本文選題：乙型肝炎病毒 + 慢加亞急性肝衰竭�。� 參考：《蘇州大學》2013年碩士論文

【摘要】：背景在我國，慢性乙型病毒性肝炎(CHB)是引起慢加亞急性肝衰竭(SACLF)的主要病因，有報道稱CHB占SACLF所有病因的80%。目前認為，HBV感染患者病情進展和轉歸受諸多因素影響，其中宿主的免疫功能發(fā)揮了重要作用，細胞因子在調節(jié)免疫應答中扮演了關鍵角色。輔助性T細胞（Th細胞）根據分泌的細胞因子不同分為：Th0、Th1、Th2、Th3，目前研究最多的是Th1和Th2兩個亞型。研究認為在病毒性肝炎感染中，Th1細胞有利于病毒的清除，而Th2細胞主要與組織損傷及慢性化有關。最近，CD4+Th細胞家族新型成員-Th17細胞亞群的出現改寫了經典的Th1/Th2細胞反應模式。該細胞以高分泌IL-17為特征，具有很強的促炎癥作用。2005年Kim等人發(fā)現了IL-32，，該因子可由T細胞、NK細胞、單核細胞、上皮細胞產生，進一步研究表明其有促炎癥因子的特性。IL-10是機體一種強有力的免疫和炎癥抑制因子，由Th2細胞、巨噬細胞、樹突狀細胞（Dendritic cells，DC）和B細胞等產生，它可以減低T細胞活性，從而降低免疫反應的效應，導致機體清除病毒能力減弱。上述細胞及細胞因子在CHB中的變化已有報道，但其是否參與了HBV相關慢加亞急性肝衰竭（HBV-SACLF）的發(fā)病過程以及在肝衰竭病程中的動態(tài)變化趨勢、與ALT的相關性研究未見報道。 目的探討HBV-SACLF患者外周血Th1、Th2、Th17及血清中IL-32、IL-10的動態(tài)變化趨勢及其臨床意義。 方法采用流式細胞技術檢測38例HBV-SACLF患者、46例肝衰竭前期患者、20例CHB患者、20例健康體檢者（對照組），外周全血標本中Th1、Th2、Th17的表達水平，比較四組之間上述指標的差異；動態(tài)觀察HBV-SACLF患者早、中、晚期Th1、Th2、Th17的變化趨勢；比較感染組與非感染組、存活組與非存活組Th1、Th2、Th17表達水平的變化；分析Th1、Th2、Th17與ALT的相關性。同時采用ELISA檢測上述四組血清中IL-32、IL-10的表達水平，并觀察IL-32、IL-10在HBV-SACLF患者早、中、晚期的動態(tài)變化。 結果1.HBV-SACLF組、肝衰竭前期組、CHB組、對照組Th1、Th2、Th17的表達水平分別為：①T h1：（22.58±3.86）%、（20.80±3.32）%、（5.23±1.51）%、（6.45±1.27）%；Th1比例在HBV-SACLF組與CHB組及對照組比較，均明顯升高，差異具有顯著性（P_2=0.04，P3=0.032）。②Th2：（1.73±0.64）%、（1.03±0.34）%、（6.15±0.97）%、（1.98±0.46）%；Th2比例在HBV-SACLF組與CHB組及對照組比較，均明顯下降，差異具有顯著性（P_2=0.007，P3=0.041）。③T h17：（3.48±0.80）%、（3.61±1.20）%、（1.09±0.4）%、（0.72±0.11）%；Th17比例在HBV-SACLF組與CHB組及對照組比較，均明顯升高，差異具有顯著性（P_2=0.003，P30.001）。 2.HBV-SACLF早期、中期、晚期Th1、Th2、Th17的表達水平分別為：①Th1：（26.11±5.19）%、（22.45±4.06）%、（18.33±3.21）%；Th1比例在HBV-SACLF早期與中期，中期與晚期相比逐漸降低，兩組之間比較差異均具有顯著性(P1=0.001，P_2=0.004)。②T h2：（0.95±0.20）%、（1.66±0.41）%、（2.54±1.03）%；Th2比例在HBV-SACLF早期與中期，中期與晚期相比逐漸升高，兩組之間比較差異均具有顯著性(P1=0.003，P_2=0.048)。③Th17：（2.71±0.34）%、（3.39±0.73）%、（4.45±1.22）%；Th17比例在HBV-SACLF早期與中期，中期與晚期相比逐漸升高，兩組之間比較差異均具有顯著性(P1=0.002，P_2=0.007)。 3.HBV-SACLF感染組與非感染組Th1、Th2、Th17的表達水平分別為：①Th1：（23.59±3.91）%、（21.44±3.51）%；兩組比較差異無顯著意義。②T h2：（1.92±0.70）%、（1.76±0.55）%；兩組比較差異無顯著意義。③T h17：（4.65±1.33）%、（3.92±1.27）%，兩組比較差異具有顯著性（P=0.032）。 4.HBV-SACLF存活組與非存活組Th1、Th2、Th17的表達水平分別為：①Th1：（20.78±3.37）%、（25.61±4.05）%；兩組比較差異無顯著意義。②T h2：（1.65±0.59）%、（1.88±0.63）%；兩組比較差異無顯著意義。③T h17：（3.21±1.02）%、（4.53±1.29）%，兩組比較差異具有顯著性（P=0.029）。 5.對HBV-SACLF患者Th17、Th1、Th2與ALT進行Pearson相關性分析，結果發(fā)現Th17與ALT呈正相關（r=0.616，P=0.044），差異具有統計學意義；Th1、Th2與ALT無明顯相關性。 6. HBV-SACLF組、肝衰竭前期組、CHB組、對照組IL-32、IL-10的表達水平分別為：①IL-32：（500.98±152.33）pg/ml、（486.45±129.06）pg/ml、（281.72±99.28）pg/ml、（178.16±50.54）pg/ml；IL-32在HBV-SACLF組與CHB組及對照組比較，均顯著升高，差異具有顯著性（P_2=0.021，P3=0.033）。②I L-10：（2.82±1.03）pg/ml、（3.05±1.83）pg/ml、（13.15±3.37）pg/ml、（7.62±2.17）pg/ml；IL-10在HBV-SACLF組與CHB組及對照組比較，均顯著下降，差異具有顯著性（P_2=0.024，P3=0.019）。 7. HBV-SACLF早期、中期、晚期IL-32、IL-10的表達水平分別為：①IL-32：（540.69±155.71）pg/ml、（498.43±135.56）pg/ml、（450.77±102.33）pg/ml；IL-32在HBV-SACLF早期與中期，中期與晚期相比逐漸降低，兩組之間比較差異均具有顯著性(P1=0.046，P_2=0.001)。②I L-10：（1.94±0.44）pg/ml、（2.83±0.97）pg/ml、（3.69±1.23）pg/ml；IL-10在HBV-SACLF早期與中期，中期與晚期相比逐漸升高，兩組之間比較差異均具有顯著性(P1=0.004，P_2=0.032)。 結論Th1細胞和IL-32在HBV-SACLF患者中明顯升高，隨著病情發(fā)展呈逐漸下降趨勢；Th2細胞和IL-10在HBV-SACLF患者中明顯降低，其在HBV-SACLF早、中、晚期逐漸升高；Th17細胞在HBV-SACLF患者中明顯升高，隨著病情發(fā)展呈逐漸升高趨勢；繼發(fā)感染組Th17細胞較非感染組明顯升高；存活組Th17細胞低于非存活組；且Th17細胞與肝細胞損害呈正相關。本文研究輔助性T細胞1、2、17及細胞因子IL-32、IL-10的紊亂是導致HBV-SACLF發(fā)生、發(fā)展的關鍵因素，通過檢測其在肝衰竭早、中、晚期的動態(tài)變化可以判斷機體的免疫狀態(tài)，為臨床的免疫調控治療提供理論依據。
[Abstract]:Background chronic hepatitis B (CHB) is the main cause of chronic acute hepatic failure (SACLF) in China. It is reported that 80%., which accounts for all the causes of SACLF, is currently considered to be affected by many factors in the progression and prognosis of HBV infected patients, in which the immune function of the host plays an important role and the cytokine is regulating the immune response. It plays a key role. Auxiliary T cells (Th cells) are divided into Th0, Th1, Th2, and Th3 according to the secreted cytokines. At present, the most research is the two subtypes of Th1 and Th2. It is believed that in viral hepatitis infection, Th1 cells are beneficial to the clearance of viruses, while Th2 cells are mainly related to tissue damage and chronicity. The emergence of a new member of the cell family, -Th17 cell subgroup, rewrites the classic Th1/Th2 cell response pattern. This cell is characterized by hypersecreting IL-17 and has a strong pro-inflammatory role in.2005, Kim and others found IL-32, which can be produced by T cells, NK cells, monocytes, epithelial cells, and further studies show that they have a pro-inflammatory factor. Characteristic.IL-10 is a powerful immune and inflammatory inhibitor in the body, which is produced by Th2 cells, macrophages, dendritic cells (Dendritic cells, DC) and B cells, which can reduce the activity of T cells and reduce the effects of the immune response, resulting in the weakening of the body's ability to clear the virus. The changes of these cells and cytokines in CHB have already existed. It is reported whether it is involved in the process of HBV related chronic acute hepatic failure (HBV-SACLF) and the trend of dynamic changes in the course of liver failure, and the correlation with ALT has not been reported.
Objective to investigate the dynamic changes of Th1, Th2, Th17 and serum IL-32 and IL-10 in patients with HBV-SACLF and their clinical significance.
Methods the flow cytometry was used to detect 38 HBV-SACLF patients, 46 patients with pre liver failure, 20 CHB patients and 20 healthy persons (control group), the expression levels of Th1, Th2 and Th17 in the peripheral blood samples were compared and the differences between the above indexes were compared between the four groups; the trends of the early, middle and late Th1, Th2, Th17 in the HBV-SACLF patients were observed and compared. The changes in the expression level of Th1, Th2 and Th17 in the infected and non infected groups, the survival group and the non survival group, and the correlation between the Th1, Th2, Th17 and ALT were analyzed. At the same time, ELISA was used to detect the expression level of IL-32 and IL-10 in the four groups of serum, and IL-32, IL-10 was in the early, middle, and late stages of dynamic changes.
Results the expression levels of Th1, Th2, Th17 in the 1.HBV-SACLF group, the pre liver failure group, the CHB group and the control group were as follows: T h1: (22.58 + 3.86)%, (20.80 + 3.32)%, (5.23 + 1.51)%, (6.45 + 1.27)%, and Th1 ratio in both HBV-SACLF group and CHB group and control group, with significant difference (P_2=0.04, P3=0.032). (1.73 + 0.64)%, 1 (1.73 + 0.64)%), (1.73 + 0.64)%, (1)%, (1.73 + 0.64)%, (1.73 + 0.64)%), (1.73 + 0.64)%, (1)%, (1.73 + 0.64)%, (1.73 + 0.64)%, (1.73 + 0.64)%) .03 + 0.34)%, (6.15 + 0.97)%, (1.98 + 0.46)%, the proportion of Th2 in HBV-SACLF group and CHB group and control group decreased obviously, the difference was significant (P_2=0.007, P3=0.041), T h17: (3.48 + 0.80)%, (3.61 + 1.20)%, (1.09 + 0.4)%, (0.72 + 0.11)%, Th17 ratio was significantly higher in HBV-SACLF group than CHB group and control group, the difference has obviously increased, the difference has obvious It is significant (P_2=0.003, P30.001).
The expression level of 2.HBV-SACLF early, middle, late Th1, Th2, Th17 were respectively Th1: (26.11 + 5.19)%, (22.45 + 4.06)%, (18.33 + 3.21)%, Th1 ratio decreased gradually in the early and middle stages of HBV-SACLF, and the difference between the two groups was significant (P1=0.001, P_2=0.004). (2) T h2: (0.95 + 0.20)%, (1.66 + 0.41)%, 2.54 + 1.03)%; the ratio of Th2 was higher in the early and middle stages of HBV-SACLF than in the middle and late stages. The difference between the two groups was significant (P1=0.003, P_2=0.048). (2.71 + 0.34)%, (3.39 + 0.73)%, (4.45 + 1.22)%, and the proportion of Th17 was higher in the early and middle period of HBV-SACLF than in the middle and late stage, and the difference was compared between the two groups. They were both significant (P1=0.002, P_2=0.007).
The expression level of Th1, Th2, Th17 in 3.HBV-SACLF infection group and non infection group were as follows: (23.59 + 3.91)%, (21.44 + 3.51)%, and there was no significant difference in the two groups. (2) T h2: (1.92 + 0.70)%, (1.76 + 0.55)%, and there was no significant difference in two groups. (P=0) h17: (4.65 + 1.33)%, (3.92 +%)%, and there was significant difference (P=0, P=0). .032).
The expression levels of Th1, Th2, and Th17 in the 4.HBV-SACLF and non survival groups were as follows: (20.78 + 3.37)% and (25.61 + 4.05)%, and there was no significant difference in the two groups. (2) T h2: (1.65 + 0.59)%, (1.88 + 0.63)%, and there was no significant difference in two groups. (P=0) h17: (3.21 + 1.02)%, (4.53 +%)%, and there was significant difference (P=0, P=0). .029).
5. HBV-SACLF patients Th17, Th1, Th2 and ALT were analyzed with Pearson correlation. The results showed that Th17 was positively correlated with ALT (r=0.616, P=0.044), and the difference was statistically significant. Th1, there was no significant correlation between Th2 and ALT.
6. HBV-SACLF group, the expression level of IL-32, IL-10 in the pre liver failure group, CHB group and the control group were respectively IL-32: (500.98 + 152.33) pg/ml, (486.45 + 129.06) pg/ml, (281.72 + 99.28) pg/ml and (178.16 + 50.54) pg/ml, and IL-32 was significantly higher in HBV-SACLF group than in CHB and control groups. L-10: (2.82 + 1.03) pg/ml, (3.05 + 1.83) pg/ml, (13.15 + 3.37) pg/ml, (7.62 + 2.17) pg/ml, and IL-10 in HBV-SACLF group were significantly lower than those of CHB and control groups, and the difference was significant (P_2=0.024, P3=0.019).
7. HBV-SACLF early, middle and late IL-32, IL-10 expression levels are: IL-32: (540.69 + 155.71) pg/ml, (498.43 + 135.56) pg/ml, (450.77 + 102.33) pg/ml; IL-32 in the early and middle stages of HBV-SACLF, compared to the middle and late gradually decreased, between the two groups has a significant difference (P1=0.046, P_2=0.001). (1.94 + 0 I). .44) pg/ml, (2.83 + 0.97) pg/ml, (3.69 + 1.23) pg/ml; IL-10 increased gradually in the early and middle stages of HBV-SACLF, compared to the middle and late stages, and the difference was significant between the two groups (P1=0.004, P_2=0.032).
Conclusion Th1 cells and IL-32 were significantly increased in HBV-SACLF patients, and gradually decreased with the development of the disease. Th2 cells and IL-10 were obviously decreased in HBV-SACLF patients. It was gradually increased in the early, middle and late stages of HBV-SACLF, and Th17 cells increased significantly in HBV-SACLF patients, and gradually increased with the development of the disease; secondary infection group Th17. The cells in the survival group were significantly lower than those in the non infected group; the Th17 cells in the survival group were lower than those in the non surviving group; and the Th17 cells were positively related to the liver cell damage. This paper studied the auxiliary T cell 1,2,17 and the cytokine IL-32, and the disorder of IL-10 was the key factor leading to the occurrence of HBV-SACLF, and the dynamic changes in the early, middle and late stages of the liver failure could be detected. To determine the immune state of the body, and to provide a theoretical basis for clinical immune regulation and treatment.

【學位授予單位】：蘇州大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R575.3;R512.62

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