Department of Pathology, New York University, Langone Medical Center, 550 First Avenue, New York, NY 10016, USA.
Clin Immunol. 2010 May;135(2):169-82. doi: 10.1016/j.clim.2010.01.011. Epub 2010 Mar 1.
Lymphocyte activation requires Ca(2+) influx through specialized Ca(2+) channels in the plasma membrane. In T cells the predominant Ca(2+) channel is the Ca(2+) release activated Ca(2+) (CRAC) channel encoded by the gene ORAI1. ORAI1 is activated by stromal interaction molecule (STIM) 1 that is localized in the ER where it senses the concentration of stored Ca(2+). Following antigen binding to immunoreceptors such as the TCR, ER Ca(2+) stores are depleted, STIM1 is activated and ORAI1-CRAC channels open resulting in what is referred to as store-operated Ca(2+) entry (SOCE). Mutations in ORAI1 and STIM1 genes in human patients that lead to expression of non-functional ORAI1 or complete lack of ORAI1 or STIM1 protein are associated with a unique clinical phenotype that is characterized by immunodeficiency, muscular hypotonia and anhydrotic ectodermal dysplasia, as well as, in the case of STIM1 deficiency, autoimmunity and lymphoproliferative disease. The immunodeficiency in these patients is due to a severe defect in T cell activation but not in lymphocyte development. This review describes the immunological and non-immunological phenotypes of patients with defects in SOCE and CRAC channel function and discusses them in the context of similar immunodeficiency diseases and animal models of ORAI1 and STIM1 function.
淋巴细胞的激活需要通过质膜中的专门钙离子通道进行钙离子内流。在 T 细胞中，主要的钙离子通道是由基因 ORAI1 编码的钙释放激活钙（CRAC）通道。ORAI1 被定位于内质网中的基质相互作用分子（STIM）1 激活，内质网在其中感知储存钙离子的浓度。在抗原结合到免疫受体（如 TCR）后，内质网钙储存被耗尽，STIM1 被激活，ORAI1-CRAC 通道打开，导致所谓的储存操纵的钙离子内流（SOCE）。人类患者中 ORAI1 和 STIM1 基因的突变导致无功能 ORAI1 的表达或完全缺乏 ORAI1 或 STIM1 蛋白与一种独特的临床表型相关，其特征是免疫缺陷、肌肉张力减退和无汗性外胚层发育不良，以及在 STIM1 缺乏的情况下，自身免疫和淋巴增生性疾病。这些患者的免疫缺陷是由于 T 细胞激活的严重缺陷，但不是淋巴细胞发育的缺陷。这篇综述描述了 SOCE 和 CRAC 通道功能缺陷患者的免疫学和非免疫学表型，并在类似的免疫缺陷疾病和 ORAI1 和 STIM1 功能的动物模型的背景下讨论了这些表型。
