5.1. Innate and adaptive immunity and the role of complement

Adaptive immunity in vertebrates can be traced to the appearance of ancestral RAG genes in ancestral jawed vertebrates. Innate immunity is more ancient and appeared about 450 million? years ago. The complement system a central subsystem within innate immunity has been identified throughout the animal groups but seems to be restricted to deuterostomes. The evolutionary history of complement can be traced from sea urchins (phylum Echinodermata), which have a simplified system homologous with the alternative pathway, through the agnathans (hagfish and lamprey) and the elasmobranchs (sharks and rays) to the teleosts (bony fish) and tetrapods, with increases in the numbers of complement components and duplications in complement pathways [42], Complement in vertebrates comprises a complex enzyme system and non-enzymatic proteins essential for effecting innate and adaptive immune responses and for exerting immunoregu-latory functions. Complement protein C3 is a central molecule in the complement system whose activation is essential for this system to function [43], Complement activation can be induced through three pathways: 1) the classical initiated by antibody-antigen complexes; 2) the alternative initiated by certain structures on microbial surfaces; 3) an antibody-independent initiated by binding of mannan-binding lectin (MBL; first described as mannan-binding protein) to carbohydrates. MBL is structurally related to the complement CI subcomponent, Clq, and seems to activate the complement system through an MBL associated serine protease known as MASP or p 100, that is similar to C1 r and C1 s of the classical pathway. MBL binds to specific carbohydrate structures found on the surfaces of numerous microorganisms, including bacteria, yeasts, parasitic protozoa and viruses. Complement exhibits antibacterial activity effected through killing mediated by the terminal, lytic complement components or by promoting phagocytosis. MBL level in plasma is genetically determined, and deficiency is associated with frequent infections in childhood, and possibly also in adults. A new MBL-associated serine protease (MASP-2) has been identified. It shows a striking homology with MASP (MASP-1) and the two Clq-associ-ated serine proteases CIr and Cls. Thus complement activation through MBL, like the classical pathway, involves two serine proteases and may have evolved before the development of the adaptive immune system of vertebrates [44].

5.2. How does complement work?

In lower vertebrates, the poikilotherms or ectotherms (fish, amphibians and reptiles), complement is activated by the alternative and lectin pathways and is primarily involved in the opsonization of foreign material. The Agnatha (the most primitive vertebrate-a jawless fish) possess the alternative and lectin pathways while cartilaginous fish are the first group in which the classical pathway appears following the emergence of immunoglobulins. All poikilotherms possess a well-developed complement system resembling that of the homeothermic (endothermic) vertebrates, i.e., birds and mammals. Most complement components seem to have evolved after the duplication of primordial genes encoding C3/C4/C5, fB/C2, Cls/Clr/MASP-1/MASP-2, and C6/C7/C8/C9 molecules, a process that may have led to the formation of distinct activation path ways. Unlike homeotherms, certain poikilotherms (e.g., trout) possess multiple forms of complement components (C3, factor B(fB)) that are structurally and functionally more diverse than those of higher vertebrates. Evidence strongly suggests that the complement system is present in all deuterostomes, and regulatory complement components have been identified in all species beyond the protochordates. Therefore, the mechanisms of complement activation and regulation probably developed in parallel [45],

5.3. Interaction of complement with other recognition factors

The recognition factor, MBL, is associated with a serine protease MASP which, upon MBL binding to the microbial ligand, activates the complement component C3, leading to either (a) phagocytosis of the opsonized target via the complement receptor, or (b) humoral cell killing via assembly of the membrane attack complex. Galectins (formerly S-type lectins) modulate activity of the complement receptor 3 (CR3), the macrophage membrane receptor for complement components C3b and iC3b, downstream products of the MBL pathway that are covalently bound to target cells. Galectins also mediate macrophage- and dendrocyte-adhesion to lymphocytes activated by signaling through another C-type lectin, the L-selectin, leading to immunoglobu-lin-mediated responses. The functional interplay of MBL, galectins and L-selectin in the acute phase response neutralizes the microbial challenge, and leads to adaptive immunity. Although the observation of various components of the lectin pathway in different invertebrate species demonstrates the high conservation and ancient roots of the components of innate immunity, there has previously been no evidence supporting the possibility that the integral lectin-medi-ated complement activation pathway is present in invertebrates. There is now evidence for the coexistence of homologs of all the pathway's key components (MBL, MASP, C3, and galectin) in the protochordate Clavelina picta. This suggests that the lectin-mediated pathway, an ancient pathway of complement activation preceded the immunoglobulin pathway and has been conserved intact throughout its evolution [46],

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