A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency.
A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency.
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DOI：
10.1002/cyto.b.20473
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发表时间：
2009-09
影响因子：
3.4
通讯作者：
Bleesing, Jack J.
中科院分区：
文献类型：
--
作者：
Marsh, Rebecca A.;Villanueva, Joyce;Zhang, Kejian;Snow, Andrew L.;Su, Helen C.;Madden, Lisa;Mody, Rajen;Kitchen, Brenda;Marmer, Dan;Jordan, Michael B.;Risma, Kimberly A.;Filipovich, Alexandra H.;Bleesing, Jack J.
关键词：
由 BIRC4 基因突变引起的 X 连锁凋亡抑制剂 (XIAP) 缺乏，是 X 连锁淋巴细胞增殖性疾病 (XLP) 的第二个已知原因，XLP 是一种罕见的原发性免疫缺陷，通常表现为危及生命的噬血细胞性淋巴组织细胞增多症 (HLH)。快速诊断 HLH 的已知遗传原因（包括 XIAP 缺陷）有助于启动挽救生命的治疗并为同种异体造血细胞移植 (HCT) 做好准备。到目前为止，还没有针对 XIAP 缺陷的快速筛查测试。为了开发针对 XIAP 缺陷的流式细胞术筛查测试，我们首先使用从具有 BIRC4 突变的对照和患者产生的淋巴母细胞系来鉴定 2 种对天然细胞内 XIAP 具有特异性的市售抗体。接下来，我们使用这些抗体来研究对照全血白细胞 XIAP 表达。然后，我们研究了 BIRC4 突变导致的 XLP 患者、母体携带者和 HCT 后患者白细胞中 XIAP 的表达。正常对照中大多数全血有核细胞都表达 XIAP。相比之下，由于 BIRC4 突变，4 名不相关的 XLP 患者的所有淋巴细胞亚群、单核细胞和粒细胞中 XIAP 均缺失或减少。 XIAP 表达的双峰分布在两个母体携带者中很明显，并且显着偏向表达正常 XIAP 的细胞。在 HCT 后的患者中也观察到双峰分布。细胞内 XIAP 的流式细胞术分析为 XIAP 缺陷导致的 XLP 提供了快速筛查测试。它还允许携带者检测，并可用于监测 HCT 后供体与受体的重建。
Deficiency of X-linked Inhibitor of Apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked Lymphoproliferative Disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. In order to develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify 2 commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from 4 unrelated patients with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing towards cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT.
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