探討IL-17及IL-21於自體免疫性膽管炎的免疫調控作用

Abstract

原發性膽汁性膽管炎 (Primary biliary cholangitis；PBC) 為一具有肝臟特異性的慢性自體免疫疾病，患者的肝內膽管受自體免疫細胞的攻擊與浸潤，造成膽汁淤積在肝臟導致肝損傷，且隨著疾病發展至肝纖維化、肝硬化等。近期研究發現Th17細胞可能與PBC疾病晚期的患者大多發展至肝纖維化有關，但其中機制尚未清楚，因此，本研究探討Th17分泌之細胞激素IL-17A、 IL-17F及IL-21在PBC扮演的角色跟作用機轉。我們使用實驗室長期建立的2-OA-OVA分子誘發PBC之小鼠模式，藉助腺相關病毒載體 (Adeno-associated virus；AAV) 攜帶IL-17A、IL-17F與IL-21基因以感染小鼠，探討上述細胞激素對於PBC的影響。首先，我們發現給予AAV-IL-21的小鼠，疾病發炎情形明顯變嚴重且肝臟浸潤細胞數升高，主要增加的細胞為CD8 T細胞，其數目、活化情形與毒殺能力皆上升。我們也觀察到IL-21具有促進肝臟內記憶T細胞生成的效果。此外，IL-21也加劇疾病晚期肝纖維化病程。另一方面，PBC小鼠給予AAV-IL-17A後不影響疾病的發炎情形，但可觀察到肝臟內浸潤的CD11b+ Ly6G+ 多核性白血球數量增加，以及Th1免疫反應降低的現象。最後，疾病小鼠給予AAV-IL-17F也不影響PBC的病程。綜合以上結果，顯示IL-21在PBC扮演促進發炎的角色，反之IL-17A與IL-17F則無顯著促發炎效果。

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. Recent studies have showed that the imbalance towards Th17 in advanced PBC may contribute to liver fibrosis, but the mechanism is unclear. Therefore, we investigated whether Th17 secreting cytokines including IL-17A, IL-17F and IL-21 could exacerbate disease severity and liver fibrosis. We treated mice with 2-OA conjugated OVA to induce PBC. We also injected adeno-associated virus (AAV) as a vector to overexpress cytokines in mouse liver. Our results showed that PBC mice administered with AAV-IL-21 enhanced liver inflammation and cell infiltration. CD8+ T cells were significantly increased and accompanied with increased activation and cytotoxic function in AAV-IL-21-treated mice. We found IL-21 boosted memory T cells expansion in the liver. Additionally, IL-21 aggravated the course of liver fibrosis. AAV-IL-17A administration didn’t enhance liver inflammation in PBC mice. However, increased CD11b+ Ly6G+ cells and decreased Th1 cells in the liver were observed. Lastly, AAV-IL-17F administration didn’t affect disease severity either. In conclusion, IL-21 exacerbated liver inflammation and fibrosis in our PBC model, but IL-17A and IL-17F did not.