Complement Lysis of foreign material CR2) present on many ant including B lymp After deposition of C3b or C4b onto the surface of a present them on MHC class II molecules to T cells microorganism.the microorganism can be lysed by the insertion of the MAC into its cell membrane.This process Complement is important for the formation of memory B the of the cell lipid membrane bilayer cells,as has been shown by the CR2-mediated localization rupt killing the microorganism by osmotic lysis and retention of immune complexes by germinal centres.It has also been demonstrated that coligation of the C21(CR2)/CD19/TAPA-1 corece Pto with the B-cell Inflammatory processes ant ugen recepto (BCR)lowers 10-to 100-fold the Complement activation results in the generation of the quantity of antigen required for activation. example,when an antigen is coupled to the C3d fragment C3a,C4a and C5a anaphylotoxins.The effect of these (the protein of C3 containing the thioester site),the molecules is mediated through specific receptors present on antibody response is dependent upon binding of C3d to the surface of various cell types(Table 2).The overall role of CR2 and is greatly enhanced:in fact.C3d acts as a natural these anaphylotoxins is to recruit cells that play particular adjuvant,bridging the innate with the acquired immune roles in inflammation.as well as to trigger their r gh CR2.Comple ase in vascular ment,furthe C3a,C4a and C5a generally induce a dsmothmlciecogce permeability(all to reach the e place of injury) tolerance. e contraction.Activation of mast cells by these three anaphylotoxins results in the release of various mediators with similar activities.C5a is much more active than C3a and C4a and induces degranulation and respiratory burst activation in neutrophils.In addition. C5a pr notes the production of prostaglandins and Complement Deficiencies ds Deficiencies of specific complement components have been identified in the classical,alternative and terminal path- Solubilization and clearance of immune ways,as well as in regulatory proteins and complement complexes receptors. Clearance of immune complexes is necessary to preven damage to autol gous tiss e resulting from Deficiencies in classical pathway complement act vation. fcomplement components pathway inhibits the fo rmation of precipitating antigen- Deficiencies in Clq.CIr,Cls,C2(the most common)or C4 antibody complexes.The alternative pathway is respon- sible for the solubilization of precipitated antigen-anti produce deficiencies in classical pathway activation.A body complexes.In humans the immune complexes with common disorder that is associated with of all these deposited C3 are cleared from the circulation by erythro- deficiencies is the autoimmune disease systemic lupus cytes through binding to CRI present on their surfaces erythematosus(SLE).SLE is thought to develop as Ma consequenc f the defe from the liv ct in cle mpiexe on with cla erythrocytes without affecting the erythrocyte integrity.In eficiencies are not nece nly correlate with increased infections,implying that the alternative some autoimmune diseases(such as lupus erythematosus) the formation and deposition of immune complexes can be and/or lectin pathways are sufficient for the elimination of massive,and in such cases the action of complement can most foreign microorganisms.However,deficiencies in C3 are normally associated with a higher susceptibility to damage the surface of the cells on which the complexes are nfection In addition c3 deficienc s are also associated present. with olom rulonephritis,a patholo gic condition charac ter zed by kidr ney damage resulti from compleme Bridging innate and adaptive immune activation that has been stimulated by the presence of responses immune complexes in the basement membranes of blood vessels in the renal glomerulus.This pathology refects the Complement plays a fundamental role in mediating and importance of C3 in immune complex clearance.In enhancing humoral immunity.As a result of complement general.C3 deficiencies (and any deficiency that results in n for ire C3b or C3 fra ag a defect in C3activation n or depositio on forei rticles' are bound their surfaces the particles are taken up by complement receptors(C l-independent antigens ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group/www.els.net 9Lysis of foreign material After deposition of C3b or C4b onto the surface of a microorganism, the microorganism can be lysed by the insertion of the MAC into its cell membrane. This process disrupts the integrity of the cell lipid membrane bilayer, killing the microorganism by osmotic lysis. Inflammatory processes Complement activation results in the generation of the C3a, C4a and C5a anaphylotoxins. The effect of these molecules is mediated through specific receptors present on the surface of various cell types (Table 2). The overall role of these anaphylotoxins is to recruit cells that play particular roles in inflammation, as well as to trigger their responses. C3a, C4a and C5a generally induce an increase in vascular permeability (allowing cells to reach the place of injury) and smooth muscle contraction. Activation of mast cells by these three anaphylotoxins results in the release of various mediators with similar activities. C5a is much more active than C3a and C4a and induces degranulation and respiratory burst activation in neutrophils. In addition, C5a promotes the production of prostaglandins and eicosanoids. Solubilization and clearance of immune complexes Clearance of immune complexes is necessary to prevent damage to autologous tissue resulting from complement activation. Activation of complement through the classical pathway inhibits the formation of precipitating antigen– antibody complexes. The alternative pathway is respon￾sible for the solubilization of precipitated antigen–anti￾body complexes. In humans the immune complexes with deposited C3 are cleared from the circulation by erythro￾cytes through binding to CR1 present on their surfaces. Macrophages from the liver and spleen remove and degrade the complexes present on the surface of the erythrocytes without affecting the erythrocyte integrity. In some autoimmune diseases (such as lupus erythematosus) the formation and deposition of immune complexes can be massive, and in such cases the action of complement can damage the surface of the cells on which the complexes are present. Bridging innate and adaptive immune responses Complement plays a fundamental role in mediating and enhancing humoral immunity. As a result of complement activation, foreign particles acquire C3b or C3 fragments which are covalently bound to their surfaces. These particles are taken up by complement receptors (CR1, CR2) present on many antigen-presenting cells (APCs), including B lymphocytes, which process the antigens and present them on MHC class II molecules to T cells. Complement is important for the formation of memory B cells, as has been shown by the CR2-mediated localization and retention of immune complexes by germinal centres. It has also been demonstrated that coligation of the C21(CR2)/CD19/TAPA-1 coreceptor with the B-cell antigen receptor (BCR) lowers by 10- to 100-fold the quantity of antigen required for B-cell activation. For example, when an antigen is coupled to the C3d fragment (the protein of C3 containing the thioester site), the antibody response is dependent upon binding of C3d to CR2 and is greatly enhanced; in fact, C3d acts as a natural adjuvant, bridging the innate with the acquired immune response, through CR2. Complement, furthermore, has also been found to play an important role in B-cell tolerance. Complement Deficiencies Deficiencies of specific complement components have been identified in the classical, alternative and terminal path￾ways, as well as in regulatory proteins and complement receptors. Deficiencies in classical pathway complement components Deficiencies in C1q, C1r, C1s, C2 (the most common) or C4 produce deficiencies in classical pathway activation. A common disorder that is associated with of all these deficiencies is the autoimmune disease systemic lupus erythematosus (SLE). SLE is thought to develop as a consequence of the defect in clearing immune complexes that occur in individuals with classical pathway deficien￾cies. C2 and C4 deficiencies are not necessarily correlated with increased infections, implying that the alternative and/or lectin pathways are sufficient for the elimination of most foreign microorganisms. However, deficiencies in C3 are normally associated with a higher susceptibility to infection. In addition, C3 deficiencies are also associated with glomerulonephritis, a pathologic condition charac￾terized by kidney damage resulting from complement activation that has been stimulated by the presence of immune complexes in the basement membranes of blood vessels in the renal glomerulus. This pathology reflects the importance of C3 in immune complex clearance. In general, C3 deficiencies (and any deficiency that results in a defect in C3 activation or deposition on foreign particles), produce an impairment of the immune response to T-cell￾dependent and T-cell-independent antigens. Complement ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 9