Complement:Terminal Pathway Relevance in Protection and Pathology evade destruction by complement and MAC.Som examples are human cytomegalovirus.human T-cell Complement has a role in protection against pathogeni euka MAC easts,pa ype n ine th defenc against ram-negative bacteria such as Ness Herpesvirus saimiri encodes a protein that is50 identical in sequence to human CD59 and is anchored by a have an impaired M d Nand are GPI linkage ells expressing this homologue are resistant v.gonor- coccal and systemic infections.respectively subjected to MAC undergo pro ive resn Rpa a central MACalso elicits other important responses(Mold,1998 ary I type an n be el s th cal,lectin or alternative pathways and in some cases s al are important in host response to injury or in the three and produce MAC.Channels formed by MACon the at hogenesis of disease.For example. superoxide anion outer membrane (e.g.hydrogen els durin an produce lysis and the exact mechanism by which MAC microorganisms.Both neutrophils and macrophages Dissipation of the release these metabolites when exposed to MAC and thei inne lula ha een te d h with the to MAC oids e and MAC does not translocate from the outer membrane triene B4.etc.).which are synthesized from arachidonic membrane.E id by the and lipoxygenase pathways. h an are di pa mm sed by MAC into the sm where the rally re translocate and interact with the inner membrane (Esser. quire a calcium influx,activation of protein kinases and 1994) ohospholipases and thus may involve the same mechan- bacteria are su epltibe blytic MAC ell surfa sto susceptible whereas those with longer LPS chains (more ranules.phosphorvlation of protein kinases and induc PP2ieadoeesn s by pron 6 insertion of MAC into othr (FV bacteria tend to resist lysis because MAC is unable to FXa)enzyme complexes of the coagulation system.MAC layer in th vide are gener rally diti esiculhtionandreeaeweoideon the prot Enveloped viruses are particularly susceptible to MAC gg egate they have membrane-like lipid Sublytic MAC formed on endothelial cells elicits several r surrou ing the prot (capsid) n intact end m,it med from the membr 、endothelial cells and like lesions on these viruses and promotes disruption of increases procoagulant activity by altering membrane of intraviral constituents and osph lipid bilayers t t support prothrom ase actv DAF MCP )The ng cytokine syn CD59 during the pre on and budding fron ctivator inhibitor 1,both of the membrane of the cell of origin.These are then used to which contribute to widespread coagulation and persis- ENCYCLOPEDIA OF LIFE s.neRelevance in Protection and Pathology Complement has a role in protection against pathogenic strains of bacteria, viruses, mycobacteria, yeasts, parasites and protozoa. MACitself is especially important in defence against Gram-negative bacteria such as Neisseria. Humans with hereditary deficiencies of C5, C6, C7, C8 or C9 have an impaired ability to form MAC and are particularly susceptible to N. meningitidis and N. gonor￾rhoeae. These individuals may have recurrent meningo￾coccal and systemic gonococcal infections, respectively. Gram-negative bacteria have an outer lipid bilayer containing embedded lipopolysaccharide (LPS), a central periplasmic space containing peptidoglycan and an inner cytoplasmic membrane. Many strains activate the classi￾cal, lectin or alternative pathways and in some cases all three and produceMAC. Channels formed byMAC on the outer membrane of sensitive strains enables the release of periplasmic enzymes and influx of serum lysozyme, which degrades peptidoglycans. However, this alone does not produce lysis and the exact mechanism by which MAC mediates bacterial killing is unknown. Dissipation of the inner membrane potential and loss of cellular energy are required for killing, however this is not caused by MAC directly since the inner membrane is inaccessible to MAC and MACdoes not translocate from the outer membrane to form channels on the inner membrane. Experimental evidence suggests a direct role for C9 and a possible mechanism in which C9 or cytotoxic fragments of C9 are released by MACinto the periplasm where they can translocate and interact with the inner membrane (Esser, 1994). Not all strains of Gram-negative bacteria are susceptible toMAC. Those with shorter LPS chains (less carbohydrate or ‘rough phenotype’) on the cell surface tend to be more susceptible whereas those with longer LPS chains (more carbohydrate or ‘smooth phenotype’) tend to be resistant. In the latter case, longer LPS chains and the more hydrophilic nature of the membrane surface impairs insertion of MACinto the membrane. Gram-positive bacteria tend to resist lysis because MACis unable to penetrate the relatively thick peptidoglycan layer in their cell wall. Bacteria resistant to lysis by MACare generally killed by opsonization and phagocytosis. MACalso has a role in protection against viruses. Enveloped viruses are particularly susceptible to MAC￾mediated lysis because they have a membrane-like lipid bilayer surrounding the protein shell (capsid) that contains viral genetic material. This lipid bilayer is usually acquired from the membrane of the cell of origin. MACforms pore￾like lesions on these viruses and promotes disruption of viral integrity, release of intraviral constituents and loss of viability. Interestingly, some viruses acquire normal complement regulatory molecules such as DAF, MCP or CD59 during the process of maturation and budding from the membrane of the cell of origin. These are then used to evade destruction by complement and MAC. Some examples are human cytomegalovirus, human T-cell leukaemia virus type I and human immunodeficiency virus type 1(HIV-1). Other viruses encode within their own genome proteins that mimic the regulatory components. Herpesvirus saimiri encodes a protein that is
50% identical in sequence to human CD59 and is anchored by a GPI linkage. Cells expressing this homologue are resistant to lysis by MAC. Nucleated cells subjected to even sublytic amounts of MACundergo protective responses to resist lysis, however MACalso elicits other important responses (Mold, 1998). These vary with cell type and in some cases can be elicited by C5b-7 or C5b-8 as well as MAC. Some of these lead to the production and release of inflammatory mediators that are important in host response to injury or in the pathogenesis of disease. For example, superoxide anion and its toxic reactive oxygen metabolites (e.g. hydrogen peroxide, hydroxyl radical) are produced by phagocytic cells during the respiratory burst and are used to kill microorganisms. Both neutrophils and macrophages release these metabolites when exposed to MACand their release has been implicated in tissue damage associated with the inflammatory response. These cells also release eicosanoids (e.g. prostaglandins, thromboxanes, leuco￾triene B4, etc.), which are synthesized from arachidonic acid by the cyclo-oxygenase and lipoxygenase pathways. Eicosanoids are diverse activators of pain and inflamma￾tion and are also mediators of acute and chronic inflammatory conditions. These responses generally re￾quire a calcium influx, activation of protein kinases and phospholipases and thus may involve the same mechan￾isms that protect cells from lysis. In platelets, calcium influx in response to sublytic MAC initiates secretion of mediators such as ATP from storage granules, phosphorylation of protein kinases and induc￾tion of shape changes. It also enhances the procoagulant properties of platelets by promoting membrane phospho￾lipid rearrangement and exposure of binding sites for the tenase (FVIIIa and FIXa) and prothrombinase (FVa and FXa) enzyme complexes of the coagulation system. MAC is removed by vesiculation and released vesicles provide additional sites for generation of the prothrombinase complex. Vesiculation also tends to activate the platelet surface, thus increasing the ease with which the cells aggregate. Sublytic MACformed on endothelial cells elicits several responses. In intact endothelium, it mediates disruption of intracellular junctions leading to formation of gaps that can affect permeability. It activates endothelial cells and increases procoagulant activity by altering membrane phospholipid bilayers that support prothrombinase activ￾ity and by inducing cytokine synthesis (interleukin 1a, IL- 1a). The latter leads to upregulated expression of tissue factor and plasminogen activator inhibitor 1, both of which contribute to widespread coagulation and persis￾Complement: Terminal Pathway ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5