Also used alone to indicate a sequence of reactions that convert one biological material to another metabolic pathway. This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The terminal sequence of complement activation involves C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called Membrane attack complex. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. Figure 1 Classical and alternative pathways shown with their corresponding proteins. They both cleave C3 to C3b and C3a. This C3b binds with Factor B and Factor D forming C3 convertase C3bBb.
The complex is believed to be unstable until it binds , a serum protein. However, the classical complement pathway activation can also be initiated by non-immunological means. Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes In the early phases of an infection, the cascade can be activated on the surface of a pathogen through any one, or more, of the three pathways shown in. Subsequent interactions between C5b and other terminal components C6, C7, C8, and C9 form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing. The anaphylotoxin C5a can enhance phagocytosis of opsonized microorganisms. Properdin stabilizes it, preventing its inactivation by factors H and factor I.
A series of protective mechanisms, mediated by other proteins, has evolved to ensure that the binding of a small number of C3 or C4 molecules to host cell membranes results in minimal formation of and little amplification of activation. Generation of complement-derived chemotactic activity is also moderately diminished. Electron Micrographs of Polymerized C9 Row A: Polymerized C9 in several orientations. However, excessive complement activation or insufficient regulation causes tissue injury in many autoimmune or inflammatory diseases. These steps are summarized in Figure 19-8. Indeed, it now seems clear that complement first evolved as part of the innate , where it still plays an important role.
Factor H competes with factor B for binding to C3b and displaces Bb from C3bBb. C3bBb complex then acts as the C3 convertase and generates more C3b through an amplification loop. It simply does not require specific antigen-antibody interactions for initiation. Second, the small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Furthermore, their respective binding partners, C3 and C4, both contain thioester bonds that provide the means of covalently attaching the C3 convertases to a pathogen surface. It is present at low concentrations in normal plasma of most individuals, and, as we will see in the last part of this chapter, its production by the liver is increased during the acute-phase reaction of the innate.
Row C: Photographs of a ceramic model of polymerized C9, positioned in different orientations to match Row A. The alternative pathway of the is an component of the 's natural defense against infections. This causes the disease paroxysmal nocturnal hemoglobinuria, which is characterized by episodes of intravascular red blood cell lysis by complement. As with the , their cleavage products are designated by the addition of lower-case a and b: thus, the large fragment of B is called and the small fragment Ba. Complement component C3b present on the surface of foreign cells can bind another serum protein called Complement factor B Factor B to form a complex.
Urate crystals, bacterial endotoxins, and heparin may also non-immunologically initiate classical complement pathway activation. Inhibitors of the complement syste The complement cascade is tightly controlled to protect host cells from indiscriminate attack. Each complement pathway has unique proteins for the initiating step, but shares the same or related proteins for the intermediate steps, and uses the same components in the last step, culminating in the same activities. Complement inhibition may prevent further glomerular damage until pathogenic antibodies disappear. However, many details of lectin pathway are yet to be known. The C4b fragment attaches to the microbial cell surface. The incidence of bacterial meningitis is 0.
The cut went through her skin and she is bleeding. The activation of complement can therefore contribute to producing a strong response see Chapters 6 and 9. Host cell membranes also contain an intrinsic protein, or protectin, which inhibits the binding of C9 to the C5b,6,7,8 complex see , bottom row. The binding of C7 triggers a conformational change in the complex, exposing several hydrophobic regions that, by their chemical nature, recoil from the aqueous environment surrounding the cell. C4 is cleaved into C4a and C4b fragments. The freed complex is very unstable, with a half-life of about 0.
The generation of is the end of the lectin pathway. Convertase formation can also be prevented by cleaving C3b to its inactive derivative. Clinical improvement is further delayed as the reduction of proteinuria lags behind immunological remission disappearance of antibodies by several months ,. Surface polyanions increase the affinity of factor H for surface-bound C3b, exposing its complement regulatory domains to inactivate C3b —. The next step in the cascade is the generation of the convertases.
Complement Activation Alternative Pathway References 1. Complement Activation Alternative Pathway Regulation Carbohydrate composition and its sialic acid content on the cell surface play an important role in the activation of the alternate pathway. This is achieved principally by the covalent binding of C4b to the pathogen surface. In this regard, glomerular C3c staining indicates ongoing complement activation while C3d is a marker of past complement activation. Complement fragments named opsonins, i. The dysregulation of the alternative complement pathway can be caused by a genetic mutation or acquired inhibitory autoantibodies.
There are also plasma proteins with cofactor activity for factor I. The disease has been treated with monoclonal antibody to C5 eculizumab , leading to dramatic decrease in hemolysis 44. Terminal Steps of Complement Activation Once C5 convertases regardless of derivation are fixed on the pathogen surface, they cleave serum C5 to yield C5a anaphylatoxin and C5b remains bound to the convertase. Activation of the complement pathway through the classical, or complement pathway is followed by a cascade of reactions eventually leading to the membrane attack complex. Acyclovir is the empiric treatment of choice for suspected viral meningitis. At sites of infection, however, they are activated locally and trigger a series of potent inflammatory events. The central role of the alternative complement pathway in human disease.