2004 Fiscal Year Final Research Report Summary
Role of G-CSF and C-CSF receptor gene polymorphisms for the development of lupus nephritis
| Project/Area Number |
15300145
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
HIROSE Sachiko Juntendo Univ., Sch Med,. Dept Pathol., Associate Prof., 医学部, 助教授 (00127127)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUOKA Shuji Juntendo Univ., Sch Med,. Dept Pathol., Instructor, 医学部, 助手 (20286743)
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| Project Period (FY) |
2003 – 2004
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| Keywords | G-CSF / G-CSF receptor / gene polymorphism / lupus nephritis / linkage analysis / susceptibility gene / (NZB x NZW) F1 mouse / Th1 / Th2 balance |
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| Research Abstract |
Systemic lupus erythematosus(SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex(IC)-type tissue inflammation, most prominently in the kidney. In SLE-prone (NZB x NZW) Fl mice, IC-type lupus nephritis more severe than parental NZB develop due to the contribution of susceptibility genes derived from both NZB and NZW strains. Our genome-wide scans to search for susceptibility genes for lupus nephritis in backcross mice of (NZB x NZW) Fl to NZB or NZW mice showed evidence that the NZB gene located in the vicinity of Clq and G-CSF receptor gene on chromosome 4 and NZW gene located in the vicinity of G-CSF gene on chromosome 11 are involved in severe nephritis. Sequence and functional analyses of Clq and G-CSF receptor genes revealed that the candidate gene on chromosome 4 seems to be Clq. Sequence analysis of G-CSF genes showed that there are sequence polymorphisms in 3' UTR region between NZB and NZW. Possibly due to these polymorphisms, G-CSF mRNA level and G-CSF production capacity by macrophages were significantly higher in NZW than in NZB. Furthermore, number of peripheral neutrophil was significantly higher in NZW than in NZB, and NZW neutrophil seemed to be more activated, estimated by enlarged cell size. In addition, in vitro cytokine analysis in anti-CD3 antibody-stimulated splenic T cells showed that G-CSF is able to enhance Th2-type cytokine, IL-4.
Based on these findings, it was suggested that NZW-type polymorphic G-CSF gene possibly contribute to high G-CSF levels, which in turn contribute to the susceptibility to lupus nephritis due to the increase in neutrophil number and activity, and due to the up-regulation of IC-formation through the high level of Th2 cytokine production.
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