Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes
Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes
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DOI：
10.4049/jimmunol.1200467
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发表时间：
2012-06-15
影响因子：
4.4
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
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作者：
Czyzyk, Jan;Henegariu, Octavian;Flavell, Richard A.
细胞内（进化枝 B）OVA-丝氨酸蛋白酶抑制剂在组织稳态中发挥重要作用，可保护细胞免于响应低渗应激、热休克和其他刺激而死亡。目前尚不清楚这些丝氨酸蛋白酶抑制剂是否会影响免疫耐受性和自身免疫性疾病的风险。我们发现，一小部分年轻的易患自身免疫性糖尿病的 NOD 小鼠体内针对 B 家族成员 serpinB13 的自身抗体水平升高。高水平的抗丝氨酸蛋白酶抑制剂 B13 抗体伴随着低水平的抗胰岛素自身抗体、胰岛相关 T 细胞数量的减少以及糖尿病的延迟发作。单独接触抗-serpinB13 mAb 也可减少胰岛炎症，同时使用该试剂和次优剂量的抗-CD3 mAb 可加速糖尿病的恢复。与 NOD 模型中发现的方式类似，针对 serpinB13 的体液活性缺陷与人类 1 型糖尿病的早期发病有关。这些发现表明，除了限制细胞内蛋白酶的暴露之外，进化枝 B 丝氨酸蛋白酶抑制剂还通过诱导保护性体液免疫来帮助维持体内平衡。免疫学杂志，2012，188：6319-6327。
Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity. The Journal of Immunology, 2012, 188: 6319-6327.