The Complement System CHAPTER 13 311 CLINICAL FOCUS Paroxymal nocturnal them would be rarer than the 1 in Hemoglobinuria: a Defect in 100.000 incidence of pNh. the answer Regulation of Complement is that neither protein itself is defective in PNH: the defect lies in a posttransla Lysis tional modification of the peptide anchor that binds them to the cell membrane While most proteins that are expressed on the surface of cells have hydrophobic Common conditions different stages of the proceasociation doung cell mer市mne ment components include increased and inactivation of the C3 convertases of phosphatidylinositol, or GPD) attached to susceptibility to bacterial infections and the classical, lectin, and alternative path- amino acid residues in the protein With- systemic lupus erythematosus which is ways(see Figure 13-9b) MIRL acts later out the ability to form GPl anchors, pro related to the inability to clear immune in the pathway by binding to the C5b678 teins that attach in this manner will be complexes. Deficiency in the proteins complex, which inhibits c9 binding and absent from the cell surface, including that regulate complement activity can prevents formation of the pores that de- both DAF and MIRL. cause equally serious disorders. An ex- stroy the cell under attack. Both proteins The defect identified in PNH lies early ample is paroxymal nocturnal hemoglo- are expressed on erythrocytes as well as in the enzymatic path to formation of a binuria, or PNH, which manifests as a number of other hematopoetic cell gPl anchor and resides in the pig- a gene increased fragility of erythrocytes, lead- types. Deficiency in these proteins leads (phosphatidylinositol glycan comple ng to chronic hemolytic anemia, pancy- to highly increased sensitivity of host mentation class A gene). Transfection of topenia(loss of blood cells of all types) cells to the lytic effects of the hosts com- cells from PNH patients with an intact and venous thrombosis( formation of plement activity. PNH, the clinical con- pig-a gene restored the cells resistance lood clots). The name PNH derives sequence of deficiency in DAF and MIRL, to host complement lysis. Examination from the presence of hemoglobin in the is a chronic disease with a mean sur- of pig-a sequences in PNH patients re- urine, most commonly observed in the vival time between 10 and 15 years. The veals a number of different defects in first urine passed after a nights sleep. most common causes of mortality in this X-linked gene, indicating somatic The cause of PNH is a general defect in PNH are venous thrombosis affecting rather than genetic origin of the defect affects the expression of two regulators marrow lane and progressive bone- This description of PNH underscores synthesis of cell-surface proteins, which hepatic veins the fact that the complement system is a of complement, daF (decay accelerating An obvious question about this rare powerful defender of the host but also a factor or CD55)and MIRL (membrane but serious disease concerns the fact dangerous one. Complex systems of reg- inhibitor of reactive lysis or CD59) that two different proteins are involved ulation are necessary to protect host teins that function as inhibitors of com. occurrence of a genetic defect in each of complexes generated to lyse inle 2 DAF and MIRl are cell-surface pro. in its pathogenesis. The simultaneous cells from the activated complement all-enveloped viruses are susceptible to complement- damage (Table 13-5). For example, a few gram-negative bac mediated lysis. The viral envelope is largely derived from teria can develop resistance to complement-mediated lysis the plasma membrane of infected host cells and is there- that correlates with the virulence of the organism. In Es- fore susceptible to pore formation by the membrane cherichia coli and salmonella, resistance to complement is as- attack complex. among the pathogenic viruses susceptible sociated with the smooth bacterial phenotype, which to lysis by complement-mediated lysis are herpesviruses, characterized by the presence of long polysaccharide side orthomyxoviruses, paramyxoviruses, and retroviruses chains in the cell-wall lipopolysaccharide(LpS) component. The complement system is generally quite effective in It has been proposed that the increased LPS in the wall of re- lysing gram-negative bacteria(Figure 13-11). However, sistant strains may prevent insertion of the MAC into the some gram-negative bacteria and mo bacterial membrane, so that the complex is released from the teria have mechanisms for evading complement-mediated bacterial cell rather than forming a pore. Strains of Neisseriaall—enveloped viruses are susceptible to complement￾mediated lysis. The viral envelope is largely derived from the plasma membrane of infected host cells and is there￾fore susceptible to pore formation by the membrane￾attack complex. Among the pathogenic viruses susceptible to lysis by complement-mediated lysis are herpesviruses, orthomyxoviruses, paramyxoviruses, and retroviruses. The complement system is generally quite effective in lysing gram-negative bacteria (Figure 13-11). However, some gram-negative bacteria and most gram-positive bac￾teria have mechanisms for evading complement-mediated damage (Table 13-5). For example, a few gram-negative bac￾teria can develop resistance to complement-mediated lysis that correlates with the virulence of the organism. In Es￾cherichia coli and Salmonella, resistance to complement is as￾sociated with the smooth bacterial phenotype, which is characterized by the presence of long polysaccharide side chains in the cell-wall lipopolysaccharide (LPS) component. It has been proposed that the increased LPS in the wall of re￾sistant strains may prevent insertion of the MAC into the bacterial membrane, so that the complex is released from the bacterial cell rather than forming a pore. Strains of Neisseria The Complement System CHAPTER 13 311 plement-mediated cell lysis, but act at different stages of the process. DAF in￾hibits cell lysis by causing dissociation and inactivation of the C3 convertases of the classical, lectin, and alternative path￾ways (see Figure 13-9b). MIRL acts later in the pathway by binding to the C5b678 complex, which inhibits C9 binding and prevents formation of the pores that de￾stroy the cell under attack. Both proteins are expressed on erythrocytes as well as a number of other hematopoetic cell types. Deficiency in these proteins leads to highly increased sensitivity of host cells to the lytic effects of the host’s com￾plement activity. PNH, the clinical con￾sequence of deficiency in DAF and MIRL, is a chronic disease with a mean sur￾vival time between 10 and 15 years. The most common causes of mortality in PNH are venous thrombosis affecting hepatic veins and progressive bone￾marrow failure. An obvious question about this rare but serious disease concerns the fact that two different proteins are involved in its pathogenesis. The simultaneous occurrence of a genetic defect in each of them would be rarer than the 1 in 100,000 incidence of PNH. The answer is that neither protein itself is defective in PNH; the defect lies in a posttransla￾tional modification of the peptide anchor that binds them to the cell membrane. While most proteins that are expressed on the surface of cells have hydrophobic sequences that traverse the lipid bilayer in the cell membrane, some proteins are bound by glycolipid anchors (glycosyl phosphatidylinositol, or GPI) attached to amino acid residues in the protein. With￾out the ability to form GPI anchors, pro￾teins that attach in this manner will be absent from the cell surface, including both DAF and MIRL. The defect identified in PNH lies early in the enzymatic path to formation of a GPI anchor and resides in the pig-a gene (phosphatidylinositol glycan comple￾mentation class A gene). Transfection of cells from PNH patients with an intact pig-a gene restored the cells’ resistance to host complement lysis. Examination of pig-a sequences in PNH patients re￾veals a number of different defects in this X-linked gene, indicating somatic rather than genetic origin of the defect. This description of PNH underscores the fact that the complement system is a powerful defender of the host but also a dangerous one. Complex systems of reg￾ulation are necessary to protect host cells from the activated complement complexes generated to lyse intruders. Common conditions associated with deficiency in the comple￾ment components include increased susceptibility to bacterial infections and systemic lupus erythematosus which is related to the inability to clear immune complexes. Deficiency in the proteins that regulate complement activity can cause equally serious disorders. An ex￾ample is paroxymal nocturnal hemoglo￾binuria, or PNH, which manifests as increased fragility of erythrocytes, lead￾ing to chronic hemolytic anemia, pancy￾topenia (loss of blood cells of all types) and venous thrombosis (formation of blood clots). The name PNH derives from the presence of hemoglobin in the urine, most commonly observed in the first urine passed after a night’s sleep. The cause of PNH is a general defect in synthesis of cell-surface proteins, which affects the expression of two regulators of complement, DAF (decay accelerating factor or CD55) and MIRL (membrane inhibitor of reactive lysis or CD59). DAF and MIRL are cell-surface pro￾teins that function as inhibitors of com￾CLINICAL FOCUS Paroxymal Nocturnal Hemoglobinuria: a Defect in Regulation of Complement Lysis