Combined immunodeficiency evolving into predominant CD4+ lymphopenia caused by somatic chimerism in JAK3.
Combined immunodeficiency evolving into predominant CD4+ lymphopenia caused by somatic chimerism in JAK3.
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DOI：
10.1007/s10875-014-0088-2
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发表时间：
2014-11
影响因子：
9.1
通讯作者：
Wolf, Hermann M.
中科院分区：
文献类型：
--
作者：
Ban, Sol A.;Salzer, Elisabeth;Eibl, Martha M.;Linder, Angela;Geier, Christoph B.;Santos-Valente, Elisangela;Garncarz, Wojciech;Lion, Thomas;Ott, Raphael;Seelbach, Christoph;Boztug, Kaan;Wolf, Hermann M.
关键词：
特发性CD 4淋巴细胞减少症是一组异质性免疫缺陷，具有特征性低CD 4 + T细胞计数，遗传病因基本未知。在此，我们试图确定一个索引家族的潜在分子原因，该家族有两名患有联合免疫缺陷的患者，这些患者演变为主要的CD 4+淋巴细胞减少症。受影响更严重的索引患者也提出了选择性抗体缺乏症对细菌多糖抗原。对于遗传分析，我们使用了纯合性作图和外显子组测序相结合的方法。功能测定包括免疫印迹分析、流式细胞术和TCR Vβ谱分析。在JAK 3激酶结构域发现了一个新的纯合错义突变（c.T3196C，p.Cys1066Arg）。进一步分析显示，在这两名患者的CD 8 + T细胞的回复嵌合体。回复突变CD 4 + T细胞的额外存在与第二例患者较温和的临床和免疫表型相关，尽管体细胞嵌合体在改善疾病表型中所发挥的作用尚不确定，因为回复突变细胞的存在对残留CD 4细胞JAK 3信号传导功能没有影响。在永生化B细胞系中也发现JAK 3依赖性STAT 3和STAT 5信号传导的残余活性，表明所述突变的亚型性质，这可能有助于较温和的临床表型。我们在这里提出了第一例JAK 3缺陷的回复突变嵌合体，表现为联合免疫缺陷演变为主要的CD 4+淋巴细胞减少症。在评估轻度联合免疫缺陷患者时，应考虑与更严重的T细胞缺乏症相关的基因中的回复突变嵌合体或亚型突变。本文的在线版本（doi：10.1007/s10875-014-0088-2）包含补充材料，可供授权用户使用。
Idiopathic CD4 lymphopenia constitutes a heterogeneous group of immunodeficiencies with characteristically low CD4+ T-cell counts with largely unknown genetic etiology. We here sought to determine the underlying molecular cause in an index family with two patients suffering from combined immunodeficiency that evolved into predominant CD4+ lymphopenia. The more severely affected index patient also presented with selective antibody deficiency against bacterial polysaccharide antigens. For the genetic analysis, we used combined homozygosity mapping and exome sequencing. Functional assays included immunoblot analysis, flow cytometry and TCR Vβ spectratyping. A novel homozygous missense mutation was revealed in the kinase domain of JAK3 (c.T3196C, p.Cys1066Arg). Further analysis showed revertant chimerism in CD8+ T-cells in both patients. The additional presence of revertant CD4+ T-cells was associated with a milder clinical and immunological phenotype in the second patient, although the role somatic chimerism plays in amelioration of disease phenotype is uncertain, as presence of revertant cells had no effect on residual CD4 cell JAK3 signaling function. Residual activity of JAK3-dependent STAT3 and STAT5 signaling was also found in immortalized B-cell lines indicating a hypomorphic nature of the described mutation which likely contributes to the milder clinical phenotype. We here present the first case of revertant mosaicism in JAK3 deficiency, manifesting as combined immunodeficiency evolving into predominant CD4+ lymphopenia. Revertant chimerism or hypomorphic mutations in genes typically associated with more severe T-cell deficiency should be considered when assessing patients with milder forms of combined immunodeficiencies. The online version of this article (doi:10.1007/s10875-014-0088-2) contains supplementary material, which is available to authorized users.
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