Cell surface expression of an endoplasmic, reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases
Cell surface expression of an endoplasmic, reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases
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DOI：
10.1073/pnas.2635458100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Li, ZH
中科院分区：
文献类型：
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作者：
Liu, B;Dai, J;Li, ZH
热休克蛋白被认为是树突状细胞(DC)的内源性激活剂。在没有组织损伤或死亡的情况下，这些细胞内分子无法与DC上的表面受体(S)结合，可能是为了避免DC失控激活和免疫耐受的崩溃。在这里，我们在转基因小鼠中通过强制细胞表面表达gp96来解决这一假设，gp96是内质网中普遍存在的一种热休克蛋白。尽管转基因表达使用了PAN特异性启动子，但内源性gp96的表达水平和组织分布都没有因此而改变。然而，尽管淋巴细胞室的发育/功能没有改变，但细胞表面gp96诱导了显著的DC激活和自发的狼疮样自身免疫性疾病。使用骨髓嵌合体方法，我们进一步证明了细胞表面gp96诱导的DC激活和自身免疫都依赖于下游的Toll/IL-1受体家族信号转导蛋白MyD88。我们的研究不仅在体内证实了细胞表面gp96的致炎特性，而且提示gp96对DC的慢性刺激是引发自发性自身免疫性疾病的一条途径。
Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Without tissue distress or death, these intracellular molecules are inaccessible to surface receptor(s) on DCs, possibly to avoid uncontrolled DC activation and breakdown of immunologic tolerance. We herein addressed this hypothesis in transgenic mice by enforcing cell surface expression of gp96, a ubiquitous heat shock protein of the endoplasmic reticulum. Although a pan-specific promoter is used for transgene expression, neither the expression level nor the tissue distribution of the endogenous gp96 was altered by this maneuver. However, cell surface gp96 induced significant DC activations and spontaneous lupus-like autoimmune diseases, even though the development/ functions of lymphocytic compartments were unaltered. Using a bone marrow chimera approach, we further demonstrated that both DC activation and autoimmunity elicited by cell surface gp96 are dependent on the downstream adaptor protein MyD88 for signaling by Toll/IL-1 receptor family. Our study not only established the proinflammatory property of cell surface gp96 in vivo, but also suggested a chronic stimulation of DCs by gp96 as a pathway to initiate spontaneous autoimmune diseases.