San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
J Allergy Clin Immunol. 2010 Feb;125(2):439-448.e8. doi: 10.1016/j.jaci.2009.11.034.
The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS.
The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation.
A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up.
The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells.
Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS.
Wiskott-Aldrich 综合征（WAS）是一种罕见的遗传性疾病，其特征为血小板减少、免疫缺陷、自身免疫和血液系统恶性肿瘤。在患有 WAS 的患者中，导致 WAS 蛋白（WASP）重新表达的继发突变相对频繁。
研究了新型 WAS 基因继发突变病例中回复细胞的组织分布和功能。
使用广泛的方法组合来表征第二部位突变，研究回复细胞功能，并在 18 年的临床随访中追踪其分布。
WAS 基因继发突变是 4 个核苷酸的插入，位于原始缺失的下游 4 个核苷酸处。这种体细胞突变允许 T 细胞受限表达稳定的全长 WASP，与野生型蛋白相比有 3 个氨基酸的变化。与野生型蛋白相比，WASP(+)T 细胞在脾脏中出现较早（10 岁时），并在稍后的时间（23 岁时）在肠系膜淋巴结中高度富集。回复细胞具有多样化的 T 细胞受体库，并表现出体外和体内的选择性优势。它们在 T 细胞受体刺激下正常增殖并产生细胞因子。一致地，回复的 WASP 正确定位于免疫突触和迁移 T 细胞的前缘。
尽管功能性回复 T 细胞的比例很高，但患者仍存在严重感染和自身免疫性疾病，这表明在 WAS 患者中，T 细胞中 WASP 的重新表达不足以完全正常化免疫功能。
