Abstract
CD59 antigen is a membrane glycoprotein that inhibits the activity of the C9 component of the C5b-9 membrane attack complex, thereby protecting human cells from lysis by human complement. The complement-inhibitory activity of CD59 is species-selective and is most effective toward C9 derived from human or other primate plasma. By contrast, rabbit C9, which can substitute for human C9 in the membrane attack complex, mediates unrestricted lysis of human cells. To identify the peptide segment of human C9 that is recognized by CD59, rabbit C9 cDNA clones were isolated, characterized, and used to construct hybrid cDNAs for expression of full-length human/rabbit C9 chimeras in COS-7 cells. All resulting chimeras were hemolytically active, when tested against chicken erythrocytes bearing C5b-8 complexes. Assays performed in the presence or absence of CD59 revealed that this inhibitor reduced the hemolytic activity of those chimeras containing human C9 sequence between residues 334-415, irrespective of whether the remainder of the protein contained human or rabbit sequence. By contrast, when this segment of C9 contained rabbit sequence, lytic activity was unaffected by CD59. These data establish that human C9 residues 334-415 contain the site recognized by CD59, and they suggest that sequence variability within this segment of C9 is responsible for the observed species-selective inhibitory activity of CD59.
Highlights
The nucleotide sequencers) reported in this paper has been submitted to the GenBankTM / EMBL Data Bank with accession numberis) U2005
Because the activity of CD59 is largely restricted to regulating human C9, and the activity of analogous complement inhibitors expressed by cells of other species is likewise generally selective for homologous C9, xenotypic cells and tissue are susceptible to complement-mediated destruction due to unregulated activity of MAC
Whereas CD59 binds to human C9 and to peptides derived from human C9, such binding is not detected with rabbit C9, consistent with the apparently unrestricted lytic activity of rabbit complement toward human cells containing CD59 [4,5,6, 8]
Summary
The nucleotide sequencers) reported in this paper has been submitted to the GenBankTM / EMBL Data Bank with accession numberis) U2005. The lytic activity of full-length recombinant human C9 (panel C) was markedly inhibited by CD59, whereas that of full-length recombinant rabbit C9 (panel D) was virtually unaffected, consistent with the species-selective regulation by CD59 observed for the corresponding plasma-derived proteins (panels A and B).
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