Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors.
Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors.
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DOI：
10.1111/j.1365-2222.2008.03173.x
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Bochner BS
中科院分区：
文献类型：
--
作者：
Bochner BS
唾液酸结合免疫球蛋白样凝集素（Siglecs）是一个主要在白细胞上发现的单次跨膜细胞表面蛋白家族。它们独特的结构特征包括一个能结合唾液酸的N末端碳水化合物结合（“凝集素”）结构域，其后是数量可变的免疫球蛋白样结构域，因此这些结构是免疫球蛋白基因超家族的一个子集。Siglecs的另一个独特特征是，大多数（但不是全部）在其胞质结构域中拥有所谓的基于免疫受体酪氨酸的抑制性基序（“ITIMs”），这表明这些分子具有抑制功能。Siglec - 8是当时鉴定出的第8个成员，它是大约十年前为鉴定新型人类嗜酸性粒细胞和肥大细胞蛋白而发起的一项研究工作的一部分。从那时起，它在人类嗜酸性粒细胞和肥大细胞上的选择性表达已得到证实。在嗜酸性粒细胞上，Siglec - 8的结合会导致细胞凋亡，而在肥大细胞上，会出现抑制FcεRI依赖性介质释放但不发生细胞凋亡的情况。随后确定小鼠中与之功能最接近的同源物是Siglec - F，它选择性地在嗜酸性粒细胞上表达，但不在肥大细胞上表达。尽管只有适度的同源性，Siglec - 8和Siglec - F都优先识别一种与唾液酸化路易斯X密切相关的硫酸化聚糖配体，唾液酸化路易斯X是选择素家族黏附分子的一种常见配体。在正常的、Siglec - F缺陷型小鼠和嗜酸性粒细胞增多症小鼠中进行的小鼠实验得出了类似的结论，即Siglec - F和Siglec - 8一样，在体内调节嗜酸性粒细胞的聚集和存活方面起着独特而重要的作用。鉴于对针对各种疾病的嗜酸性粒细胞导向疗法重新产生兴趣，以及Siglec - 8还具有靶向肥大细胞的独特额外能力，针对Siglec - 8的疗法有朝一日可能会被证明是我们目前用于治疗哮喘、过敏及相关疾病（这些疾病中嗜酸性粒细胞和肥大细胞过度产生和过度活跃）的治疗手段的一种有用补充。
Siglecs (sialic acid-binding, immunoglobulin [Ig]-like lectins) are a family of single-pass transmembrane cell surface proteins found predominantly on leukocytes. Their unique structural characteristics include an N-terminal carbohydrate-binding (“lectin”) domain that binds sialic acid, followed by a variable number of Ig-like domains, hence these structures are a subset of the Ig gene superfamily. Another unique feature of Siglecs is that most, but not all, possess so-called immunoreceptor tyrosine-based inhibitory motifs (“ITIMs”) in their cytoplasmic domains, suggesting that these molecules function in an inhibitory capacity. Siglec-8, the eighth member identified at the time, was discovered as part of an effort initiated almost a decade ago to identify novel human eosinophil and mast cell proteins. Since that time, its selective expression on human eosinophils and mast cells has been confirmed. On eosinophils, Siglec-8 engagement results in apoptosis, whereas on mast cells, inhibition of FcεRI-dependent mediator release, without apoptosis, is seen. It has subsequently been determined that the closest functional paralog in the mouse is Siglec-F, selectively expressed by eosinophils but not expressed on mast cells. Despite only modest homology, both Siglec-8 and Siglec-F preferentially recognize a sulfated glycan ligand closely related to sialyl Lewis X, a common ligand for the selectin family of adhesion molecules. Murine experiments in normal, Siglec-F-deficient mice and hypereosinophilic mice have resulted in similar conclusions that Siglec-F, like Siglec-8, plays a distinctive and important role in regulating eosinophil accumulation and survival in vivo. Given the resurgent interest in eosinophil-directed therapies for a variety of disorders, plus its unique additional ability to also target the mast cell, therapies focusing on Siglec-8 could some day prove to be a useful adjunct to our current armamentarium for the treatment of asthma, allergies and related disorders where overproduction and overactivity of eosinophils and mast cells is occurring.
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