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NEJM：Volume 361:345-357

Alternative Pathway of Complement Activation and Regulation.

In this schematic representation, the alternative pathway cascade on a complement-activating surface is shown on the right side, and the proposed mechanisms of complement regulation by thrombomodulin on host cells are shown on the left side. C3 spontaneously undergoes cleavage at a slow rate, amplified by bacterial and viral products. C3 releases the anaphylatoxin C3a and the fragment C3b, which is deposited on almost all cell surfaces that are in contact with plasma. C3b deposited on bacterial surfaces that lack complement regulators binds to CFB to form the C3 convertase of the alternative pathway, an enzyme complex (C3bBb) that cleaves additional C3 molecules. C3b also participates in the formation of the C5 convertase (C3b2Bb), which by cleaving C5, releases C5a, an anaphylatoxin, and C5b, which initiates assembly of the membrane attack complex (MAC), a pore-like structure that inserts into the cell membranes, causing cell activation or lysis. In host cells, several membrane-anchored and fluid-phase regulators control this cascade. CFH and C4bBP in the fluid phase bind to cell-surface glycosaminoglycans and to C3b and act as cofactors for CFI-mediated cleavage of C3b to iC3b. This reduces downstream activation of C3 and C5, thereby protecting the cell membrane. Thrombomodulin, an integral membrane protein on all endothelial cells, provides additional protection of the membrane by enhancing CFI-mediated inactivation of C3b in the presence of either CFH or C4bBP; by binding to thrombin, thereby preventing it from activating C5; and by promoting the generation of carboxypeptidase B (TAFIa), which inactivates C3a and C5a.