The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins.
The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins.
复制标题
RAG缺陷型SCID患者骨髓中的免疫表型和免疫基因型B细胞分化停滞对应于突变RAG蛋白的残余重组活性。
DOI：
10.1182/blood.v100.6.2145
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发表时间：
2002
期刊：
影响因子：
20.3
通讯作者：
J. V. van Dongen
中科院分区：
文献类型：
--
作者：
J. Noordzij;S. de Bruin;N. Verkaik;J. Vossen;R. de Groot;E. Bernatowska;A. Langerak;D. V. van Gent;J. V. van Dongen
重组激活基因（RAG 1和RAG 2）的蛋白产物启动免疫球蛋白（IG）和T细胞受体的形成，这分别是B细胞和T细胞发育所必需的。RAG基因的突变导致严重的联合免疫缺陷病（SCID），其特征通常是缺乏成熟的B和T淋巴细胞，但存在自然杀伤（NK）细胞。在生物化学上，RAG基因的突变导致非功能性蛋白质或具有部分重组活性的蛋白质。采用染色体外重组底物、RAG基因转染的非淋巴细胞内源性IG位点重排或骨髓（BM）中存在IG基因重排的方法，分析了来自7个家系的9例患者的突变RAG基因的重组活性。在RAG核心结构域突变的所有6例患者中几乎不存在抑制活性，但在其他3例RAG缺陷患者中存在部分活性，其中2例患有Omenn综合征伴寡克隆T淋巴细胞。使用4色流式细胞术，我们可以定义在5个RAG缺陷的SCID患者的BM中B细胞分化被阻止的确切阶段。在5名患者中的4名中，重组活性的缺乏与从胞质（Cy）Igmu（-）前B-I细胞向CyIgmu（+）前B-II细胞转变时的完全B细胞分化停滞相关。然而，第5例患者表现出低频率的具有CyIgmu和表面膜IgM的前体B细胞，这与患者突变的RAG基因的部分重组活性和BM中框内IG基因重排的检测一致。
The protein products of the recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulin (Ig) and T-cell receptors, which are essential for B- and T-cell development, respectively. Mutations in the RAG genes result in severe combined immunodeficiency disease (SCID), generally characterized by the absence of mature B and T lymphocytes, but presence of natural killer (NK) cells. Biochemically, mutations in the RAG genes result either in nonfunctional proteins or in proteins with partial recombination activity. The mutated RAG genes of 9 patients from 7 families were analyzed for their recombination activity using extrachromosomal recombination substrates, rearrangement of endogenous Ig loci in RAG gene-transfected nonlymphoid cells, or the presence of Ig gene rearrangements in bone marrow (BM). Recombination activity was virtually absent in all 6 patients with mutations in the RAG core domains, but partial activity was present in the other 3 RAG-deficient patients, 2 of them having Omenn syndrome with oligoclonal T lymphocytes. Using 4-color flow cytometry, we could define the exact stage at which B-cell differentiation was arrested in the BM of 5 RAG-deficient SCID patients. In 4 of 5 patients, the absence of recombination activity was associated with a complete B-cell differentiation arrest at the transition from cytoplasmic (Cy) Igmu(-) pre-B-I cells to CyIgmu(+) pre-B-II cells. However, the fifth patient showed low frequencies of precursor B cells with CyIgmu and surface membrane IgM, in line with the partial recombination activity of the patient's mutated RAG gene and the detection of in-frame Ig gene rearrangements in BM.
影响因子：
56.9
作者：
OETTINGER, MA;SCHATZ, DG;BALTIMORE, D
通讯作者：
BALTIMORE, D