Expression and tissue localization of donor-specific complement C3 synthesized in human renal allografts.
Recent evidence suggests that the third component of complement, C3, is synthesized in renal tissue, and that increased C3 synthesis occurs in allograft rejection and immune complex-mediated nephritis. However, it is unclear whether intrinsic renal cells or migratory cells in the inflammatory infiltrate, possibly of recipient bone marrow origin, are the source of the C3 detected. This was investigated by determining the C3 allotypes of mRNA and protein produced by transplanted human kidney. Twenty donor-recipient pairs were examined, of which nine pairs had C3 allotypes that were informatively mismatched at the C3 F/S locus. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by amplification refractory mutation system analysis showed intracellular donor-specific mRNA expression in six of these nine cases, at up to 61 days post-transplantation. Nested PCR reactions and the size of PCR products excluded contamination by genomic DNA. Allotype-specific staining of frozen sections of renal cortex demonstrated donor-derived C3 protein in both glomeruli and tubules of all biopsies examined, in a predominantly tubular distribution. These results imply that at least some of the pro-inflammatory effects of complement arise from intrinsic tissue synthesis of donor C3, and that this may represent a previously unrecognized source of tissue injury. The occurrence of local synthesis of C3 of donor allotype may have functional implications related to C3 allotype, and may also be relevant to strategies to inhibit intrarenal complement-mediated injury.
Andrews
P A
PA
Department of Nephrology, Guy's Hospital, London, GB.
Finn
J E
JE
Lloyd
C M
CM
Zhou
W
W
Mathieson
P W
PW
Sacks
S H
SH
D000483:Alleles; D001483:Base Sequence; D003176:Complement C3 / Q000096:biosynthesis* / Q000235:genetics; D018076:DNA, Complementary; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis*; D014184:Transplantation, Homologous
D003176:Complement C3; D018076:DNA, Complementary; D012333:RNA, Messenger