Complement:Alternative Secondary article Pathway Artice Contents Peter FZipfel,Bemhard-Nocht-Institute for Tropical Medicine,Hamburg,Germany scription of Pathwa ogical Conse ces of Co The altemative pathway of complement is a powerful and evolutionarily old defence system of innate immunity that inactivates invading microorganisms and pathogens.For survival in an immunocompetent host microbes,viruses,pathogensormodified tissue cells must provide means to interfere with and control alternative pathway reactions at severa levels Introduction tha The alternative pathway,the phylogenetically oldest and face-bound C3b in the close vicinity of the initial enzyme most importa mecha On foreign particles,unrestricted activation leads to the powerful initiation of the complement ascade,while on san further activation of this central com onent is tightly controlled by a large number of both soluble and of der sited molecules un ory prot I hes and simulta ect self cells fr Initiation the destructive effects of this defence system.If left Activation of c3 is pi otal and central to the alternative ntectious agent furnovefd bya spontancous and con induce inflammatory reactions by recruiting and stimulat- C).a molecule with acsb'-like functior occurs slowly ing immune effector cells (0.005%per min)and results from a spontaneous reaction of thioester bond with water This tickover Description of Pathway ke mo as th factor B.After enzymatic cleavage the active Bb fra The alternative pathway of complement is a host defence remains attached to C3(H2O).forming the initial C3 system that assists in maint ing the integrity of an convertase 3b(H:O)Bb H ative pathway.This ich ha removed and which exposes the highly reactive Activation thioester.The reactive C3b molecule has the ability to form ovalent bonds between its internal thioester and any ation and limited time of the reactive which leads to the formation of an enzyme complex that state ensures that activation is restricted in time e and space cleaves further C3 molecules and sets in motion an to the vicinity of newly formed molecules.Most of the thioester bonds of the activated C3(H2O)interac with f a large numbe A cleaved and activated c3h molecule is highly reactive covalently attached C3 molecules can form functional C and covalently interacts with any molecule in its vicinity convertases.allowing the activation and amplification of the pathway.w ile the initial on of C3b-generating enzymes.i.e. ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net Complement: Alternative Pathway Peter F Zipfel, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany The alternative pathway of complement is a powerful and evolutionarily old defence system of innate immunity that inactivates invading microorganisms and pathogens. For survival in an immunocompetent host microbes, viruses, pathogens or modified tissue cells must provide means to interfere with and control alternative pathway reactions at several levels. Introduction The alternative pathway, the phylogenetically oldest and most important activation pathway of the complement system, provides a highly efficient defence mechanism against invading microorganisms and bacteria. Formation of C3b occurs spontaneously and continuously, while the further activation of this central component is tightly controlled by a large number of both soluble and membrane-bound regulatory proteins. These regulators restrict activation to the surface of foreign cells and microorganisms and simultaneously protect self cells from the destructive effects of this defence system. If left uncontrolled, the activated alternative pathway deposits C3b molecules on the surface of infectious agents (micro￾organisms) to prepare them for phagocytosis or lysis, and the activation products (chemotactic anaphylatoxins) induce inflammatory reactions by recruiting and stimulat￾ing immune effector cells. Description of Pathway The alternative pathway of complement is a host defence system that assists in maintaining the integrity of an organism by inactivating invading organisms, pathogens and modified tissue cells. Activation Activation of the pathway starts in the fluid phase, in plasma, by a spontaneous conformational change of C3 which leads to the formation of an enzyme complex that cleaves further C3 molecules and sets in motion an amplification reaction leading to complement activation and deposition of a large number of C3b molecules on the cell surface. A cleaved and activated C3b molecule is highly reactive and covalently interacts with any molecule in its vicinity. Attachment allows powerful amplification reactions by the formation of C3b-generating enzymes, i.e. C3 convertases, that use plasma C3 as a substrate. This positive feedback amplification loop generates increasing amounts of sur￾face-bound C3b in the close vicinity of the initial enzyme. On foreign particles, unrestricted activation leads to the powerful initiation of the complement cascade, while on self cells and tissues these reactions are tightly controlled by inhibition of enzyme complex formation and inactivation of deposited molecules. Initiation Activation of C3 is pivotal and central to the alternative pathway. It is initiated by a spontaneous and continuous turnover of fluid-phase C3, which is present in plasma in a high concentration of 1.5 mg mL 2 1 (Lambris, 1988). In human plasma, formation of C3(H2O) (also known as iC3), a molecule with a ‘C3b’-like function, occurs slowly (0.005% per min) and results from a spontaneous reaction of the internal thioester bond with water. This tickover mechanism generates a ‘C3b-like molecule’ which has the C3a part attached to the a chain and can associate with factor B. After enzymatic cleavage the active Bb fragment remains attached to C3(H2O), forming the initial C3 convertase C3b(H2O)Bb of the alternative pathway. This spontaneously formed C3(H2O)Bb molecule can generate metastable C3b, a molecule which has the C3a part removed and which exposes the highly reactive internal thioester. The reactive C3b molecule has the ability to form covalent bonds between its internal thioester and any adjacent molecule. The rapid activation and limited time of the reactive state ensures that activation is restricted in time and space to the vicinity of newly formed molecules. Most of the thioester bonds of the activated C3(H2O) interact with water and are not further active, but a small fraction interacts with nearby molecules and cell surfaces. These covalently attached C3 molecules can form functional C3 convertases, allowing the activation and amplification of the pathway. While the initial reaction occurs at a low rate, it proceeds continuously and an amplification reaction Article Contents Secondary article . Introduction . Description of Pathway . Biological Consequences of Complement Activation . Components . Control . Microbes ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1