glomerular capillary wall thickening and mesangial cell The gPl anchor is synthesized separately by the cell and proliferation with increased amounts of mesangial extra- attached to the protein polypeptides posttranslationally celuerai over t in facto pathogenesis of MPGN I.The affected piglets invariably developed glomerular changes typical for MPGN II (Rosse,1997).The gene(PIG-A for phosphatidylinositol ilure at a m n age of 37 days (X22 1 In PNH the mutation in the X-chromosomal P/G-4 Human factor H deficiency is rare and appears to cause cell.Thus,all sever pigs.Som ers of ghter cel cell are ir he neous autoimmune disorders or are healthv. been shown to be of clonal origin.Hov er.in man In addition to Hdeficiency other mechanisms can lead to Datients.two or more de fective clones arise.Thus the P/C ative pathway hype H gene appears to (C3Nef)binds the C3bBb the e mu prevents its intrinsic or factor H-mediated decay.Also.a cells.The reason for this dominance is vet unknown and 山 cto caus path al und cas h 9ntrgulaprPpotcins,D enhan re are rtially missi turnover and becomes consumed.I addition to MPGN faulty stem pre GBM of part ophy the deficieney ofs sinc anisolated an DAF s A sin complement membrane regulators on these structure deficiency of CD59has been described in the literature:this Complement components e free access to the GBM patient suffered from a severe form of PNH fenestrat n the glomerular of protectin ontrolled h inte the lvtic s ms ofte i.e.when complement activation is enhanced.The lack of protectin from pla elets allows the assembly of terminal n at consequence,co mplemen the platele the surfac and in ed prothro activity.Subsequently,excessive thrombin generation Paroxysmal nocturnal haemoglobinuria he of venous thrombo ells totall Deficiency of complement regulators CD59 and Daf leads to a disease called paroxysmal nocturnal haemoglo usually done by measuring CD59 expression on erythro- binuria (PNH).PNH is a rare haemolytic disorder charac ular haemolysis, (PNH eney of PNH is a ximately 1-10 pe one millio II cells)or partially (PNH II cells).In ral the The course of PNH varies,the median survival time from oroportion of CD59-deficient cells in PNH can vary diagnosis is 10-15 years but spontaneous recoveries are betweer re and of PNH i nta relativel y well unde es and event thrombose Some patients may benefit from cytes of PNH patients lack several GPI-anchored proteins. immunosuppressive chemotherapy. 6 ENCYCLOPEDIA OF LIFE SCIENCES/2001glomerular capillary wall thickening and mesangial cell proliferation with increased amounts of mesangial extra￾cellular matrix. The discovery of Norwegian piglets deficient in factor H was a major breakthrough in fevunderstanding the pathogenesis of MPGN II. The affected piglets invariably developed glomerular changes typical for MPGN II and died of renal failure at a median age of 37 days. Infusion on normal plasma or purified factor H increased plasma H levels and significantly prolonged the median survival time. Human factor H deficiency is rare and appears to cause less severe consequences than in pigs. Some members of families with hereditary H deficiency have MPGN II, a few have haemolytic uraemic syndrome, others have miscella￾neous autoimmune disorders or are healthy. In addition to H deficiency other mechanisms can lead to alternative pathway hypercatabolism and MPGN II. An immunoglobulin G (IgG) antibody called C3 nephritic factor (C3Nef) binds to the C3bBb convertase and prevents its intrinsic or factor H-mediated decay. Also, a monoclonal immunoglobulin light chain dimer has been shown to bind to factor H, prevent its function and cause MPGN II. The net effect in all these cases is that the alternative complement pathway undergoes enhanced turnover and becomes consumed. In addition to MPGN II, patients with alternative pathway dysfunction may present with symptoms of partial lipodystrophy. The fact that GBMs become the target for complement attack in factor H deficiency is probably due to the lack of complement membrane regulators on these structures. Complement components have free access to the GBM through fenestrations in the glomerular endothelium. While under normal circumstances complement activation is controlled by an interaction between the anionic components of the GBM and factor H, an absolute or relative lack of factor H leads to alternative pathway activation at this site. As a consequence, complement activation may result in subsequent intraglomerular inflammation and mesangial cell proliferation. Paroxysmal nocturnal haemoglobinuria Deficiency of complement regulators CD59 and DAF leads to a disease called paroxysmal nocturnal haemoglo￾binuria (PNH). PNH is a rare haemolytic disorder characterized by intravascular haemolysis, haemoglobi￾nuria and a tendency to vascular thrombosis. The frequency of PNH is approximately 1–10 per one million. The course of PNH varies, the median survival time from diagnosis is 10–15 years but spontaneous recoveries are known to occur. The basic pathogenetic mechanism of PNH is now relatively well understood. The erythrocytes and leuco￾cytes of PNH patients lack several GPI-anchored proteins. The GPI anchor is synthesized separately by the cell and attached to the protein polypeptides posttranslationally. Several enzymes are needed for the synthesis of the GPI anchor. In PNH, a block of GPI anchor synthesis occurs at an early step, during the transfer of an N-acetyl￾glucosamine moiety to the phosphatidylinositol acceptor (Rosse, 1997). The gene (PIG-A for phosphatidylinositol glycan complementation class A) coding for the enzyme needed for this step has been cloned and mapped to the X chromosome (Xp22.1). In PNH the mutation in the X-chromosomal PIG-A gene occurs in a haematopoietic stem cell. Thus, all daughter cells of this stem cell are incapable of synthesizing the GPI anchor and proteins attached to the cell membrane by GPI anchoring are not expressed. The affected cells have been shown to be of clonal origin. However, in many patients, two or more defective clones arise. Thus the PIG￾A gene appears to be unduly susceptible to mutations or the circumstances in the bone marrow favour the mutation. Also, the defective clone tends to dominate over normal cells. The reason for this dominance is yet unknown and remains as the main unresolved question in PNH. Two complement regulatory proteins, DAF (CD55) and protectin (CD59), are GPI anchored. In PNH these regulators are totally or partially missing from the leucocytes, platelets and erythrocytes deriving from the faulty stem cell. Most of the symptoms of PNH can be traced to the deficiency of CD59 since an isolated deficiency of DAF (the Inab phenotype) causes no symptoms. A single case of an inherited homozygous deficiency of CD59 has been described in the literature; this patient suffered from a severe form of PNH. The deficiency of protectin renders the erythrocytes susceptible to lysis by autologous complement. The haemolytic symptoms often aggravate during infections, i.e. when complement activation is enhanced. The lack of protectin from platelets allows the assembly of terminal complement complex C5b-9 on the platelet surface. This may lead to the release of granule contents and shedding of vesicles from the surface and increased prothrombin activity. Subsequently, excessive thrombin generation may result in the development of venous thromboses, another manifestation of PNH. PNH is diagnosed by demonstrating cells totally or partially deficient in GPI-anchored proteins. This is usually done by measuring CD59 expression on erythro￾cytes or leucocytes by fluorescence-activated cell sorter (FACS) analysis. Normally, CD59 is expressed on all cells. In PNH, a proportion of cells may lack CD59 totally (PNH III cells) or partially (PNH II cells). In general, the proportion of CD59-deficient cells in PNH can vary between 5 and 95%. In severe anaemia PNH has been treated by blood transfusions and bone marrow trans￾plantation. Anticoagulation therapy is often indicated to prevent thromboses. Some patients may benefit from immunosuppressive chemotherapy. Complement Regulatory Proteins 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net