2.4.2 Complement
The complement system is an ancient innate immune mechanism present in both vertebrate and invertebrate species. The mammalian complement system appears more developed and is composed of ∼30 different proteins, either plasma- or membraneassociated.
The proteins and glycoproteins that constitute the complement system are synthesized by hepatocytes, but significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinary tract and gastrointestinal tract. Complement proteins have a wide range of functions, including the elimination of invading pathogens, promotion of inflammatory responses, clearance of cell debris, and modulation of adaptive immune responses (Walport, 2001a, 2001b).
hepatocyte 간세포
They are normally present as inactive precursors until the system is activated by one of the three biochemical activation pathways: the classical pathway, the alternative pathway, and the lectin pathway.
The three cascades of activation lead to the formation of a protease complex, the protease C3 convertase, that activates a further cascade of cleavage and activation events, mainly the release of opsonic and chemotactic components and the activation of the C5 component, part of the membrane-attack complex (MAC), which damages the membrane of the target (pathogens or cells).
The classical pathway is part of the specific immune response and requires immune complexes (antigenantibody complexes) for the activation of the C1 complex that, together with C2 and C4 components, lead to the formation of the protease C3 convertase. The alternative and lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies as part of the innate response.
In the alternative pathway, the spontaneous activation of C3 and its binding to microbial surfaces leads to the interaction with plasmatic factors B and D and, finally, to the formation of the protease C3 convertase.
The lectin pathway is based on the interaction of lectins, such as mannose-binding lectin and ficolins, with sugar moieties found on the surface of microbes, activating in this manner a system of proteases (MBL-associated serine proteases, MASPs) that cleave the C2 and C4 complement components in a similar way as the classical pathway.
Complement components participating in the alternative and lectin pathways have been described in jawless fish, whereas molecules involved in all three pathways have been reported in both Chondrichthyes (Smith, 1998) and Osteichthyes (Nakao et al., 2011).
In teleosts, mRNAs encoding complement components show not only a wide tissue distribution in the liver, but also substantial extrahepatic expression in the kidney, intestine, gill, skin, brain, and gonads.
Functional assays performed with some of these molecules revealed conserved effector activities recognized in the mammalian system such as opsonization, killing of target cells, and anaphylotoxin leukocyte stimulation (reviewed in Boshra et al., 2006; Nakao et al., 2011).
Based on the data obtained in zebrafish, carp, and trout, it is evident that almost all the homologs of the mammalian complement components are present in teleost with the particularity that some of the key components show multiple isoforms in fish species.
For example, the components C3, C4, C5, C7, MBL, factor B, and factor I are present in several isoforms being the product of different genes (Nakao et al., 2006; Nakao et al., 2000; Sunyer et al., 1997). Teleost complement is active at very low temperatures, and their alternative pathway titers are several orders of magnitude higher than that of the mammalian order.
Different expression studies performed with immunostimulants or microbial infections suggest that fish complement is a powerful defense mechanism against viral, bacterial, or parasitic infections (reviewed in Boshra et al., 2006; Nakao et al., 2011). Furthermore, complement proteins are among the immune factors delivered to eggs from a maternal source. During early egg development and before the transcription and functionality of their own immune factors is established, embryo survival relies on the maternal transfer of several immune molecules, including various complement components (Lovoll et al., 2006; Swain and Nayak, 2009; Wang et al., 2009b).