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標題: | 探討雄性和雌性小鼠在原發性膽汁性膽管炎初期的肝臟免疫反應 Investigation of liver immune responses of males and females in the initiation of primary biliary cholangitis |
作者: | Chih-Yu Liu 劉芝宇 |
指導教授: | 莊雅惠(Ya-Hui Chuang) |
關鍵字: | 原發性膽汁性膽管炎,性別差異,免疫失衡,effector T cells,regulatory T cells,chemokine, primary biliary cholangitis,sex disparity,effector T cells,regulatory T cells,chemokine, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 原發性膽汁性膽管炎(primary biliary cholangitis; PBC)為一好發於女性的慢性肝臟自體免疫疾病,發病機率女比男約為10:1,目前對於PBC好發於女性的機制仍不清楚。免疫系統能維持著免疫耐受性的狀態,是因為促進發炎的effector T cells (Teff)和抑制免疫反應的regulatory T cells (Tregs)維持著平衡,但是當Teff或Tregs細胞數目改變或者功能缺失時,造成Teff發炎反應過強,便會導致自體免疫疾病。本篇研究推測PBC好發於女性可能為疾病初期時Teff與Tregs在性別間失衡程度不同所導致,因此運用2-OA-OVA-induced PBC小鼠模式,分別致敏C57BL/6的公母鼠,探討小鼠在相同基因與環境的情況下,性別的不同是否會影響PBC的疾病嚴重程度,並研究肝臟中Teff或Tregs的平衡。我們發現病程嚴重時期的PBC小鼠,母鼠肝臟的免疫細胞浸潤、發炎與纖維化情況顯著比公鼠嚴重,確認2-OA-OVA-induced PBC小鼠模式具有性別差異。在疾病初期,母鼠肝臟的免疫細胞浸潤、發炎情況也比公鼠嚴重。其中,母鼠CD8+ Teff比例顯著高於公鼠,CD4+ Teff與Foxp3+ Tregs的比例則沒有統計上的差異。功能方面,CD8+ T cells在性別間活化、分化以及分泌的功能都沒有差異,不過公鼠的CD4+ Teff較母鼠更加活化與耗竭、公鼠的Foxp3+ Tregs則表現比母鼠更高比例的免疫抑制功能相關蛋白。我們也發現母鼠肝臟CXCL9與CXCL10的表現量顯著高於公鼠,於是推測母鼠肝臟有大量免疫細胞浸潤是受到chemokine的招募,但在分析肝臟中各種免疫細胞CXCR3 (CXCL9與CXCL10的receptor)的表現量後,發現母鼠免疫細胞上CXCR3表現量並沒有顯著高於公鼠。本篇研究發現2-OA-OVA-induced PBC小鼠模式具有母鼠疾病較嚴重的性別差異,而此差異可能由疾病初期時,性別間Teff與Tregs之間的失衡程度不同所導致。 Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease which caused by inflammation targeting intrahepatic small bile ducts. A sex disparity happens in PBC with a female-to-male ratio of 10:1. However, the reason why females outnumber males remains unclear. In this study, we investigated whether the female-predominant effect of PBC results from female and male experience different immune responses in the initiation of PBC by using the xenobiotic-induced PBC murine model. Our results showed that the female PBC mice expressed more exacerbating liver inflammation and cell infiltration than the male PBC mice in the initiation of diseases. The percentage of liver CD8+ T cells was increased in female PBC mice, while effector CD4+ T cells and Foxp3+ regulatory cells were comparable. Although the two groups exhibited parallel functions of CD8+ T cells, CD4+ Teff expressed more activation and inhibition markers, and Foxp3+ Tregs expressed more suppression-maintaining markers in the male PBC mice.CXCL9 and CXCL10, which play crucial roles in trafficking infiltrating cells, expressed higher levels in the liver of female PBC mice. However, there were no differences between the chemokines receptor, CXCR3, between the two groups. In summary, our data indicated that the female mice exhibited more effector immune response might result from an imbalance of Teff/ Tregs in the initiation of PBC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72867 |
DOI: | 10.6342/NTU201901833 |
全文授權: | 有償授權 |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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