Aging Regulation Section, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan; Department of Nephrology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan; Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Clin Exp Immunol. 2014 Jul;177(1):353-65. doi: 10.1111/cei.12333.
The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, a model of human crescentic glomerulonephritis (CrGN) and systemic vasculitis, is characterized by the production of myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) and marked leucocytosis. This study was performed to identify the specific populations of leucocytes associated with CrGN and susceptibility loci for pathogenic leucocytosis. Four hundred and twenty female (C57BL/6 × SCG/Kj) F2 intercross mice were subjected to serial flow cytometry examination of the peripheral blood (PB). Kidney granulocytes and monocytes were examined histopathologically. Linkage analyses were performed with 109 polymorphic microsatellite markers. Correlation studies revealed that increase of the granulocytes, F4/80(+) cells, CD3(+) CD4(-) CD8(-) T cells and dendritic cells (DCs) in peripheral blood (PB) were associated significantly with glomerulonephritis, crescent formation and vasculitis. In kidney sections, F4/80(low) cells were observed in crescent, while F4/80(high) cells were around the Bowman's capsules and in the interstitium. Numbers of F4/80(+) cells in crescents correlated significantly with F4/80(+) cell numbers in PB, but not with numbers of F4/80(+) cells in the interstitium. Genome-wide quantitative trait locus (QTL) mapping revealed three SCG/Kj-derived non-Fas QTLs for leucocytosis, two on chromosome 1 and one on chromosome 17. QTLs on chromosome 1 affected DCs, granulocytes and F4/80(+) cells, but QTL on chromosome 17 affected DCs and granulocytes. We found CrGN-associated leucocytes and susceptibility QTLs with their positional candidate genes. F4/80(+) cells in crescents are considered as recruited inflammatory macrophages. The results provide information for leucocytes to be targeted and genetic elements in CrGN and vasculitis.
自发性新月体肾小球肾炎形成/Kinjoh (SCG/Kj) 小鼠是人类新月体肾小球肾炎 (CrGN) 和系统性血管炎的模型,其特征是产生髓过氧化物酶特异性抗中性粒细胞胞质自身抗体 (MPO-ANCA) 和明显的白细胞增多。本研究旨在鉴定与 CrGN 相关的特定白细胞群和致病性白细胞增多的易感基因座。将 420 只雌性 (C57BL/6 × SCG/Kj) F2 杂交小鼠进行外周血 (PB) 的连续流式细胞术检查。对肾脏粒细胞和单核细胞进行组织病理学检查。采用 109 个多态性微卫星标记进行连锁分析。相关性研究表明,外周血 (PB) 中粒细胞、F4/80(+)细胞、CD3(+) CD4(-) CD8(-) T 细胞和树突状细胞 (DC) 的增加与肾小球肾炎、新月体形成和血管炎显著相关。在肾脏切片中,新月体中观察到 F4/80(low)细胞,而 F4/80(high)细胞位于肾小球囊周围和间质中。新月体中的 F4/80(+)细胞数量与 PB 中的 F4/80(+)细胞数量显著相关,但与间质中的 F4/80(+)细胞数量无关。全基因组数量性状基因座 (QTL) 作图显示,白细胞增多有三个源自 SCG/Kj 的非 Fas QTL,两个位于 1 号染色体上,一个位于 17 号染色体上。1 号染色体上的 QTL 影响 DCs、粒细胞和 F4/80(+)细胞,而 17 号染色体上的 QTL 影响 DCs 和粒细胞。我们发现了与 CrGN 相关的白细胞和易感 QTL 及其位置候选基因。新月体中的 F4/80(+)细胞被认为是募集的炎症性巨噬细胞。研究结果为靶向白细胞和 CrGN 和血管炎中的遗传因子提供了信息。