Molina I J, Sancho J, Terhorst C, Rosen F S, Remold-O'Donnell E
Division of Immunology, Children's Hospital, Boston, MA.
J Immunol. 1993 Oct 15;151(8):4383-90.
The Wiskott-Aldrich syndrome (WAS) is a disease of profound thrombocytopenia and severe immune defects caused by an unidentified defective X chromosome gene. In this study, T lymphocyte function is examined using a panel of allospecific WAS patient T cell lines, previously found to express the abnormal disease gene and the cytoarchitectural defect characteristic of the disease. Although T cell lines from normal individuals proliferate vigorously in response to immobilized anti-CD3 mAb OKT3 and SPV-T3b, five of seven WAS patient T cell lines failed to proliferate and two lines showed significantly decreased proliferation when challenged with the immobilized anti-CD3 mAb. The deficient responsiveness of the WAS T cell lines to immobilized anti-CD3 mAb is a restricted defect, because the cells proliferate normally when challenged with allospecific Ag, PHA, or PMA plus ionomycin. Addition of anti-CD28 mAb did not correct the deficient proliferation of the WAS cells challenged with immobilized anti-CD3. Deficient response of the WAS T cell lines to immobilized anti-CD3 was detected also when earlier events of the proliferation process, IL-2 production and up-regulation of activation Ag CD69 and CD28, were measured. On the other hand, WAS cell lines did not differ from normal cell lines in binding of anti-CD3 mAb, mobilization of Ca2+ in response to soluble OKT3, and tyrosine phosphorylation and GTP binding of the CD3 zeta-chain in response to OKT3. Cumulatively, these findings demonstrate a striking restricted defect in the proliferative response of WAS T cells, which because it is found in cell lines free of secondary changes that occur in the patient circulation must be a reflection of the inherited defective disease gene product.
威斯科特-奥尔德里奇综合征（WAS）是一种由未明确的X染色体缺陷基因导致的严重血小板减少和严重免疫缺陷疾病。在本研究中，使用一组同种特异性WAS患者T细胞系来检测T淋巴细胞功能，这些T细胞系先前已被发现表达异常疾病基因以及该疾病特有的细胞结构缺陷。尽管来自正常个体的T细胞系在固定化抗CD3单克隆抗体OKT3和SPV-T3b刺激下能强烈增殖，但7个WAS患者T细胞系中有5个未能增殖，另外2个细胞系在受到固定化抗CD3单克隆抗体刺激时增殖明显减少。WAS T细胞系对固定化抗CD3单克隆抗体反应不足是一种局限性缺陷，因为当用同种特异性抗原、PHA或PMA加离子霉素刺激时，细胞能正常增殖。添加抗CD28单克隆抗体并不能纠正受到固定化抗CD3刺激的WAS细胞增殖不足的情况。当检测增殖过程的早期事件，即IL-2产生以及活化抗原CD69和CD28的上调时，也发现WAS T细胞系对固定化抗CD3反应不足。另一方面，WAS细胞系在抗CD3单克隆抗体结合、对可溶性OKT3的Ca2+动员以及对OKT3的CD3 ζ链酪氨酸磷酸化和GTP结合方面与正常细胞系没有差异。总的来说，这些发现表明WAS T细胞的增殖反应存在明显的局限性缺陷，由于这种缺陷存在于没有患者循环中发生的继发性变化的细胞系中，所以必定反映了遗传性缺陷疾病基因产物的情况。
