Institut fur Immunologie der Universitat Heidelberg, Heidelberg, GermanyComplement is an essential part of the humoral hostdefence system. Following activation on bacterial sur-faces, either by bound antibodies or by the bacterialsurface proper, several mediators essential for an effi-cient defence against bacteria are generated. The coat-ing of bacteria with the complement activation productC3b enhances phagocytosis, C5a mediates leukocyteinfiltration and the terminal complement complex C5b-9 (membrane attack complex) may eventually killbacteria. The complement activation products alsostimulate leukocytes to release mediators, includingeicosanoids, interleukins or oxygen radicals, therebyamplifying the host defence. In consequence, at sitesof bacterial infection infiltration of leukocytes andenhanced permeability of blood vessels, increasedblood flow is seen, evident as rubor, dolor, calor andtumour, several of the classical signs of inflammation.Though an essential and beneficial reaction, aninflammatory response may also become harmful oreven deleterious. Overshooting reactions, lack orexhaustion of control mechanisms, but also a 'mistar-geted bystander attack' might contribute to the devel-opment of an inflammatory disease [for review, see1,2].In early reports on experimentally-induced glom-erulonephritis the development of proteinuria wasdescribed to be critically dependent on the presence ofcomplement. At that time, the complement, i.e. theC5a-mediated leukocyte infiltration, was considered tobe the decisive event [3]. Indeed, infiltrating leukocyteswith their load of proteolytic enzymes, including colla-genases and elastases, may participate in tissue destruc-tion, especially since complement activation productssuch as C5a and C5b-9 may mediate their release.More recently, the role of the terminal complementcomplex C5b-9 has also gained in interest [for review,see 4,5]. Deposits of C5b-9 were found in variousforms of glomerulonephritis as well as in experiment-ally-induced glomerulonephritis, usually in associationwith the initiating immune complexes [1,4]. This, inturn, raised the question of whether C5b-9 mightactively participate in the development of inflamma-tion. As pointed out above, the terminal complementcomplex was initially identified by its bactericidal andlytic activity. However, nucleated cells such as tissuecells resist the complement attack, especially whentarget cells and complement are from the same species,i.e. under physiological conditions. The relative resist-anc towards the complement attack is due to(i) cellular repair mechanisms leading to a removal ofthe complexes from the surface [for review see 6] and(ii) to specialized membrane proteins which inhibit thecomplement action on the cell surface, thereby pro-tecting cells against complement attack [for review, see7].The effect of complement on glomerular cells wasmainly studied with cultivated cells. When complementis activated in the vicinity of the cultivated mesangialcells, the terminal complement proteins will bind; thecomplement control proteins are upregulated, the C5b-9 complexes are removed and the cells survive thecomplement attack. This result is in line with in vivoobservations: deposition of C5b-9 e.g. in the glomer-ulus is not associated with massive cell killing or'mesangiolysis'. Thus, mesangial cell killing is surelynot an important consequence of the C5b-9 attack [8].In recent years, further consequences of the C5b-9attack were found. As first shown for monocytes,binding of C5b-9 in a 'sublethal' dose causes cellactivation, as indicated by the de novo synthesis ofeicosanoids, interleukin 1 and 6, and oxygen radicals.Glomerular mesangial cells respond in a similar way;after binding of C5b-9 increased synthesis of eicosan-oids and cytokines was measured [4,5,8].As a further consequence of C5b-9 attack, glomer-ular mesangial cells react with enhanced synthesis ofextracellular matrix proteins, including collagen typeIV and fibronectin [1,4]. Production of matrix proteinsmay be considered as a repair process; however, a shiftin quantity and quality may lead to sclerosis andconsequent loss of functionally relevant tissue [9].Mesangial cells also release collagen type IV degrad-ing matalloproteinases, suggesting that deposition ofextracellular matrix proteins not only depends on therate of protein synthesis, but also on the availabilityand activity of matrix degrading enzymes. Takentogether, complement may perturb the physiologicalbalance between matrix synthesis and degradation,thereby pushing the reaction either towards tissuedestruction or towards scarring and sclerosis [10].In the initial phase of an immunologically-inducedinflammatory reaction, deposited immune complexes
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Jan 12, 2021
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