Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1)
Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1)
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DOI：
10.4049/jimmunol.175.11.7185
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Yoshida, H
中科院分区：
文献类型：
--
作者：
Shimizu, S;Sugiyama, N;Yoshida, H
MRL/lpr小鼠发生自发性肾小球肾炎，其与人狼疮肾炎中的弥漫性增殖性肾小球肾炎（世界卫生组织IV类）基本相同。狼疮性肾炎是系统性红斑狼疮最严重的并发症之一。弥漫性增生性肾小球肾炎与产生高水平IFN-γ的Th 1细胞主导的自身免疫反应有关。Th 1应答的初始安装取决于WSX-1基因的功能，该基因编码与IL-12 R同源的IL-27 R亚基。在WSX-1基因缺陷的小鼠中，在感染某些细胞内病原体期间，观察到适当的Th 1分化受损和异常的Th 2偏斜。破坏WSX-1基因显著改变了MRL/lpr小鼠肾小球肾炎的病理生理学。WSX-1（-/-）MRL/lpr小鼠发生了类似于人膜性肾小球肾炎（世界卫生组织V类）的疾病，肾小球沉积物中以IgG 1为主，伴有血清中IgG 1和IgE升高。WSX-1（-/-）MRL/lpr小鼠中的T细胞显示出IFN-γ产生的显著降低，沿着IL-4表达的升高。因此，WSX-1的缺失有利于Th 2型自身免疫反应，这表明Th 1/Th 2平衡可能是人类狼疮肾炎发展的关键决定因素。
MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-gamma. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1(-/-) MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1(-/-) MRL/lpr mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.