Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.
Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.
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DOI：
10.1084/jem.20151110
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发表时间：
2016-06-27
期刊：
影响因子：
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通讯作者：
Stepensky P
中科院分区：
文献类型：
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作者：
Keller B;Zaidman I;Yousefi OS;Hershkovitz D;Stein J;Unger S;Schachtrup K;Sigvardsson M;Kuperman AA;Shaag A;Schamel WW;Elpeleg O;Warnatz K;Stepensky P
Keller等人首次描述了人类LAT缺陷，其导致严重的免疫失调，伴有自身免疫、淋巴细胞增殖和进行性免疫缺陷。用于活化T细胞的衔接蛋白接头（LAT）是连接T细胞抗原受体触发与下游T细胞应答的关键信号传导枢纽。在这项研究中，我们描述了第一个有缺陷的LAT信号转导引起的外显子5中的纯合突变，导致提前终止密码子删除LAT的大部分胞质尾，包括信号传播的关键酪氨酸残基。这三名患者从儿童早期就患有联合免疫缺陷和严重的自身免疫性疾病。与小鼠不同，患者中T细胞数量减少。尽管LAT在Ca2+动员中的作用是非冗余的，但残留的T细胞能够诱导Ca2+内流和核因子（NF）κB信号传导，而细胞外信号调节激酶（ERK）信号传导完全消失。这是第一次报告的人类LAT相关疾病，表现为进行性联合免疫缺陷与严重的自身免疫性疾病。
Keller et al. describe for the first time human LAT deficiency, which causes severe immune dysregulation with autoimmunity, lymphoproliferation, and progressive immunodeficiency. The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.