregulated amplification and to protect the host. Complement activation poses a potential threat to host cells, because it could lead to cell lysis. To defend against this threat a family of regulators has evolved alongside the complement system to prevent uncontrolled activation and protect cells from attack.
C1 inhibitor controls the classical and lectin pathways
In the activation pathways, the regulators target the enzymes that drive amplification:
• activated C1 is controlled by a plasma serine protease inhibitor (serpin) termed C1 inhibitor (C1inh), which removes C1r and C1s from the complex, switching off classical pathway activation;
• C1inh also regulates the lectin pathway in a similar manner, removing the MASP enzymes from the MBL complex to switch off activation.
C3 and C5 convertase activity are controlled by decay and enzymatic degradation
The C3 and C5 convertase enzymes are heavily policed with plasma and cell membrane inhibitors to control activation. In the plasma:
• factor H (fH) and a related protein factor H-like 1 (fHL-1) destroy the convertase enzymes of the
alternative pathway;
• C4 binding protein (C4bp) performs the same task in
the classical pathway.
On membranes, two proteins, membrane cofactor
protein (MCP) and decay accelerating factor (DAF),
collaborate to destroy the convertases of both pathways (Fig. 4.8).
The regulators of the C3 and C5 convertases are structurally related molecules that have arisen by gene duplication in evolution. These duplicated genes are tightly linked in a cluster on chromosome 1, termed the
regulators of complement activation (RCA) locus.
This locus also encodes several of the complement receptors (see below).
Control of the convertases is mediated in two complementary ways
THE FIRST CONTROL IS DECAY ACCELERATION – The convertase complexes are labile, with a propensity to dis- sociate within a few minutes of creation. The regulators
THE COMPLEMENT SYSTEM IS CONTROLLED TO PROTECT THE HOST
Regulation of the amplification loop
Fig. 4.7 Alternative pathway activation depends on the presence of activator surfaces. C3b bound to an activator surface recruits factor B, which is cleaved by factor D to produce the alternative pathway C3 convertase C3bBb, which drives the amplification loop, by cleaving more C3. However, on self surfaces the binding of factor H is favored and C3b is inactivated by factor I. Thus the binding of factor B or factor H controls the
development of the alternative pathway reactions. In addition, proteins such as membrane cofactor protein (MCP) and decay accelerating factor (DAF) also limit complement activation on self cell membranes (see Fig. 4.9). C3 C3bBb C3b* C3bB C3bH D iC3b H B H I protected surface self surface
fH, fHL-1, and C4bp from the fluid phase and DAF on cell membranes bind the convertase complex and markedly accelerate decay, knocking out:
• C2a from the classical pathway convertase; and • Bb from the alternative pathway enzyme (Fig. 4.9). Very recently, genetic defects in fH have been implicated in patients with the non-diarrheal form of hemolytic uremic syndrome (HUS).
Point mutations in fH inhibit binding to host cells and weaken defense against complement, resulting in the hemolysis, platelet dysfunction, and renal damage that typify the syndrome.
THE SECOND CONTROL MECHANISM IS FACTOR I COFACTOR ACTIVITY – Factor I (fI) is a fluid-phase
enzyme that, in the presence of an appropriate cofactor, can cleave and irreversibly inactivate C4b and C3b (see Fig. 4.9). MCP is a cofactor for fI cleavage of both C4b and C3b, whereas:
• C4bp specifically catalyzes cleavage of C4b; and • fH/fHL-1 catalyzes cleavage of C3b.
It is interesting to note that, whereas the plasma regulators contain both activities in a single molecule, the two membrane regulators each contain only one activity.
Efficient regulation of the convertases on membranes therefore requires the concerted action of:
• DAF to dissociate the complex; and
• MCP to irreversibly inactivate it by catalyzing cleavage of the central component.
The alternative pathway also has a unique positive regu- lator, properdin, which stabilizes the C3 convertase and markedly increases its life span.
Complement receptor 1 (CR1) is often included in
the list of membrane regulators of C3 convertase activity, and, indeed, CR1 is a powerful regulator with both decay accelerating and cofactor activities in both pathways. Nevertheless, it is excluded from the above discussion because CR1 is primarily a receptor for complement-
C3 and C5 convertase regulators
Fig. 4.8 The five proteins listed are widely distributed and control aspects of C3b and C4b dissociation or breakdown. Each of these proteins contains a number of short consensus
repeat (SCR) domains. They act either by enhancing the dissociation of C3 and C5 convertases or by acting as cofactors for the action of factor I on C3b or C4b.
dissociation of C3 and C5 convertases cofactor for factor I on number of SCR domains classical pathway alternative pathway C4b C3b localization factor H (fH) 20 – + – + plasma + + 4 – – decay accelerating factor (DAF) (CD55)
blood cells, endothelia, epithelia C4b binding protein (C4bp) 52 or 56 in 7or 8 chains + – + – plasma + + membrane cofactor protein (MCP) (CD46)
4 – – blood cells (not erythrocytes),
endothelia, epithelia
+ + +
complement receptor 1 (CR1) (CD35)
30 + erythrocytes, B cells, follicular
dendritic cells, macrophages
SCR, short consensus repeat
The two processes by which C3 convertase regulators inactivate the enzymes
C3b/C4b C2a/fB C2a/fB C3b/C4b MCP fI DAF iC3b/iC4b decay acceleration cofactor activity
Fig. 4.9 DAF binds the enzyme complex, displacing the enzymatically active component (C2a or Bb). Membrane cofactor protein (MCP) binds the C3b/C4b unit released after decay and acts as a cofactor for factor I (fI) cleavage of C3b or C4b, resulting in the irreversible inactivation of the convertase.
coated particles and does not have a role in protecting the host cell.
THE MEMBRANE ATTACK PATHWAY