Complement in Urochordates

The complement system is a cascade of serine proteases initiated by the detection of foreign agents, and it results in several different effector responses. In mammals, the cascade as a whole uses around 30 different proteins, which are all constitui-tively present in the blood serum.

Many components of the mammalian complement system can be traced back to urochordates. In the absence of antibodies, the activation pathway is of the lectin type and consists of mannose-binding lectins (MBLs), mannose associated serine proteases (MASPs), C3, and corresponding CR3/CR4 receptors present on macro-phage-like cells (Kenjo et al. 2001; Sekine et al. 2001; Marino et al. 2002; Endo et al. 2003; for a review, see Fujita 2002). Thus, a lectin-based complement system is present in urochordates and functions in an opsonic manner. Obviously, this system has remained unchanged since its appearance at least 600 myr ago, well ahead of the emergence of adaptive immunity. From an evolutionary point of view, Fujita (2002) proposed that the primitive lectin pathway in innate immunity evolved into the classic pathway to serve as an effector system of adaptive immunity.

In mammals, the crusial step of complement function is the covalent attachement of serum protein C3 to the surface of autologous and bacterial cells and activation the complement cascade causing elimination of the "alien" cell by lysis and/or phagocytosis (Sahu and Lambris 2001). Attachment of C3 to normal autolo-gous cells is prevented by the expression of "self" markers. The main markers of normal "self' in mammals are membrane cofactor protein (MCP/CD46), decay accelerating factor (DAF/CD55), and CD59, a member of the Ly6 family (Liszewski et al. 1991; Vanderpuye et al. 1992). These receptors function by interfering with complement components. CD46 and CD55 interact with C3 by preventing the formation of active C3 convertase. CD59 associates with C8 and/or C9 and thereby blocks the polymerization of C9 monomers required for the formation of lytic pores. As a final result, membrane attack complex (MAC) is not formed properly and cells are protected from complement-mediated lysis. Interestingly, the number of genes encoding proteins with multiple short consensus repeats (structurally similar to CD46, CD55, CR1, CR2) is much higher in number in ascidians than in mammals (Azumi et al. 2003). For poorly understood reasons (for a discussion, see Khalturin and Bosch 2007), this group of molecules has expanded considerably in the urochordate lineage.

The lytic pathway in urochordates consists of a large set of soluble proteins present in hemolymph, which have MAC/Perforin domains and an organization similar to that of the terminal vertebrate complement components, C6/C7/C8/C9 (Azumi et al. 2003).

Very recently, genomic views on the structure and evolution of the complement system in urochordates have been published (Nonaka and Yoshizaki 2004; Nonaka and Kimura 2006). Interestingly, most individual structural domains found in the urochordate complement components are specific to metazoans and are present in both invertebrates and vertebrates but are missing from yeast and plants. However, the unique domain architecture characteristic of vertebrate complement proteins is not present in protostomes, which led the authors (Nonaka and Yoshizaki 2004; Nonaka and Kimura 2006) to propose that the present-day complement system in vertebrates evolved by a unique combination of preexisting domains rather than by the invention of new domains.

In mammals the complement components are not variable between individuals, except for the C4 component in mice (Natsuume-Sakai et al. 1980). Surprisingly, in Ciona the number of genes encoding complement system components is greatly expanded compared with mammals (Azumi et al. 2003). In addition, some complement-related transmembrane proteins such as variable complement receptor-like 1 (vCRL1; Kurn et al. 2006) are highly variable between individuals. We have proposed elsewhere (Kurn et al. 2006; Khalturin and Bosch 2007) that these features allow us to explain the allorecognition reactions in Ciona by the involvement of complement-related receptors on the basis of the "missing self" concept: since cells in different individuals bear non-overlapping receptors and the corresponding ligands, cells within one individual are appropriately marked and are referred to as "self', while any cell of conspecific, but genetically different individuals are distinguished as "non-self".

In conclusion, there is accumulating evidence that early during chordate phylog-eny the components of the complement system, in addition to their role in pathogen elimination, were involved in allorecognition. From an evolutionary point of view, the development of the adaptive immune system in the vertebrate lineage may have included the concomitant loss of involvement of complement molecules in allorec-ognition. This conclusion has an important implication. It indicates that urochor-dates use an allorecognition system which is unique and different from the one used by vertebrates (Khalturin and Bosch 2006).

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