Gatselis Nikolaos K, Vakrakou Aigli G, Zachou Kalliopi, Androutsakos Theodoros, Azariadis Kalliopi, Hatzis Gregorios, Manoussakis Menelaos N, Dalekos George N
a Department of Medicine and Research Laboratory of Internal Medicine , School of Medicine, University of Thessaly , Larissa , Greece.
b Department of Pathophysiology , School of Medicine, National and Kapodistrian University of Athens , Athens , Greece.
Autoimmunity. 2017 Mar;50(2):125-132. doi: 10.1080/08916934.2017.1279610. Epub 2017 Feb 14.
Deoxyribonuclease1 (DNase1) is involved in chromatin degradation of apoptotic cells. Its deficiency results in accumulation of self-DNA, which in turn may induce inflammation and autoimmunity. We assessed for the first time serum DNase1-activity in a large consecutive cohort of treatment-naïve patients with autoimmune liver diseases (ALD). DNase1-activity was determined by single radial enzyme-diffusion (SRED) at diagnosis of 224 patients with autoimmune hepatitis (AIH), 249 with primary biliary cirrhosis (PBC) and 36 with primary sclerosing cholangitis (PSC). Sera from 146 patients with chronic hepatitis B or C, 140 with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and 114 healthy individuals served as disease and healthy controls. Available serum samples during remission from 50 AIH and 39 PBC patients were also investigated by paired analyzes. DNase1-activity was significantly lower in AIH, PBC and PSC compared to viral hepatitis (p < 0.02, p < 0.001, p = 0.03), NAFLD/NASH (p < 0.001) and healthy (p < 0.001). No significant difference was found in between each specific ALD. In AIH, DNAse1-activity was positively correlated with aspartate aminotransferase (AST) (p < 0.02), bilirubin (p < 0.01) and increased IgG (>1400 mg/dl; p < 0.05); in PBC, with AST (p < 0.01), alanine aminotransferase (ALT) (p < 0.03) and anti-mitochondrial antibodies (AMA) (p = 0.008). In PSC, DNase1-activity was inversely associated with alkaline phosphatase (ALP) (p < 0.05). In AIH, complete responders were characterized by increased baseline DNase1-activity compared to partial responders, relapsers and non-responders (p < 0.02), whereas it was significantly increased after achievement of remission (p < 0.001). Serum DNase1-activity is significantly decreased in ALD patients, indicating its potential implication in their pathogenesis. Furthermore, DNase1-activity could be used as a new surrogate biomarker for predicting response to AIH treatment.
脱氧核糖核酸酶1（DNase1）参与凋亡细胞的染色质降解。其缺乏会导致自身DNA积累，进而可能引发炎症和自身免疫。我们首次在一大组未经治疗的自身免疫性肝病（ALD）连续队列患者中评估了血清DNase1活性。在224例自身免疫性肝炎（AIH）、249例原发性胆汁性肝硬化（PBC）和36例原发性硬化性胆管炎（PSC）患者诊断时，通过单放射酶扩散法（SRED）测定DNase1活性。146例慢性乙型或丙型肝炎患者、140例非酒精性脂肪性肝病/非酒精性脂肪性肝炎（NAFLD/NASH）患者和114名健康个体的血清作为疾病和健康对照。还通过配对分析对50例AIH和39例PBC患者缓解期的可用血清样本进行了研究。与病毒性肝炎（p < 0.02，p < 0.001，p = 0.03）、NAFLD/NASH（p < 0.001）和健康个体（p < 0.001）相比，AIH、PBC和PSC患者的DNase1活性显著降低。各特定ALD之间未发现显著差异。在AIH中，DNAse1活性与天冬氨酸转氨酶（AST）（p < 0.02）、胆红素（p < 0.01）和IgG升高（>1400mg/dl；p < 0.05）呈正相关；在PBC中，与AST（p < 0.01）、丙氨酸转氨酶（ALT）（p < 0.03）和抗线粒体抗体（AMA）（p = 0.008）呈正相关。在PSC中，DNase1活性与碱性磷酸酶（ALP）呈负相关（p < 0.05）。在AIH中，与部分缓解者、复发者和无反应者相比，完全缓解者的基线DNase1活性升高（p < 0.02），而在达到缓解后显著升高（p < 0.001）。ALD患者血清DNase1活性显著降低，表明其在发病机制中可能具有潜在作用。此外，DNase1活性可作为预测AIH治疗反应的新替代生物标志物。
