The Alternative Complement Pathway

In the alternative pathway, C3 is the initiating peptide (Fig. 5.2). In the serum, C3 is somewhat unstable (it is sensitive to proteases) and spontaneously decomposes into a large, active C3b fragment and a smaller, catalytically inactive

Figure 5.2 • Control of the alternative complement pathway by activating surfaces. When complement component C3b binds to a surface, there exist two possible outcomes. Under normal conditions, when no activating surface is present (e.g., if C3b has contacted normal tissue), sequential addition of blood cofactors H and I converts C3b into C3c, inactivating the complement protein. If an activating surface such as a microbe or damaged tissue is encountered, sequential addition of factors B and D drives the alternative pathway to the normal properdin (P) intermediate, and the complement cascade is triggered. The properdin-containing component (C3bBbP) feeds back to the beginning of the pathway, generating more C3.

Figure 5.2 • Control of the alternative complement pathway by activating surfaces. When complement component C3b binds to a surface, there exist two possible outcomes. Under normal conditions, when no activating surface is present (e.g., if C3b has contacted normal tissue), sequential addition of blood cofactors H and I converts C3b into C3c, inactivating the complement protein. If an activating surface such as a microbe or damaged tissue is encountered, sequential addition of factors B and D drives the alternative pathway to the normal properdin (P) intermediate, and the complement cascade is triggered. The properdin-containing component (C3bBbP) feeds back to the beginning of the pathway, generating more C3.

Figure 5.3 • The function of interferon. When a virus infects a host cell, the cell expresses interferon. Interferon activates natural killer cells, causing killing of the infected host cells and elimination of the reservoir of infection. At the same time, interferon induces an antiviral state in neighboring cells, effectively breaking the cycle of infection.

Figure 5.3 • The function of interferon. When a virus infects a host cell, the cell expresses interferon. Interferon activates natural killer cells, causing killing of the infected host cells and elimination of the reservoir of infection. At the same time, interferon induces an antiviral state in neighboring cells, effectively breaking the cycle of infection.

C3a fragment. C3b now becomes bound to a surface, and it has two fates. We can define two types of surfaces. One, the nonactivating surface, is a surface that contains sialic acid or other acidic polysaccharides. The other, an activating surface, contains none of the acidic polysaccharides or sialic acid. This type conforms to a bacterial cell surface. Under normal circumstances, C3b will bind to a nonactivating surface. On binding, the C3b fragment becomes associated with factor H, a ^-globulin that associates with an a chain on C3b. Sialic acid increases the affinity for factor H 100fold. Factor H alters the shape of C3b in such a way that it becomes susceptible to attack by factor I, a serine esterase that cleaves the a chain of C3b, producing inactive iC3b. Attack by another protease produces a fragment designated C3c. In this pathway, factor H accelerates the decay of C3b. When factors H and I work together, they destroy C3b as fast as it is produced and shut down the pathway.

If C3b binds to an activating surface, the ability to bind to factor H is reduced, and C3b binds to a protein called factor B, forming C3bB. Bound factor B is cleaved by factor D into a fragment called Bb. The complex C3bBb has high C3-convertase activity and stimulates the pathway further. Factor P (properdin) binds to the complex, extending the half-life of C3bBbP. This fragment binds to the terminal complement components (C5-C9), creating a membrane attack complex and thus lysing the cell.

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