Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes.
Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes.
复制标题
DOI：
10.1016/j.jaci.2013.11.028
复制
发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
van der Burg M
中科院分区：
文献类型：
--
作者：
IJspeert H;Driessen GJ;Moorhouse MJ;Hartwig NG;Wolska-Kusnierz B;Kalwak K;Pituch-Noworolska A;Kondratenko I;van Montfrans JM;Mejstrikova E;Lankester AC;Langerak AW;van Gent DC;Stubbs AP;van Dongen JJ;van der Burg M
V（D）J重组发生在淋巴细胞发育过程中，以产生大量T细胞和B细胞受体。重组激活基因1（RAG1）和RAG2的突变导致V（D）J重组的丧失或减少。已知RAG基因中的不同突变在残余重组酶活性方面不同，并产生广谱的临床表型。我们试图研究引起RAG缺乏症临床谱的免疫学机制。我们纳入了22例具有相似RAG1突变（c.519delT或c.368_369delAA）的患者，这些突变导致N端截短的RAG1蛋白具有残余重组活性，但表现出不同的临床表型。我们研究了前体B细胞发育、免疫球蛋白和T细胞受体库形成、受体编辑以及B和T细胞数量。临床上，患者分为3大类：T−B−重度联合免疫缺陷、Omenn综合征和联合免疫缺陷。所有患者均表现出前体B细胞发育受阻、B细胞和T细胞数量减少、免疫球蛋白基因使用正常、B细胞和T细胞库有限以及受体编辑轻微受损。这项研究表明，相似的RAG突变可以导致相似的免疫生物学效应，但不同的临床表型，表明残余重组酶活性的水平不是临床结果的唯一决定因素。我们假设一个模型，其中的类型和时刻的抗原压力影响这些患者的临床表型。
V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T- and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D)J recombination. It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes. We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency. We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. We studied precursor B-cell development, immunoglobulin and T-cell receptor repertoire formation, receptor editing, and B- and T-cell numbers. Clinically, patients were divided into 3 main categories: T−B− severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency. All patients showed a block in the precursor B-cell development, low B- and T-cell numbers, normal immunoglobulin gene use, limited B- and T-cell repertoires, and slightly impaired receptor editing. This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes, indicating that the level of residual recombinase activity is not the only determinant for clinical outcome. We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients.
登录
查看更多内容
影响因子：
20.3
作者：
Kuijpers, Taco W.;IJspeert, Hanna;van der Burg, Mirjam
通讯作者：
van der Burg, Mirjam
影响因子：
11.4
作者：
Lefranc, MP
通讯作者：
Lefranc, MP
影响因子：
8.6
作者：
Haq, Iram J.;Steinberg, Laura J.;Gennery, Andrew R.
通讯作者：
Gennery, Andrew R.
影响因子：
9.1
作者：
Ohm-Laursen, Line;Nielsen, Christian;Barington, Torben
通讯作者：
Barington, Torben
影响因子：
15.9
作者：
DESAINTBASILE, G;LEDEIST, F;FISCHER, A
通讯作者：
FISCHER, A