Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A AvogadroUniversity of Eastern Piedmont, Novara, Italy.
Haematologica. 2010 Nov;95(11):1897-904. doi: 10.3324/haematol.2010.023085. Epub 2010 Jun 30.
Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome and its variant Dianzani's autoimmune lymphoproliferative disease. Analysis of the lymphocyte transcriptome from a patient with this latter condition detected striking over-expression of osteopontin and tissue inhibitor of metalloproteinases-1. Since previous work on osteopontin had detected increased serum levels in these patients, associated with variations of its gene, the aim of this work was to extend the analysis to tissue inhibitor of metalloproteinases-1.
Tissue inhibitor of metalloproteinases-1 levels were evaluated in sera and culture supernatants from patients and controls by enzyme-linked immunosorbent assay. Activation- and Fas-induced cell death were induced, in vitro, using anti-CD3 and anti-Fas antibodies, respectively.
Tissue inhibitor of metalloproteinases-1 levels were higher in sera from 32 patients (11 with autoimmune lymphoproliferative syndrome and 21 with Dianzani's autoimmune lymphoproliferative disease) than in 50 healthy controls (P<0.0001), unassociated with variations of the tissue inhibitor of metalloproteinases-1 gene. Both groups of patients also had increased serum levels of osteopontin. In vitro experiments showed that osteopontin increased tissue inhibitor of metalloproteinases-1 secretion by peripheral blood monocytes. Moreover, tissue inhibitor of metalloproteinases-1 significantly inhibited both Fas- and activation-induced cell death of lymphocytes.
These data suggest that high osteopontin levels may support high tissue inhibitor of metalloproteinases-1 levels in autoimmune lymphoproliferative syndrome and Dianzani's autoimmune lymphoproliferative disease, and hence worsen the apoptotic defect in these diseases.
Fas 死亡受体功能缺失的遗传性缺陷可导致自身免疫性淋巴增生综合征及其变体 Dianzani 的自身免疫性淋巴增生性疾病。对该疾病患者的淋巴细胞转录组进行分析，发现骨桥蛋白和金属蛋白酶组织抑制剂-1 的表达显著上调。由于之前对骨桥蛋白的研究发现，这些患者的血清水平升高与基因变异有关，因此本研究旨在对金属蛋白酶组织抑制剂-1 进行扩展分析。
采用酶联免疫吸附试验检测患者和对照组血清和培养上清中的金属蛋白酶组织抑制剂-1 水平。体外分别使用抗 CD3 和抗 Fas 抗体诱导细胞凋亡。
32 名患者（11 名自身免疫性淋巴增生综合征患者和 21 名 Dianzani 的自身免疫性淋巴增生性疾病患者）的血清中金属蛋白酶组织抑制剂-1 水平高于 50 名健康对照者（P<0.0001），与金属蛋白酶组织抑制剂-1 基因的变异无关。两组患者的血清骨桥蛋白水平也均升高。体外实验表明，骨桥蛋白可增加外周血单核细胞分泌的金属蛋白酶组织抑制剂-1。此外，金属蛋白酶组织抑制剂-1 显著抑制 Fas 和激活诱导的淋巴细胞凋亡。
这些数据表明，高骨桥蛋白水平可能支持自身免疫性淋巴增生综合征和 Dianzani 的自身免疫性淋巴增生性疾病中高金属蛋白酶组织抑制剂-1 水平，从而加重这些疾病中的凋亡缺陷。
