Paroxysmal nocturnal hemoglobinuria: deficiency in factor H-like functions of the abnormal erythrocytes.
Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) contained a subpopulation that lacked membrane-associated Factor H-like activity present on normal human erythrocytes. Initial deposition of C3b on the erythrocytes was effected using a fluid phase C3 convertase. The cells were then treated with fluorescein-labeled C3 and the cell-bound C3 convertase. Analysis utilizing the fluorescence-activated cell sorter revealed two distinct cell populations, one of which was highly fluorescent, indicating a large number of C3b molecules per cell. Only this population (43%) was susceptible to lysis (44%) when exposed to acidified serum before C3b deposition. The less fluorescent population resembled normal human erythrocytes and was not affected by prior treatment with acidified serum. Since C3b deposition occurred almost exclusively on the complement-sensitive cells in the PNH erythrocyte population, these cells could be examined for the Factor H-like regulatory activities without prior isolation. These functions include enhancement of inactivation of erythrocyte-bound C3b by Factor I and acceleration of the decay of erythrocyte-bound C3 convertase, C3b,Bb. It was found that C3b on PNH erythrocytes was 100-fold less susceptible to inactivation by Factor I than C3b on normal human erythrocytes. The half-life at 22 degrees C of C3b,Bb on PNH erythrocytes was threefold greater than on normal human erythrocytes and similar to that of the enzyme bound to particles that do not possess Factor H-like activity. These observations suggest that the abnormal susceptibility of PNH erythrocytes to lysis by complement is due to a functional deficiency in one or more of the Factor H-like proteins present on normal human erythrocytes.
D003176:Complement C3 / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000097:blood; D003179:Complement C3b / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000172:deficiency*; D017242:Complement Factor H; D017244:Complement Factor I; D010450:Endopeptidases / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood*; D006801:Humans; D011951:Receptors, Complement / Q000378:metabolism; D017463:Receptors, Complement 3b
C493495:CFH protein, human; D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003179:Complement C3b; D017242:Complement Factor H; D010450:Endopeptidases; D050577:Complement C3-C5 Convertases; D017244:Complement Factor I