| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
To define genetic factors for vasculitis, crescentic glomerulonephritis and MPOANCA production in the spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, we performed genome-wide QTL mapping using female (B6×SCG/Kj) F_2 intercross mice. Fourteen non-Fas QTLs were identified: QTLs for glomerulonephritis were located on chromosomes 1, 10, 13, 16,and 17, those for vasculitis on chromosomes 1 and 17, and those for aberrant MPOANCA production on chromosomes 1 and 10. Statistically significant QTLs from SCG/Kj were designated Scg-1 to Scg-5 and those from B6 were designated Sxb-1 to Sxb-4. Two QTLs linked to aberrant MPO-ANCA were designated Man-1 and Man-2.
We also investigated the immunopathological mechanism of spontaneous vasculitis, crescentic glomerulonephritis and abnormal MPOANCA production by flow cytometry. Correlation between values of leukocyte count including granulocytes, monocytes, T lymphocytes, B lymphocytes and dendritic cells (DCs) in peripheral blood and autoimmune phenotypes were statistically examined. As a result, increase of granulocytes, monocytes, CD4-CD8-double negative T cells and DCs were significantly associated with all of autoimmune phenotypes including MPO-ANCA and autoantibody levels, glomerulonephritis, vasculitis and splenomegaly. Subset study of dendritic cells revealed classical DCs, but not plasmacytoid DCs, were correlated with autoimmune phenotypes. Classical DCs were thus supposed to play some role in the disease pathogenesis. QTL analyses found out three to four significant loci for increase in cDCs and such loci were independent of previously known QTLs for autoimmunity in SCG/Kj. These facts suggested that QTLs for DCs acted as early susceptibility genes and caused initial activation of immune system in multistep pathogenesis of autoimmune diseases.
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