Oyama A, Muso E, Ono T, Matsushima H, Yashiro M, Suyama K, Kamata T, Nogaki F, Kobayashi I, Miyawaki S, Yoshida H, Sasayama S
Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Nephron. 2001 Aug;88(4):368-75. doi: 10.1159/000046022.
BACKGROUND/AIMS: Recently, we established a high serum IgA-prone inbred (HIGA) mouse strain as a murine model of spontaneous IgA nephropathy by selective mating of high serum IgA ddY mice, and found that they showed enhanced production of glomerular extracellular matrix components with increased expression of TGF-beta mRNA and protein in the kidneys. In this study, we examined the roles of lymphocytes in the development of high serum IgA in this strain.
We performed flow cytometric analyses of T and B cells in splenic mononuclear cells (SMNCs) from these mice using BALB/c mice as normal controls. We also compared serum TGF-beta1 concentrations and TGF-beta mRNA expression levels in the B-cell-depleted (T-cell-rich) fraction of SMNCs in these mice.
HIGA mice showed significantly fewer CD3-positive cells compared with BALB/c mice when young, but not when aged. The CD4/CD8 ratio of HIGA mice was lower than that of BALB/c mice, but this difference was not significant. Although the number of B220-positive cells did not vary significantly, the ratio of surface IgA-positive B cells was significantly increased in both young and adult HIGA mice. The B-cell-depleted SMNCs from HIGA mice exhibited higher levels of expression of TGF-beta and TGF-beta1 mRNA than controls from a young age, which were maintained throughout life, but there were no differences in PDGF, MCP-1 or bFGF expression between these two strains. In contrast to local mRNA expression, serum TGF-beta1 concentration was decreased in HIGA mice compared with BALB/c controls.
These findings suggest that the mating procedure performed to establish HIGA mice selected for a unique phenotype of local up-regulation of TGF-beta production in the kidneys, as well as T cells that may contribute to both the early and consistently high serum IgA expression and enhanced production of renal extracellular matrix components in HIGA mice. Additionally, TGF-beta1 may act locally, not systemically, in a paracrine or autocrine manner.
背景/目的：最近，我们通过选择性交配高血清IgA的ddY小鼠，建立了一种高血清IgA易感性近交系（HIGA）小鼠品系，作为自发性IgA肾病的小鼠模型，并发现它们肾脏中肾小球细胞外基质成分的产生增强，同时肾脏中TGF-β mRNA和蛋白的表达增加。在本研究中，我们研究了淋巴细胞在该品系高血清IgA发生过程中的作用。
我们以BALB/c小鼠作为正常对照，对这些小鼠脾单核细胞（SMNCs）中的T细胞和B细胞进行了流式细胞术分析。我们还比较了这些小鼠SMNCs中B细胞缺失（富含T细胞）部分的血清TGF-β1浓度和TGF-β mRNA表达水平。
幼年时，HIGA小鼠的CD3阳性细胞明显少于BALB/c小鼠，但成年后则无差异。HIGA小鼠的CD4/CD8比值低于BALB/c小鼠，但这种差异不显著。虽然B220阳性细胞的数量没有显著变化，但幼年和成年HIGA小鼠表面IgA阳性B细胞的比例均显著增加。HIGA小鼠的B细胞缺失SMNCs从幼年起就表现出比对照更高的TGF-β和TGF-β1 mRNA表达水平，且终生维持，但这两个品系在PDGF、MCP-1或bFGF表达上没有差异。与局部mRNA表达相反，HIGA小鼠的血清TGF-β1浓度低于BALB/c对照。
这些发现表明，为建立HIGA小鼠所进行的交配程序选择了一种独特的表型，即肾脏中TGF-β产生的局部上调，以及可能导致HIGA小鼠早期和持续高血清IgA表达及肾脏细胞外基质成分产生增强的T细胞。此外，TGF-β1可能以旁分泌或自分泌方式在局部而非全身发挥作用。
