Autoimmunity and glomerulonephritis in mice with targeted deletion of the serum amyloid P component gene: SAP deficiency or strain combination?
| Autor: | Winston L. Hutchinson, Ken Ichi Yamamura, Julian D. Gillmore, A Bybee, Daniel A. Mitchell, Robert P. Hasserjian, Mark B. Pepys, Misao Suzuki, Caroline A. Sabin, Jeff Herbert |
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| Rok vydání: | 2004 |
| Předmět: |
Male
genetic structures Transgene Immunology Apoptosis Autoimmunity Mice Transgenic Kidney medicine.disease_cause Mice Glomerulonephritis Rheumatoid Factor medicine Animals Humans Immune Complex Diseases Immunology and Allergy Serum amyloid P component Gene knockout Mice Knockout biology Autoantibody Original Articles medicine.disease Molecular biology Chromatin eye diseases Nucleosomes DNA-Binding Proteins Mice Inbred C57BL Serum Amyloid P-Component Antibodies Antinuclear Knockout mouse biology.protein Female Immunization |
| Zdroj: | Immunology. 112:255-264 |
| ISSN: | 1365-2567 0019-2805 |
| DOI: | 10.1111/j.1365-2567.2004.01860.x |
| Popis: | SUMMARY Human serum amyloid P component (SAP) binds avidly to DNA, chromatin and apoptotic cells in vitro and in vivo. 129/Sv 3 C57BL/6 mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoantibodies and immune complex glomerulonephritis. SAP-deficient animals, created by backcrossing the 129/Sv SAP gene deletion into pure line C57BL/6 mice and studied here for the first time, also spontaneously developed broad spectrum antinuclear autoimmunity and proliferative immune complex glomerulonephritis but without proteinuria, renal failure, or increased morbidity or mortality. Mice hemizygous for the SAP gene deletion had an intermediate autoimmune phenotype. Injected apoptotic cells and isolated chromatin were more immunogenic in SAP –/– mice than in wild-type mice. In contrast, SAP-deficient pure line 129/Sv mice did not produce significant autoantibodies either spontaneously or when immunized with extrinsic chromatin or apoptotic cells, indicating that loss of tolerance is markedly strain dependent. However, SAP deficiency in C57BL/6 mice only marginally affected plasma clearance of exogenous chromatin and had no effect on distribution of exogenous nucleosomes between the liver and kidneys, which were the only tissue sites of catabolism. Furthermore, transgenic expression of human SAP in the C57BL/6 SAP knockout mice did not abrogate the autoimmune phenotype. This may reflect the different binding affinities of mouse and human SAP for nuclear autoantigens and/or the heterologous nature of transgenic human SAP in the mouse. Alternatively, the autoimmunity may be independent of SAP deficiency and caused by expression of 129/Sv chromosome 1 genes in the C57BL/6 background. |
| Databáze: | OpenAIRE |
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