Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1888, USA.
Blood. 2010 Jun 24;115(25):5164-9. doi: 10.1182/blood-2010-01-263145. Epub 2010 Apr 1.
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B(12), interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children.
自身免疫性淋巴增生综合征（ALPS）的特征为儿童期发病的淋巴结病、肝脾肿大、自身免疫性血细胞减少症、双阴性 T（DNT）细胞数量增加，以及淋巴瘤风险增加。大多数 ALPS 病例与 FAS 基因（Ia 型）的种系突变有关，而一些病例已注意到其 DNT 细胞中存在 FAS 的体细胞突变。我们试图确定在一组无明显种系突变的 ALPS 患者中，具有体细胞 FAS 突变的患者比例，并进一步对其进行特征描述。我们发现，在所检测的患者中，超过三分之一（31 例中的 12 例）存在体细胞 FAS 突变，主要涉及 FAS 的细胞内结构域，导致正常 FAS 信号转导丧失。类似于 Ia 型 ALPS 患者，体细胞性 ALPS 患者的 DNT 细胞数量增加，血清维生素 B(12)、白细胞介素-10 和 sFAS-L 水平升高。这些数据支持对无明显种系突变且具有类似 Ia 型 ALPS 的临床和实验室表型的 ALPS 患者的 DNT 细胞进行体细胞 FAS 突变检测。这些发现还强调了体细胞突变在成人和儿童非恶性和/或自身免疫性血液疾病发病机制中的潜在作用。
