Inhibition of complement lysis

Mechanism of action

CD59 is the major cell surface inhibitor of the complement membrane attack complex (MAC), a multi-molecular assembly of complement components C5 to C9 which forms as a consequence of complement activation. At the C5b-7 stage of assembly, a labile binding site is exposed on C7 which allows the growing MAC to bind cell membranes; then as C8 and multiple copies of C9 are incorporated, the complex inserts further into the membrane and finally forms a functional pore through the bilayer, leading to cell lysis. CD59 prevents lysis by interfering with the assembly of a fully functional MAC, binding to C8 in the C5b-8 complex and thereby blocking the uptake and polymerization of C9 (Figure 1). Binding sites for CD59 are located on the a subunit of C8 and on the C9b fragment (the putative membrane-binding domain) of C9. However, the regions on CD59 which are involved in this interaction have not yet been fully elucidated. Studies using proteolytic fragments of the protein implicate sites in the N-ter-minal region. Some early observations that deglyco-sylated CD59 did not inhibit cell lysis suggested that the carbohydrate moiety was also important for function, although paradoxically the deglycosylated CD59 retained its ability to bind to isolated C8 and C9 immobilized on plastic. One possible explanation for this is that the presence of the carbohydrate moiety somehow influenced the orientation of CD59 on the cell surface and thereby influenced its interaction with the MAC, without being directly involved in the binding of C8 and C9. Subsequent studies in which the site of N-linked glycosylation was removed from the CD59 cDNA by site-directed mutagenesis have demonstrated that the carbohydrate is not necessary for complement inhibitory activity.

CD59 deficiency and paroxysmal nocturnal hemoglobinuria

Paroxysmal noctural hemoglobinuria (PNH) is an acquired hemolytic disease characterized by bouts of intravascular hemolysis. The disease is caused by somatic mutation in a pluripotent stem cell of the hematopoietic system, leading to the appearance in the circulation of a clone of cells exhibiting increased sensitivity to complement lysis. Depending upon the point in the lineage at which mutation occurs, erythrocytes, granulocytes, monocytes, platelets and lymphocytes may all be affected. Cells in the affected clone are abnormally sensitive to complement because they fail to express GPI-anchored proteins on their surfaces and therefore lack CD59 and decay accelerating factor (DAF), another complement regulatory protein. The defect in PNH arises from mutation of the PIG-A gene whose product is an enzyme involved in the biosynthesis of the GPI anchor. Various mutations in PIG-A have been identified, and since PIG-A is carried on the X chromosome, loss of function in the single active allele is sufficient for disease to be manifest. There is an isolated case of CD59 deficiency due to a mutation in

In the absence o! CD59

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