Experimental hemochromatosis due to MHC class IHFE deficiency:: Immune status and iron metabolism
Experimental hemochromatosis due to MHC class IHFE deficiency:: Immune status and iron metabolism
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DOI：
10.1073/pnas.96.23.13312
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发表时间：
1999-11-09
影响因子：
11.1
通讯作者：
Schümann, K
中科院分区：
文献类型：
--
作者：
Bahram, S;Gilfillan, S;Schümann, K
当相关基因 HFE 被鉴定出来后，遗传性血色素沉着症和组织相容性位点之间令人费解的联系变得更加明显。事实上，在明确定义的、主要是肽结合的、MHC I 类分子家族中，HFE 似乎发挥着不寻常但重要的功能。迄今为止，我们对 HFE 在铁稳态中的作用的理解还只是部分的。一个更悬而未决的问题是它在免疫系统中可能发挥的作用。为了在这两个途径上取得进展，我们报告了体内 HFE α 1 和 α 2 推定配体结合域的删除。对缺乏 HFE 的动物进行了一套全面的代谢和免疫参数分析。忠实地模仿人类血色病，这种缺失的纯合子小鼠会出现铁过载，其特征是血浆铁含量较高、转铁蛋白饱和度升高以及肝脏铁负荷升高。事实上，主要缺陷可以追溯到十二指肠铁吸收的增强。同时，测量肠粘膜铁含量以及铁调节蛋白可以更明智地评估有关 HFE 在铁稳态中的精确作用的各种假设。最后，对包括肠道在内的初级和次级淋巴器官的广泛表型分析并没有提供令人信服的证据来证明 HFE 具有明显的免疫相关功能。
The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE alpha 1 and alpha 2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE.