Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.
Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.
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DOI：
10.1016/j.jaci.2016.07.028
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Geha RS
中科院分区：
文献类型：
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作者：
Jabara HH;Lee JJ;Janssen E;Ullas S;Liadaki K;Garibyan L;Benson H;Sannikova T;Bram R;Hammarstrom L;Cruz AC;Siegel R;Manis J;Malley R;Geha RS
B细胞受体TACI对于T非依赖性抗体应答是重要的。每200个献血者中就有一个是TACI A181 E突变的杂合子。研究报告健康受试者中TACI A181 E杂合性和小鼠中相应TACI A144 E突变对B细胞功能的影响。在用野生型（WT）和突变型TACI共转染的293 T细胞中，通过荧光素酶测定法测定核因子κ B（NFκB）活化。在来自杂合TACI A144 E敲入小鼠的B细胞中测量TACI驱动的增殖、同种型转换和抗体应答。鼻内肺炎球菌攻击后监测小鼠死亡率。天然抗体的肺炎球菌多糖成分磷酸胆碱（PC）的水平显着低于A181 E杂合子比TACI足够的瑞典献血者从未接种肺炎球菌抗原。虽然过表达的hTACI A181 E和mTACI A144 E在转染子中作为显性阴性，但小鼠中A144 E的纯合性导致B细胞中TACI表达缺失，表明突变蛋白在天然表达时不稳定。与TACI+/−小鼠一样，A144 E杂合子小鼠在其B细胞上表达的TACI水平为正常水平的一半，并且在APRIL驱动的B细胞活化、对TNP-Ficoll的抗体应答、对PC的天然抗体的产生以及鼻内肺炎球菌攻击后的存活率方面表现出类似的缺陷。这些结果表明，TACI A181 E杂合性导致TACI单倍不足，增加了对肺炎球菌感染的易感性。这对无症状TACI A181 E携带者具有重要意义。
The B cell receptor TACI is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. To investigate the impact on B cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. Nuclear factor kappa B (NFκB) activation was measured by luciferase assay in 293T cells co-transfected with wild-type (WT) and mutant TACI. TACI driven proliferation, isotype switching and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. The levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine (PC) were significantly lower in A181E heterozygous than TACI sufficient Swedish blood donors never immunized with pneumococcal antigens. While overexpressed hTACI A181E and mTACI A144E acted as a dominant negative in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, like TACI+/− mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in APRIL-driven B cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to PC, and survival following intranasal pneumococcal challenge. These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.