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The complement system consists of about 30 proteins which are present in blood. It is a highly sophisticated host defence system designed to destroy pathogens. Once the complement system is activated, a chain of reactions involving proteolysis and assembly occurs, resulting in destruction of the membranes of pathogens. The cascade up to the cleavage of the third complement component (C3), which plays a central role in the complement system, is called the activation pathway. There are three categories of activation pathway; the classical pathway, alternative pathway and lectin pathway. Activation of the classical pathway requires antibodies. Upon binding of the first complement component (C1), which is composed of three subcomponents C1q, C1r and C1s, to antibodies in immune complexes via C1q, serine proteases C1r and C1s are activated in that order. Activated C1s then cleaves C4 and C2. C4bC2a, the C3 convertase formed as a result of the activation, cleaves C3 into C3a and C3b, and C3b becomes attached to immune complexes. C3b is not only important for the lytic pathway involving late components C5 to C9 but also acts as an opsonin. In the alternative pathway, C3 is activated by several components without the involvement of antibodies. The recently discovered lectin pathway (also called MBL pathway or MBLectin pathway ) is activated by the binding of mannose-binding lectin (MBL) to carbohydrates on the surfaces of pathogens.
MBL, also called MBP (mannan-binding protein), binds to mannose or N-acetylglucosamine (GlcNAc) in a calcium-dependent manner. MBL is an oligomer of subunits composed of identical polypeptide chains each of which contains a cysterine-rich, a collagen-like, a neck, and a carbohydrate-recognition domain. MBL consists of several sizes of oligomers. Binding of MBL to pathogens triggers the activation of the lectin pathway. As a result, C4 and C2 undergo limited proteolysis, which leads to the formation of the C3 convertase C4bC2a. In the lectin pathway, C3 is also directly cleaved. These proteolytic reactions are mediated by a C1r/C1s-like serine protease termed MASP (MBL-associated serine protease), which is bound to MBL. In humans, three types of MASP (MASP-1, MASP-2 and MASP-3) and sMAP (small MBL-associated protein, or called MAp19) form complexes (MBL-MASP) with MBL. RaRF (Ra-reactive factor) that has a bactericidal activity against Salmonella typhimurium, is identical to MBL-MASP. MASPs and C1s share domain structures (two CUB domains, an EGF-like domain, two CCP domains and a serine protease domain) and thus constitute a subfamily of the serine protease family. In serum, MASPs are present as proenzymes consisting of a single polypeptide chain. Upon cleavage of a peptide bond, MASPs are converted to their activated forms consisting of two polypetides linked by a disulfide bridge. Activated MASP-1 cleaves C3 and C2, while activated MASP-2 cleaves C4 and C2. The function of MASP-3 is not known. sMAP is a truncated protein, which is derived from the MASP-2 gene by alternative polyadenylation. Its function remains unknown. MBL is thought to bind to MASPs and sMAP through its collagen-like domain. However, the stoichiometry of the complexes and the activation mechanism have not been fully elucidated.
In serum, there are GlcNAc-binding lectins called ficolins, which have a collagen-like domain and a fibrinogen-like domain. Recently, it has been demonstrated that ficolins in human serum are complexed with MASPs and sMAP and that the complexes activate the complement system. This finding expands the concept of the lectin pathway since ficolins are considered to be lectins which can activate the lectin pathway. The lectin pathway plays a crucial role in innate immunity. From an evolutionary point of view, it is speculated that the lectin pathway emerged before the classical pathway. However, the fact that components of the lectin and classical pathways are homologous suggests a close relationship between the two pathways. |
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| References |
(1) |
Hoffmann, J A, et al. : Phylogenetic perspectives in innate immunity. Science 284, 1313-1318, 1999 |
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(2) |
Matsushita, M, et al. : Complement-related serine proteases in tunicates and vertebrates. Curr. Opin. Immunol. 10, 29-35, 1998 |
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(3) |
Matsushita, M, et al. : Complement-activating complex of ficolin and mannose-binding lectin-associated serine protease. J. Immunol. 164, 2281-2284, 2000 |
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