The plasma pentraxin proteins serum amyloid P component (SAP) and C-reactive protein (CRP) bind specifically to nuclear autoantigens. There is a blunted acute phase response of human CRP in systemic lupus erythematosus (SLE), and of mouse SAP in NZB/W murine SLE. SAP deficiency in (129/Sv X C57BL/6)F2 mice is associated with spontaneous antinuclear autoimmunity. The pentraxins may thus function in preventing autoimmunity. Pure line C57BL/6 SAP knockout mice, studied here for the first time, spontaneously developed broad spectrum anti-nuclear autoimmunity resembling human SLE, and, females in particular had proliferative immune complex glomerulonephritis but without proteinuria or renal failure. Mice hemizygous for the SAP gene deletion had an intermediate autoimmune phenotype. Injected apoptotic cells and isolated chromatin were more immunogenic in SAP-/- than in wild-type mice. Extrinsic chromatin was catabolised predominantly in hepatocytes, Kupffer's cells and renal parenchymal cells. Plasma clearance of long chromatin and core particles was marginally slower in SAP-/- mice, with significantly greater splenic uptake of nucleosome core particles, which may have immunological significance. SAP bound to apoptotic cells but had no effect on their phagocytosis in mice in vivo, or by human macrophages in vitro. CRP also bound to apoptotic cells but did not compete with SAP, indicating recognition of different ligands. In contrast, to the C57BL/6 strain, pure line 129/Sv SAP knockout mice did not produce autoantibodies. Formation of antinuclear autoantibodies is thus markedly strain dependent. Interestingly, transgenic expression of human SAP in the C57BL/6 SAP knockouts did not abrogate the autoimmune phenotype. Transgenic reconstitution of the knockouts with mouse SAP is currently in progress to confirm that autoimmunity is caused by SAP deficiency and not by 129/Sv genes transferred into the C57BL/6 background during homologous recombination, or by disruption of loci associated with murine SLE that are close to the mouse SAP gene.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:248417 |
| Date | January 2004 |
| Creators | Gillmore, Julian D. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1446569/ |
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