The same IκKBα mutation in two related individuals leads to completely different clinical syndromes
The same IκKBα mutation in two related individuals leads to completely different clinical syndromes
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DOI：
10.1084/jem.20040773
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发表时间：
2004-09-06
影响因子：
15.3
通讯作者：
Lankester, A
中科院分区：
文献类型：
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作者：
Janssen, R;van Wengen, A;Lankester, A
先天性和适应性免疫应答都依赖于核因子κ B（NF-κ B）的活化，其在病原体相关分子模式与Toll样受体（TLR）结合后诱导。在小鼠模型中，NF-κ B通路的缺陷通常是致命的，并且存活的敲除小鼠具有严重的免疫缺陷。类似地，迄今为止描述的人NF-κ B途径的缺陷导致严重的临床疾病。在这里，我们描述了一个高免疫球蛋白M样免疫缺陷综合征和外胚层发育不良的患者。单核细胞不产生白细胞介素12 p40刺激后，各种TLR刺激和核转位的NF-κ B受损。T细胞受体介导的增殖也受到损害。在IkappaB α的丝氨酸32处发现杂合突变。有趣的是，他的父亲有同样的突变，但显示复杂的镶嵌。他没有表现出外胚层发育不良的特征，除了复发性鼠伤寒沙门氏菌感染外，没有遭受严重感染。单核细胞功能受损，而T细胞功能相对正常。与此一致的是，他的T细胞几乎只显示野生型等位基因，而这两种等位基因都存在于他的单核细胞中。我们提出，T和B细胞隔室的嵌合父亲出现作为野生型细胞的选择的结果，这是广泛不同的临床表型的基础。
Both innate and adaptive immune responses are dependent on activation of nuclear factor kappaB (NF-kappaB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-kappaB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-kappaB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-kappaB was impaired. T cell receptor-mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IkappaBalpha. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype.