摘要
第一部分原发性胆汁性肝硬化患者进展到肝功能失代偿阶段的危险因素
目的：分析我国未发生肝功能失代偿的原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)患者的临床特点,并探索患者进展为肝功能失代偿的危险因素。
对象与方法：通过对本课题组患者资料数据库的检索,该研究纳入了就诊于我院符合入选标准的PBC患者共262人。采集患者确诊/入组时的人口学信息和临床资料,分析他们的临床特点,并探索患者进展为肝功能失代偿的危险因素。
结果：本研究共纳入262例PBC患者(女：男≈14：1,平均年龄=51.5±10.2岁),平均随访73.5月(21-201月)。245例(93.5%)患者血清抗线粒体抗体(anti-mitochondrial antibodies, AMAs)阳性。入组时,170例(64.9%)患者存在肝病相关症状,96例(36.7%)患者合并肝外自身免疫性疾病。在随访中,62例(23.7%)患者进展到肝功能失代偿阶段,其中4例患者接受了肝脏移植治疗,随访结束时,17例(6.5%)患者死于肝脏相关疾病,1例(0.4%)患者死于间质性肺病(interstitial lung disease, ILD),1例(0.4%)患者死于淋巴瘤所致的多器官功能衰竭。患者5年和10年生存率分别为96.4%和83.9%。两组间均数比较显示,在基线时失代偿组患者年龄、症状出现率、抗核抗体(antinuclear antibodies, ANA)阳性率、血清抗着丝点抗体(anticentromere antibody, ACA)阳性率、门冬氨酸氨基转移酶(aspartate aminotransferase, AST)、碱性磷酸酶(alkaline phosphatase ALP)、AST与丙氨酸氨基转移酶(alanine aminotransferase, ALT)比值(alanine aminotransferase ratio, AAR)、谷氨酰转肽酶(y-glutamyl transpeptidase, GGT)、总胆红素(total bilirubin, TBil)、间接胆红素(direct bilirubin, DBil)和IgA水平高于对照组；但熊去氧胆酸(ursodeoxycholic acid, UDCA)应答率、早期及极早期患者比例、白蛋白(albumin, ALB)水平低于对照组。Cox回归分析表明,不规律服用UDCA或对其应答不良(P<0.001；HR95%CI=2.423-7.541)、血清ACA阳性(P<0.001；HR95%CI=2.516-7.137)、AAR水平(JP<0.001；HR95%CI=1.357-2.678)、TBil水平(P=0.004；HR95%CI=1.002-1.009)和ALP水平升高(P=0.008；HR95%CI=1.000-1.002)是患者发展为肝功能失代偿的危险因素。对病理分期单独进行Cox回归分析显示,其也是患者预后不良的危险因素(P=0.006；HR95%CI=1.481-10.847)。
结论：
1.我国PBC患者的临床特点和国外患者基本相同,但有症状的患者较多。
2.初诊时,失代偿组患者年龄、症状出现率、ANA和ACA阳性率、AST、AAR、ALP、GGT、TBil、DBil和IgA水平高于未发生失代偿患者；但UDCA应答率、早期及极早期患者比例、ALB水平低。
3.不规律服用UDCA或对其应答不良、血清ACA阳性、AAR水平、TBil水平、ALP水平及病理分期都是患者发展为肝功能失代偿的独立危险因素。
第二部分Th17细胞、IL-17在原发性胆汁性肝硬化发展中的作用
目的：
研究PBC患者外周血单个核细胞(peripheral blood mononuclear cell, PBMC)、肝脏中Th17细胞的水平。分析Th17细胞水平变化的原因,探索Th17细胞/白介素-17(Interleukin-17, IL-17)介导PBC肝纤维化发生的机制。
对象与方法：
1.提取PBC患者(35例)、健康对照(35例)和慢性乙型肝炎患者(15例)的PBMC,用流式细胞术分析Th17细胞占CD4+T细胞的水平；免疫组织化学染色比较PBC患者(16例)和健康对照者(4例)肝脏IL-17阳性细胞的水平。
2.标记CD4、叉头样转录因子3(forkhead box3, Foxp3)、IL-17和干扰素-γ(Interferon-y, IFN-y)荧光标记抗体,分析PBC患者Th17细胞是否存在表型改变；流式细胞术分析调节性T细胞(regulatory T cells, Treg细胞)水平,并用磁珠分选患者(5例)和健康对照者(5例)的Treg细胞,体外培养鉴定其分类转化能力。
3.流式细胞术分析PBC患者(20例)和健康对照者(20例)CD4+CD161+细胞占CD4+T细胞水平,并用流式细胞仪分选患者(5例)和健康对照组(5例)的CD4+CD161+细胞进行体外培养,CCK8法检测细胞增殖水平,酶联免疫吸附实验(enzyme linked immunosorbent assay, ELISA)检测培养上清IL-17水平；ELISA检测血清IL-23水平。
4.流式细胞术分析PBC患者(20例)和健康对照者(20例)CD4+CCR6+细胞占CD4+T细胞水平；ELISA检测血清CCL20水平；免疫组化分析肝脏CCL20水平。
5.培养肝星状细胞(hepatic stellate cell, HSC),以0ng/mL、1ng/mL、5ng/mL、10ng/mL的重组人IL-17和10ng/mL重组人IL-17+1μg/mL兔抗人IL-17进行干预,分别在24、72、144小时用CCK8法测定HSC增殖能力；利用实时荧光定量聚合酶链反应(real-time polymerase chain reaction, real-time PCR)检测α-平滑肌肌动蛋白(smooth muscle actin, SMA)在144小时的表达水平；利用ELISA检测培养上清IL-8在24、72、144小时的分泌水平。
结果：
1.PBC患者PBMC中Th17细胞水平高于慢性乙肝患者(1.03±0.22%比0.67±0.20%,P<0.0001),高于健康对照者(1.03±0.22%比0.55±0.20%,P<0.0001);免疫组化染色表明,PBC患者肝脏IL-17阳性细胞多于健康对照者。
2.PBC患者外周血CD4+IL-17+Foxp3+细胞(0.21±0.13%比0.06±0.04%,P<0.0001)和CD4+IL-17+IFN-γ+细胞(0.39±0.16%和0.14±0.07%,P<0.0001)占CD4+T细胞比例均高于健康对照者；CD4+IL-17+Foxp3+细胞和Th17细胞正相关(r2=0.441,P<0.0001),与Treg细胞无明显相关性；而CD4+IL-17+IFN-γ+细胞与Th17细胞、Th1细胞均无显著相关性；在IL-2、IL-6和TGF-β作用下,PBC患者减少的Treg细胞(2.37±1.24%比3.57±1.57%,P=0.0068)表达IL-17显著增加(4.46±0.60%至6.6±0.5%,P=0.0003),能力高于健康对照者(3.32±0.85%至4.18±1.29%,P=0.2491)。
3.PBC患者CD4+CD161+细胞占CD4+T细胞比例较正常对照组高(22.24±5.33%比13.89±3.92%,P<0.0001),但CD4+CD161+细胞和Th17细胞比例相关性无统计学意义(P=0.279)；在IL-1β和IL-23的刺激下,患者和健康对照者CD4+CD161+细胞增殖率无统计学差异(1.079±0.093%比1.074±0.034%,P=0.9089),但ELISA测定显示PBC患者培养上清IL-17浓度高于健康对照者(45.28±35.73pg/mL比17.03±16.78pg/mL,P=0.0556)。ELISA检测证实患者血清IL-23高于健康对照者(35.8±8.34pg/mL比23.5±5.35pg/mL,P=0.023)。
4.晚期PBC患者外周血Yh17细胞水平回落(0.93±0.16%比1.09±0.23%,P=0.0351),但仍然高于健康对照者(0.93±0.16%比0.55±0.20%,P<0.0001)；相反,与早期患者相比,晚期患者肝脏浸润的IL-17阳性细胞增多。PBC患者CD4+CCR6+细胞占CD4+T细胞与对照组相似(17.69±7.11%比17.62±6.71%,P=0.975),且不受疾病分期影响(17.41±8.03%比18.11±5.98%,P=0.835),但患者血清趋化因子CCL20水平高于正常对照(53.23±38.58pg/mL比23.54±21.95pg/mL,P=0.001),且晚期高于早期(85.88±32.11pg/mL比28.98±13.57pg/mL；P=0.001)；免疫组化染色表明,患者肝细胞表达CCL20,健康者肝细胞几乎不表达CCL20,患者汇管区CCL20显著增加。
5.随重组人IL-17浓度增加,HSC增殖率增加(P<0.001)；IL-17可以通过浓度和时间依赖性促进HSC表达IL-8(P<0.001),但α-SMA表达量无明显改变(P=0.0847)。
结论：
1.与健康对照者和慢性乙型肝炎患者相比,PBC患者外周血Th17细胞升高,浸润在肝脏的IL-17阳性细胞增多。
2.在IL-6、IL-2和TGF-β的刺激下,PBC患者Treg细胞发生分类转化,表达IL-17升高。上述机制可能是PBC患者外周血Treg细胞下降、CD4+IL-17+Foxp3+T细胞升高的原因。患者外周血CD4+IL-17+IFN-γ+T细胞也升高,但具体机制不详。
3.PBC患者外周血Thl7细胞前体细胞(CD4+CD161+T细胞)增多,在升高的炎症因子IL-1β和IL-23的活化下,表达大量IL-17。
4.PBC患者升高的CCL20趋化外周血升高的Thl7细胞向肝脏浸润,导致晚期患者外周血Th17细胞回落,肝脏IL-17阳性细胞升高。
5.随IL-17浓度增加,HSC的增殖能力增强。IL-17还可以通过浓度、时间依赖性促进HSC分泌IL-8；IL-17拮抗剂可以抑制上述效应,有望延缓PBC患者肝纤维化的发生。
Part1Clinical profiles and risk factors for hepatic decompensation in patients with primary biliary cirrhosis in China
Aims:The clinical profiles and prognosis of primary biliary cirrhosis (PBC) have not been well-studied prospectively in China. In the current study, we will examine the clinical features and analyze prognostic factors in a prospective study of a large cohort of PBC patients.
Methods:From database of our research group, PBC patients without hepatic decompensation were enrolled. The risk factors for hepatic decompensation and survival were assessed by Cox regression and Kaplan-Meier analysis, respectively.
Results:Two hundred and sixty-two PBC patients were enrolled with a median follow-up of73.5months (range,21-201). Two hundred forty patients (91.6%) were female with an age of51.5±10.2yr at diagnosis. Two hundred and forty-five (93.5%) were seropositive for anti-mitochondrial antibodies (AMA). At presentation,170patients (64.9%) were symptomatic, while96patients had extra-hepatic autoimmune disease. During the follow-up period,62(23.7%) patients developed hepatic decompensation of whom4underwent liver transplantation and17(6.5%) died. One (0.4%) patient died of interstitial lung disease (ILD), while one (0.4%) died of multiple organ failure on account of lymphoma. The cumulative survival rates were96.4%and83.9%at5-year and10-year, respectively. Compared to patients with hepatic free-decompensation, the age, antinuclear antibodies (ANAs) positivity, prevalence of clinical manifestations, anticentromere antibody (ACA) positivity, the levels of aspartate aminotransferase (AST), alanine aminotransferase ratio (AAR), alkaline phosphatase (ALP), y-glutamyl transpeptidase (GGT), total bilirubin (TBil), direct bilirubin (DBil) and IgA were higher at the baseline, while the incidence of good response to ursodeoxycholic acid (UDCA) treatment and early patients, and the levels of albumin (ALB) were lower. Cox regression analysis revealed that incomplete UDCA response or inconsistent treatment (P<0.001; HR95%CI=2.423-7.541), ACA positivity (P<0.001; HR95%CI=2.516-7.137), AAR elevations (P<0.001; HR95%CI=1.357-2.678), level of TBil (P=0.004; HR95%CI=1.002-1.009), and level of ALP (P=0.008; HR95%CI=1.000-1.002) were predictors. Histological advanced liver disease was also a risk factor for hepatic decompensation(P=0.006, HR95%CI=1.481-10.847) as determined by Cox regression analysis.
Conclusions:
1. The clinical features and survival of PBC in China were consistent with those described in Western countries. However, the symptomatic patients were more.
2. Compared to patients with hepatic free-decompensation, the age, ANA and ACA positivity, prevalence of clinical manifestations, the levels of AST, AAR, ALP, GGT, TBil, DBil and IgA were higher at the baseline, while the incidence of good response to UDCA treatment and early patients, and the levels of ALB were lower.
3. Incomplete UDCA response or inconsistent treatment, ACA positivity, AAR elevations, ALP elevations, TBil elevations, and advanced histological stage were independent predictors of hepatic decompensation.
Part2The role of T help17cells and interleukin-17in PBC
Aims:To investigate the levels, subsets, and distrubition of Th17cells in peripheral blood mononuclear cells (PBMCs), and interleukin-17(IL-17)-positive cells in liver in patients with PBC and healthy controls (HC). We will explore the reasons why Th17cells elevated, and the role of IL-17in PBC fibrosis.
Methods:
1. We used flow cytometry to compare the percentage of circulating CD4+IL-17+cells between patients and HC. IL-17-positive cells that infiltrated the liver were examined by immunohistochemistry.
2. We used flow cytometry to compare the percentage of circulating CD4+IL-17+Foxp3+cells, CD4+IL-17+IFN-γ+cells, and Treg cells between patients and HC. Treg cells were cultured with IL-2, IL-6, and TGF-β for seven days, and the expressions of IL-17in these cells were measured by flow cytometry.
3. We used flow cytometry to compare the percentage of circulating CD4+CD161+cells between PBC patients and HC. IL-17expressions from stimulated CD4+CD161+cells were determined by enzyme linked immunosorbent assay (ELISA). The capcitity of proliferation of CD4+CD161+cells was indenified by cell counting kit8(CCK8). And serum IL-23levels were measured by ELISA.
4. We used flow cytometry to compare the percentage of circulating CD4+CCR6+cells between PBC patients and HC. Serum CCL20levels were measured by ELISA, and CCL20levels in liver were examined by immunohistochemistry.
5. Hepatic stellate cells (HSCs) were cultured with0ng/mL,1ng/mL,5ng/mL and10ng/mL IL-17. The capcitity of proliferation of HSCs was indenified by CCK8at24,72h and144h, respectively. The expressions of a-smooth muscle actin (SMA) were determined by real-time polymerase chain reaction (PCR) at144h. The levels of IL-8in culture supernatant were measured by ELISA at24,72h and144h, respectively.1μg/mL anti-IL-17were added to culture medium to neutralize above reactions.
Results:
1. Circulating Th17cells were elevated in PBC patients compared to HCs (1.03± 0.22%and0.55±0.20%, P<0.0001), and higher than those in chronic hepatic B (1.03±0.22%and0.67±0.20%, P<0.0001). IL-17-positive cells that infiltrated the liver were higher in PBC patients compared to HCs.
2. Circulating CD4+IL-17+IFN-y+cells (0.39±0.16%and0.14±0.07%, P<0.0001), and CD4+IL-17+Foxp3+cells (0.21±0.13%and0.06±0.04%, P<0.0001) were all increased in PBC patients. The percentage of CD4+IL-17+Foxp3+cells were positively related with Th17cells (r2=0.441, P<0.0001); however, the relationship between CD4+IL-17+Foxp3+cells and Treg cells was not statistically significant. Treg cells can produced more IL-17after stimulation with IL-2, IL-6and TGF-β in PBC patients compared to HCs (4.46±0.60%to6.6±0.5%, P=0.0003in PBC;3.32±0.85%to4.18±1.29%, P=0.2491in HCs). What's more, we found the percentage of circulating Treg cells were decreased in patients (2.37±1.24%and3.57±1.57%, P=0.0068). The relationship between CD4+IL-17+IFN-γ+cells and Thl or Th17cells was not statistically significant.
3. After stimulation with IL-23and IL-1β, the increased progenitor of Th17cells, CD4+CD161+cells from PBC patients (22.24±5.33%and13.89±3.92%, P<0.0001) expressed more IL-17(45.28±35.73pg/mL and17.03±16.78pg/mL, P=0.0556). The relationship between CD4+CD161+cells and Th17cells was not statistically significant (P=0.279). The capcitities of proliferation of CD4+CD161+cells were similar in PBC and HCs (1.079±0.093%and1.074±0.034%, P=0.9089) after stimulation with IL-23and IL-1β. Accordingly, the levels of serum IL-1β and IL-23(35.8±8.34pg/mL and23.5±5.35pg/mL, P=0.023) were increased in PBC patients.
4. Early PBC presented with more Th17cells in periphery blood (1.09±0.23%and0.93±0.16%, P=0.0351) than advanced patients. In contrast, IL-17was higher in the liver in advanced PBC patients. Accordingly, the levels of serum CCL20were higher in PBC patients (53.23±38.58pg/mL and23.54±21.95pg/mL, P=0.001), especially in advanced disease (85.88±32.11pg/mL and28.98±13.57pg/mL, P=0.001). More importantly, the levels of CCL20were more obvious in liver in PBC, especially around portal area. Whereas, the percentages of CD4+CCR6+cells were not statistically significant different between PBC patients and HCs (17.69±7.11%and17.62±6.71%, P=0.975).
5. IL-17can promote capcitity of proliferation of HSCs in a dose dependent way (P <0.001). And IL-17can also increase the IL-8expression of HSCs in both a dose and a time dependent way (P<0.001). However, the production of a-SMA may not be influenced by IL-17(P=0.0847). Anti-IL-17neutralizes above reactions.
Conclusions:
1. Compared to HCs and chronic hepatic B, the levels of circulating Th17cells and IL-17-positive cells infiltrated liver are higher in PBC patients.
2. Proimflammatory cytokines-stimulated Treg cells can secrete more IL-17in PBC patients, resulting in decreased Treg cells and increased CD4+IL-17+Foxp3+cells.
3. Increased CD4+CD161+cells produce more IL-17after stimulation with IL-1β and IL-23in PBC patients. Therefore, CD4+CD161+cells are a source of increased Th17cells in PBC.
4. The increased Th17population is greater in circulation and less in liver in early PBC patients. With disease progression, enhanced serum and hepatic CCL20induce IL-17-expressing cells to migrate to liver. Therefore, Th17cells are lower in circulation and enhance in liver in advanced patients.
5. IL-17can promote capcitity of proliferation of HSCs in a dose dependent way, and increase the IL-8expression of HSCs in both a dose and a time dependent way. Therefore, anti-IL-17is a promosing therapy for PBC fibrosis.
引文
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