Perforin gene defects in familiar hemophagocytic lymphohistiocytosis
Perforin gene defects in familiar hemophagocytic lymphohistiocytosis
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DOI：
10.1126/science.286.5446.1957
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发表时间：
1999-12-03
期刊：
影响因子：
56.9
通讯作者：
Kumar, V
中科院分区：
文献类型：
--
作者：
Stepp, SE;Dufourcq-Lagelouse, R;Kumar, V
常见的噬血细胞淋巴组织细胞增多症(FHL)是一种罕见的、迅速致死的常染色体隐性免疫疾病，其特征是T细胞和巨噬细胞的不受控制的激活和炎性细胞因子的过度产生。连锁分析表明，FHL在遗传上是异质性的，与9q21.3-22、10q21-22或另一个尚未定义的基因座连锁。对8例无关的10q21-22连锁FHL患者的穿孔素基因编码区进行测序，发现4例患者存在纯合无义突变，另外4例患者存在错义突变。患者培养的淋巴细胞具有缺陷的细胞毒活性，免疫染色显示颗粒中很少或没有穿孔素。因此，穿孔素的缺陷是10q21-22连锁FHL的原因。因此，基于穿孔素的效应系统不仅参与了异常细胞的溶解，而且还参与了细胞免疫激活的下调。
Familiar hemophagocytic Lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and Linked to 9q21.3-22, 10q21-22, or another as yet undefined Locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured Lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed Little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based effector systems are, therefore, involved not only in the Lysis of abnormal cells but also in the downregulation of cellular immune activation.