Complement - a key system for immune surveillance and homeostasis

(a) An intricate network of soluble and cell-surface- bound proteins enables the recognition, tagging, and elimination of microbial intruders and foreign cells and stimulates downstream immune responses. In the classical pathway (CP), C1q recognizes pathogen- or damage-associated patterns (such as IgG, IgM, or CRP) on foreign or apoptotic cells, inducing the formation of the CP C3 convertase (C4b2b) via cleavage of C2 and C4 by C1s. Detection of carbohydrate patches by MBL or ficolins associated with MASP via the lectin pathway enables the formation of the same convertase, which subsequently activates the abundant plasma protein C3, generating its active fragments C3a and C3b. Covalent deposition of C3b on nearby surfaces (i.e. opsonization) leads to the binding of factor B and conversion into the alternative pathway (AP) C3 convertase (C3bBb), which cleaves more C3 into C3b and thereby amplifies the complement response. In addition, a low level of complement activation is maintained in solution (i.e., tick-over), and resulting C3b or C3 convertases can be recruited to foreign surfaces and stabilized by properdin (P). Increasing densities of C3b on the surface lead to a gradual substrate shift of the convertases from C3 to C5. Cleavage of C5 into C5a and C5b initiates the assembly of the lytic terminal complement complex (TCC) on susceptible cells. Opsonization by C1q, C3b, and its degradation products iC3b, C3c, and C3d induces phagocytosis via a panel of complement receptors. In addition, the anaphylatoxins C3a and C5a cause strong proinflammatory signaling via their respective GPCR. C5a also co-regulates immunoglobulin (Ig)-mediated phagocytosis of immune complexes (IC) by modulating the differential expression of activating (FcγRI/III) and deactivating (FcγRIIB) Fc-gamma receptors. On B cells, binding of C3dg to the CR2/CD19 co-receptor complex lowers the threshold of activation by several orders of magnitude and plays an important role in their maturation. Close crosstalk between Toll-like receptors (TLR), complement receptors, and regulators modulates IL-12 in antigen-presenting cells (APC) and thereby influences activation and differentiation of T cells. (b) On healthy human cells, any complement activation or amplification is immediately attenuated by a panel of surface-bound regulators that either accelerate decay of the convertases (CR1, DAF), act as a cofactor for the factor I-mediated degradation of C3b and C4b (CR1, MCP), or prevent the formation of the TCC (CD59). In addition, solution-based regulators such as C4BP, FH, or FHL-1 recognize self-surface pattern-like glycosaminoglycans and further impair activation. Finally, a diverse set of regulators enables control at the level of initiation (C1-INH, MAP-1, sMAP, CRIT, FHR-4), the C5 convertases (FHR-1, CRIg) or TCC (FHR-1, VTN, clusterin).

Publication

Complement - a key system for immune surveillance and homeostasis. () Daniel Ricklin, et al. Nat Immunol. ;11(9):785-797. Figure: F2. All organisms Mus musculus Homo sapiens Drosophila melanogaster

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