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Genetic Dissection of Vasculitis, Myeloperoxidase-Specific Antineutrophil Cytoplasmic Autoantibody Production, and Related Traits in Spontaneous Crescentic Glomerulonephritis-Forming/Kinjoh Mice¹

Yoshitomo Hamano^2,*, Kazuyuki Tsukamoto^*, Masaaki Abe^*, Guo Dong Sun^*, Danqing Zhang^*, Hiroaki Fujii^*, Shuji Matsuoka^*, Masumi Tanaka^*, Akiko Ishida-Okawara, Hitoshi Tachikawa, Hiroyuki Nishimura, Kazuhiro Tokunaka, Sachiko Hirose^* and Kazuo Suzuki

^* Department of Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Biodefense Laboratory, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan; Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama-shi, Kanagawa, Japan; and Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan

The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse is a model of human crescentic glomerulonephritis and vasculitis associated with the production of the myeloperoxidase (MPO)-specific antineutrophil cytoplasmic autoantibody (MPO-ANCA). Although the disease is mediated initially by mutation of the Fas gene (lpr), SCG/Kj mice also have non-Fas predisposing genetic factors. To define these factors, genome-wide quantitative trait locus (QTL) mapping was performed on female (B₆x SCG/Kj) F₂ intercross mice. Fourteen non-Fas QTLs were identified. QTLs of glomerulonephritis were located on chromosomes 1, 10, 13, 16, and 17, vasculitis on chromosomes 1 and 17, splenomegaly on chromosome 1, hypergammaglobulinemia on chromosomes 1, 2, 4, 6, 7, 11, 13, and 17, antinuclear Ab on chromosomes 1, 8, 10, and 12, and MPO-ANCA production on chromosomes 1 and 10. Significant QTLs derived from SCG/Kj on chromosomes 1, 2, 7, and 13 were designated Scg-1 to Scg-5, respectively, and those derived from B₆ on chromosomes 4, 6, 17, and 10 were designated Sxb-1 to Sxb-4, respectively. Two loci linked to MPO-ANCA production on chromosomes 1 and 10 were designated Man-1 and Man-2 (for MPO-ANCA), respectively. Although both Scg-1 and Scg-2 were on chromosome 1 and shared several functions, it was of interest that aberrant MPO-ANCA production was exclusively controlled by Man-1, the centromeric half region of the Scg-2 chromosomal segment. We also examined the epistatic effects between the lpr mutation and non-Fas susceptibility genes. QTLs are discussed in relation to previously described loci, with emphasis on their candidate genes.

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