Cells and Components of Innate Immunity: MRCOG Part 1 questions and key facts

The complement system consists of numerous plasma proteins that act in a cascade to mediate innate immunity and inflammation. The vast majority of these protein components, including key players like C3, C4, C5, C6, C7, C8, C9, Factor B, and Factor H, are synthesised primarily by hepatocytes in the liver. The liver's central role in producing these proteins ensures their constant availability in the circulation at high concentrations, ready to be activated upon encountering pathogens or immune complexes.

While the liver is the major site, some complement components are produced elsewhere. For example, C1 components (C1q, C1r, C1s) can be synthesised by intestinal epithelial cells and macrophages. Factor D is mainly produced by adipocytes. Monocytes and macrophages can also synthesise several complement proteins, particularly at sites of inflammation. However, these sites contribute less to the overall circulating pool compared to the liver. The bone marrow is primarily involved in haematopoiesis (blood cell production). The spleen and lymph nodes are secondary lymphoid organs important for adaptive immune responses but not the main site of complement protein synthesis. The kidney is involved in filtration and hormone production, not significant complement synthesis.

The complement system can be activated via three main pathways: classical, lectin, and alternative. While their initiation differs (antibody-antigen complexes for classical, mannose-binding lectin for lectin, and spontaneous hydrolysis or pathogen surfaces for alternative), all three pathways converge at the point where C3 convertase enzymes are generated. These enzymes cleave the central complement component C3 into C3a (an anaphylatoxin) and C3b. C3b is the key convergence product; it acts as an opsonin, facilitates phagocytosis, and is essential for the formation of the C5 convertase, which initiates the terminal pathway leading to the membrane attack complex (MAC).

C5a is an important anaphylatoxin and chemoattractant, but it is formed downstream of C3b by the action of C5 convertase. C4b is a component generated during the classical and lectin pathways as part of their respective C3 convertases (C4b2a), but it is not involved in the alternative pathway's C3 convertase (C3bBb) and thus not the central convergence point. Factor B is a specific component of the alternative pathway, forming part of its C3 convertase, but is not produced by the classical or lectin pathways. Factor H is a crucial regulatory protein that inhibits the alternative pathway, preventing excessive complement activation on host cells; it is not a product of the activation cascade itself.

The alternative complement pathway is initiated by the spontaneous low-level hydrolysis of C3 in the plasma, forming C3(H2O). This C3(H2O) binds Factor B, which is then cleaved by Factor D to form the fluid-phase C3 convertase, C3(H2O)Bb. This convertase cleaves more C3 molecules into C3a and C3b. The nascent C3b possesses a highly reactive internal thioester bond. If this C3b lands on a suitable surface, such as a pathogen lacking complement regulatory proteins, this thioester bond can covalently bind to hydroxyl (-OH) or amine (-NH2) groups present on microbial surface molecules. This deposited C3b acts as an opsonin and can also bind Factor B, leading to the formation of the surface-bound alternative pathway C3 convertase (C3bBb), thereby amplifying the complement cascade on the pathogen surface.

C1q is the recognition component of the C1 complex, which initiates the classical complement pathway by binding to antibodies (IgM or IgG) complexed with antigen. Mannose-binding lectin (MBL) initiates the lectin pathway by binding to mannose and other sugar residues on microbial surfaces. IgM (in its pentameric form) is a potent activator of the classical pathway when bound to antigen, providing a binding site for C1q. C5 is a component downstream in the complement cascade, cleaved by C5 convertases (formed later in all pathways) to initiate the formation of the membrane attack complex (MAC).