Complement Regulatory Proteins the skinand The odema cause c ky ab d to unne Figure3 (CD59)h m example,physical trauma,dental procedures,stress or can be dentified s C9 incorporatio ient to angther. The actual mediator ofthe oedema attacks in HAEis not nown for certain.CI INH is physiologically significant in pholipid- rineound inu krein and plas atios In SDS PAGE ptoms but other factors e.g.C2b.can have an gels CD59 appears as a smear of 18-25kDa.The gene for CD59islocated onchromosome 11pl3and hasfour exons. 7 amino ogether a ed by me N the plasma level Protectin inhibits the final steps of MAC assembly on rs the threshold for Cp ent activation.As a cell membranes.By binding to the C5b-8 complex result,C2 and C4 are consumed during HAE attacks.In complex I he ng the C&achain and the Cob fragment.Like DAF.CD59car HAE patients are heterozygous readily incorporate into cell m embranes.Binding of CD59 for the mutated gene,the plasma levels of CI INH and the mcl activityare value bly b hy th Acute HAE attacks can be treated with CI INH Diseases Caused by Deficiencies of Complement Regulatory Proteins short-term ention eg before surgical procedures Hereditary angio-oedema danazol,CI INH concentrates or antifibrinolytic drugs have been used. dominant fashion and is divided in two biochemically Factor H deficiency and distinct types.Type I(approximately 85%of patients)is membranoproliferative glomerulonephritis d by low antigenic levels of CI INH type Il imental oduction of CI INH messenger RNA(mRNA).Type II HAE is caused by point mutations at or near the factor H can lead to membranoproliferative glomerulone reactive cere residues of phritis (MPGN)type II (Hogasen et al., 1998,1nth1s prote he pati se complement compo (GBMs) but the protein is functionally defective.In addition to the thickened because of clectron-dense intramembranous hereditary form,CI INH deficiency occurs in an acquired deposits.MPGN commonly begins in early adolescence form ( .AAE)which is usually ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net pholipid-containing and free forms can be found in human urine, saliva, tears, breast milk, blood plasma, amniotic fluid and seminal plasma in various ratios. In SDS-PAGE gels CD59 appears as a smear of 18–25 kDa. The gene for CD59 is located on chromosome 11p13 and has four exons. The 77 amino acids of protectin constitute together a distinct domain with five internal disulfide bridges. Protectin inhibits the final steps of MAC assembly on cell membranes. By binding to the C5b-8 complex, protectin limits C9 input and prevents formation of the polymeric C9 complex (Figure 3). The binding sites of erythrocyte protectin on C8 and C9 have been localized to the C8 a chain and the C9b fragment. Like DAF, CD59 can readily incorporate into cell membranes. Binding of CD59 has been shown to occur to HIV, Schistosoma mansoni and E. coli outer cell membranes. Diseases Caused by Deficiencies of Complement Regulatory Proteins Hereditary angio-oedema An inherited deficiency of C1 INH causes hereditary angio￾oedema (HAE). HAE is inherited in an autosomal dominant fashion and is divided in two biochemically distinct types. Type I (approximately 85% of patients) is characterized by low antigenic levels of C1 INH in plasma. It is caused by major structural changes in the C1 INH gene, e.g. deletions, insertions or mutations preventing the production of C1 INH messenger RNA (mRNA). Type II HAE is caused by point mutations at or near the gene region encoding the reactive centre residues of the C1 INH protein (Circolo and Strunk, 1997). The patients have normal or even elevated plasma levels of antigenic C1 INH but the protein is functionally defective. In addition to the hereditary form, C1 INH deficiency occurs in an acquired form (acquired angio-oedema, AAE) which is usually associated with lymphoproliferative disorders. Clinically, all forms of HAE and AAE are identical. The disease is characterized by recurrent attacks of oedema of the skin and mucosa. The extremities and face are common sites of swelling. The oedema is typically painless, nonitching and nonpitting. Gastrointestinal oedema can cause colicky abdominal pain and has led to unnecessary surgery. Laryngeal oedema can be life-threatening. The swelling episodes are self-limiting and usually subside within 12–72 hours. The attacks are triggered by, for example, physical trauma, dental procedures, stress or hormonal factors or no triggering factor can be identified. The severity and frequency of attacks may vary from one patient to another. The actual mediator of the oedema attacks in HAE is not known for certain. C1 INH is physiologically significant in the regulation of the complement, kallikrein and plasmin systems. Bradykinin is the most probable mediator of the symptoms but other factors, e.g. C2b, can have an influence. HAE can be diagnosed by measuring the plasma level and biochemical activity of C1 INH. A typical feature of HAE is a low level of C1 INH in plasma. Lack of C1 INH lowers the threshold for CP complement activation. As a result, C2 and C4are consumed during HAE attacks. In contrast, the C3 level remains normal. In AAE, C1q is characteristically low, which distinguishes AAE from the hereditary form. Surprisingly, although HAE patients are heterozygous for the mutated gene, the plasma levels of C1 INH and the biochemical activity are below the expected 50% value. This can possibly be explained by trans-inhibition of the synthesis or secretion of the normal form by the mutated form. Acute HAE attacks can be treated with C1 INH concentrates, fresh frozen plasma or with antifibrinolytic agents. In long-term prophylactic treatment, attenuated androgens like danazol have proven most effective. In short-term prevention, e.g. before surgical procedures, danazol, C1 INH concentrates or antifibrinolytic drugs have been used. Factor H deficiency and membranoproliferative glomerulonephritis type II Recent evidence from studies on humans and experimental animals indicates that the dysfunction or deficiency of factor H can lead to membranoproliferative glomerulone￾phritis (MPGN) type II (Høga˚sen et al., 1998). In this disease complement components can be found in glomer￾ular basement membranes (GBMs) which have become thickened because of electron-dense intramembranous deposits. MPGN commonly begins in early adolescence and presents with haematuria, proteinuria or nephrotic syndrome. Microscopically, MPGN is characterized by C9 C9 C5b-8 I II CD59 C9 C5b-8 I II CD59 C9 Figure 3 Inhibition of the membrane attack complex of complement by protectin (CD59). By binding to the C56-8 complex at the C8a chain and C9b sites, CD59 inhibits C9 incorporation and polymerization in the MAC. Complement Regulatory Proteins ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5