Salehi Eisa, Vodjgani Mohammad, Massoud Ahmad, Keyhani Abdolhosein, Rajab Asadollah, Shafaghi Behrooz, Gheflati Zahra, Aboufazeli Tahereh
Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran.
Iran J Immunol. 2007 Dec;4(4):197-205.
Type-I diabetes is an autoimmune inflammatory disease in which pancreatic beta-cells are selectively destroyed by infiltrating cells. TNF-related apoptosis-inducing ligand (TRAIL) is a type-II membrane protein of the TNF superfamily which is expressed in different tissues, including pancreas and lymphocytes. In humans, TRAIL interacts with four membrane receptors. TRAIL-R1 and TRAIL-R2 have cytoplasmic death domains, and can activate both caspases and NFkappaB pathways. The other two receptors, TRAIL-R3 and TRAIL-R4, are decoy receptors not capable of activating caspase cascade but may activate NF-kappaB and block apoptosis. As human beta cells are sensitive to TRAIL induced apoptosis, signaling via these molecules is considered to be a probable way of beta cell destruction. These molecules also are important in suppression of autorective T cells and immunoregulation.
To explore the importance of TRAIL and its receptors at pathogenesis of type-I diabetes, we compared expression of these molecules on T-cells of diabetic patients and healthy controls.
In this study, expression of TRAIL and its receptors at protein and mRNA levels were studied in freshly isolated peripheral T cells of 55 type I diabetic patients and 50 healthy individuals by flowcytometry, western blot and RT-PCR.
We found that expression of TRAIL and its receptors in peripheral T-cells at both protein and mRNA levels are significantly increased in patients (except for TRAIL-R2 mRNA which was slightly higher in controls) but increase in TRAIL, TRAIL-R3 (2.7% vs. >0.5%) and TRAIL-R4 (2.6% vs. >0.5%) is more considerable. sTRAIL in sera of patients was significantly lower than in controls (P=0.01).
Our results explain resistance of autoreactive T-cells to immunoregulatory mechanisms. Besides, increased expression of TRAIL in autoreactive T-cells may play an important role in beta-cell destruction. Lower level of sTRAIL in diabetic patients may be a reason for hyperactivation of autoreactive T-cells.
I型糖尿病是一种自身免疫性炎症性疾病，胰腺β细胞被浸润细胞选择性破坏。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子超家族的一种II型膜蛋白，在包括胰腺和淋巴细胞在内的不同组织中表达。在人类中，TRAIL与四种膜受体相互作用。TRAIL-R1和TRAIL-R2具有细胞质死亡结构域，可激活半胱天冬酶和NFκB途径。另外两种受体TRAIL-R3和TRAIL-R4是诱饵受体，不能激活半胱天冬酶级联反应，但可能激活NF-κB并阻断细胞凋亡。由于人类β细胞对TRAIL诱导的细胞凋亡敏感，通过这些分子的信号传导被认为是β细胞破坏的一种可能方式。这些分子在抑制自身反应性T细胞和免疫调节中也很重要。
为了探讨TRAIL及其受体在I型糖尿病发病机制中的重要性，我们比较了糖尿病患者和健康对照者T细胞上这些分子的表达。
在本研究中，通过流式细胞术、蛋白质印迹法和逆转录-聚合酶链反应，研究了55例I型糖尿病患者和50例健康个体新鲜分离的外周血T细胞中TRAIL及其受体在蛋白质和mRNA水平的表达。
我们发现，患者外周血T细胞中TRAIL及其受体在蛋白质和mRNA水平的表达均显著增加（TRAIL-R2 mRNA除外，其在对照组中略高），但TRAIL、TRAIL-R3（2.7%对>0.5%）和TRAIL-R4（2.6%对>0.5%）的增加更为显著。患者血清中的可溶性TRAIL明显低于对照组（P=0.01）。
我们的结果解释了自身反应性T细胞对免疫调节机制的抵抗。此外，自身反应性T细胞中TRAIL表达的增加可能在β细胞破坏中起重要作用。糖尿病患者可溶性TRAIL水平较低可能是自身反应性T细胞过度激活的原因。
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