Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice
Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice
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DOI：
10.4049/jimmunol.181.3.1937
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Bussolati, Benedetta
中科院分区：
文献类型：
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作者：
Fagoonee, Sharmila;Caorsi, Cristiana;Bussolati, Benedetta
有几个因素影响自身免疫反应，包括T细胞的铁依赖性调节。血凝素是血浆中与血红素结合亲和力最高的蛋白。它介导肝脏中血红素铁的恢复，从而控制外周细胞中血红素铁的可用性。本研究的目的是探讨血凝素在自身免疫反应进展中的作用。为此，我们选择了汞诱导的自身免疫小鼠模型，并与野生型对照比较，评估了血凝素缺失小鼠对汞处理的敏感性。在这项研究中，我们表明缺乏血凝素可以抑制小鼠汞诱导的自身免疫反应。与野生型小鼠相比，氯化汞处理后，血凝素缺失小鼠产生的抗核自身抗体更少，肾脏中免疫复合物的沉积也减少。这些特征与脾脏中活化T细胞减少和B细胞绝对数量降低以及IgG1和IgG2a生成受损有关。相比之下，在血凝素缺失的小鼠中，对OVA/CFA免疫的反应保持不变。此外，血凝素缺失小鼠T细胞中的转铁蛋白受体1表达降低，可能是由于血红素来源的铁增加。有趣的是，与野生型小鼠相比，从汞处理的血凝素缺失小鼠中分离的CD4(+)T细胞显示ifn - γ依赖性STAT1磷酸化降低。我们的数据表明，血凝素通过控制淋巴细胞中血红素铁的可用性，调节对ifn - γ的反应，从而调节自身免疫反应。
Several factors affect the autoimmune response, including iron-dependent modulation of T cells. Hemopexin is the plasma protein with the highest binding affinity to heme. It mediates heme-iron recovery in the liver, thus controlling heme-iron availability in peripheral cells. The aim of the present study was to investigate the role of hemopexin in the progress of an autoimmune response. To this end, we chose a mouse model of mercury-induced autoimmunity and evaluated the susceptibility of hemopexin-null mice to mercury treatment compared with wild-type controls. In this study we show that lack of hemopexin dampens mercury-induced autoimmune responses in mice. Hemopexin-null mice produced fewer antinuclear autoantibodies and had reduced deposits of immune complexes in the kidney after mercuric chloride treatment compared with wild-type mice. These features were associated with a reduction in activated T cells and lower absolute B cell number in spleen and impaired IgG1 and IgG2a production. In contrast, in hemopexin-null mice the response to OVA/CFA immunization was maintained. In addition, hemopexin-null mice had reduced transferrin receptor 1 expression in T cells, possibly due to the increase in heme-derived iron. Interestingly, CD4(+)T cells isolated from mercury-treated hemopexin-null mice show reduced IFN-gamma-dependent STAT1 phosphorylation compared with that of wild-type mice. Our data suggest that hemopexin, by controlling heme-iron availability in lymphocytes, modulates responsiveness to IFN-gamma and, hence, autoimmune responses.