Type I Interferon Receptor Deficiency Prevents Murine Sjogren's Syndrome
Type I Interferon Receptor Deficiency Prevents Murine Sjogren's Syndrome
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DOI：
10.1177/0022034513483315
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发表时间：
2013-05-01
影响因子：
7.6
通讯作者：
Deshmukh, U. S.
中科院分区：
文献类型：
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作者：
Szczerba, B. M.;Rybakowska, P. D.;Deshmukh, U. S.
在干燥综合征 (SS) 中，固有的腺体缺陷、自身免疫和唾液腺内的单核细胞浸润会导致唾液分泌减少，从而导致口干症。由环境和遗传因素引发的 I 型干扰素 (IFN) 的过量产生被认为是这种疾病的致病因素。然而，I 型干扰素的产生是否是疾病的致病原因或疾病过程的结果尚不清楚。为了解决这个问题，我们将干扰素 α 受体 1 (Ifnar1) 缺陷引入 B6.Aec1Aec2 小鼠中，已知这些小鼠具有发展 SS 样疾病所需的基因位点。这种新的小鼠品系 B6.Aec1Aec2Ifnar1(-/-) 缺乏 I 型 IFN 介导的信号传导，其特征为毛果芸香碱诱导的流涎、血清自身抗体的存在、唾液腺炎和泪腺炎。与B6.Aec1Aec2Ifnar1(+/+)（野生型）小鼠相比，B6.Aec1Aec2Ifnar1(-/-)（敲除）小鼠的唾液腺和泪腺中的单核细胞浸润明显较低。基因敲除小鼠完全免受唾液腺功能障碍的影响。令人惊讶的是，它们具有与野生型小鼠相当的强大自身抗体反应。这些发现表明，在缺乏 I 型 IFN 介导的信号传导的情况下，全身性自身抗体反应可能与腺体病理学无关。我们的研究表明，在遗传易感个体中，I 型 IFN 通路可以引发 SS 的某些特征。
In Sjogren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1(-/-), lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1(+/+) (wild-type) mice, the B6.Aec1Aec2Ifnar1(-/-)(knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.