自身免疫性肝病中CD4、CD25、Foxp3及ERα、TGF-β1的表达及意义
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摘要
目的
近年来不同类型肝炎的鉴别诊断是临床迫切需要解决的难题,尤其是各型AILD的诊断更是难中之难,虽然国际自身免疫性肝炎小组(IAIHG)制定了一套诊断标准,并经过多次修订使得诊断率有所提高,诊断也更加可靠,但还会遇到诊断与临床表现不符或是治疗效果不满意的情况。基于此许多临床医生向病理医生寻求帮助,希望通过分析肝穿标本的病理特征能够给于他们更明确的诊断及治疗方向。我们分析,虽然各种肝炎有许多相似的组织学表现,但各自有各自相对的组织学特征,为此我们通过分析几种常见的肝炎(自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)及慢性乙型肝炎(CHB)) HE染色标本的组织学特征,以此来为临床诊断提供帮助,为临床治疗提供依据。此外CD4、CD25、叉头样转录因子Foxp3(foxhead box protein 3)、雌激素受体α(ERa)及转化生长因子β1 (TGF-β1)与自身免疫性疾病的关系倍受关注,尤其是CD4+、CD25+的Treg及Foxp3在自身免疫性疾病发病机制中的作用更是研究焦点中的热中之热。为此我们比较它们在各组肝活检中的表达情况来探讨其作用及意义。
方法
应用HE染色进行29例I型AIH、18例PBC、15例CHB肝穿标本的组织学特征分析,应用免疫组化方法检测各组CD4、CD25、Foxp3、ERa及TGF-β1的表达情况,设8例正常肝组织(非肝病患者尸检来源的肝组织)为对照。
结果
1. AIH、PBC、CHB三组中羽毛状变性发生率分别为3.45%、33.33%、6.67%,PBC组明显高于AIH组(P<0.05)；桥接坏死发生率分别为27.59%、50.00%、13.33%,PBC组明显高于乙肝组(P<0.05)；胆栓发生率分别为6.92%、44.44%、6.67%,PBC组明显高于AIH和CHB组(P<0.01、P<0.05)；胆管增生发生率分别为34.48%、61.11%、13.33%,PBC组明显高于AIH和CHB组(P<0.05)。
2.CD4在各组的表达PBC组高于乙肝组(P<0.01)。
3.CD25在各组的表达差异没有统计学意义(P>0.05)。
4. Foxp3组间阳性胆管数PBC组高于正常组(P<0.01),阳性细胞数各组间差异没有统计学意义(P>0.05)。
5.ERα在各组的表达AIH和PBC组高于正常组(P<0.01)。
6. TGF-B1表达：在PBC组汇管区阳性细胞数高于肝小叶(P<0.05),各组间汇管区阳性细胞数PBC组高于其它三组(P<0.01),在正常组肝小叶内阳性细胞数高于汇管区(P<0.01)。
结论
1.不同类型的自身免疫性肝病的组织学特征有所不同,AIH以肝小叶界板的损伤为主要改变,而PBC以胆管上皮损伤为主要特征,比如羽毛状变性,胆栓及胆管增生。
2. CD4+T细胞可能在PBC发生的免疫机制中起到重要作用。
3.ERa及TGF-β1可能介导和促进了自身免疫性肝病的发生发展。
AIM
In recent years the different type hepatitis's differential diagnosis was the difficult problem which clinical urgent needed to solve, particularly each AILD diagnosis was especially difficult, although the International Immunity Hepatitis Group has formulated a set of diagnosis standard, and after many times revised the diagnosis rate was improved, the diagnosis was also more reliable, but we will also meet the situation which the diagnoses and the clinical manifestation was not correspond, or some other phenomenon could not be explained in the course of treatment. Based on this many clinicians seeked help to pathology doctor and hoped that through analyzing the pathology characteristic of the liver' specimen to be able to give them more explicit diagnosis and guide the treatment direction. We analyzed, although each kind of hepatitis has many similar histology performance, but has respectively the relative different histology characteristic, for this reason we summarized and induced the histology characteristic of the HE stained several kind of common hepatitis (AIH、PBC、CHB),and strived for to provide the help for the clinical diagnosis and the clinical care. In addition the relationship of CD4、CD25、the foxhead box protein 3 (Foxp3)、the estrogen acceptor Alpha (ERa) and the transformation growth factorβ1 (TGF-B 1) with the autoimmune disease was received much attention, Especially the function of the CD4+ CD25+ Treg and Foxp3 in the pathogenesis of the autoimmune disease was the studing focus.For that we explored the expression and significance of them in above the autoimmune liver disease.
METHODS
Histological analysis of liver biopsy specimens from 29 patients with AIH,18 patients with PBC,15 patients with CHB, and immunohistochemistry technique was used to detect the expression of CD4、CD25、FoxP3、ERaand TGF-β1 in above 3 groups and 8 normal. RESULTS
1. The incidence of the feathery degeneration are 3.45%、33.33%、6.67%, PBC
was higher than AIH (P<0.05), the incidence of the bridging necrosis are27.59%、 50.00%、13.33%, PBC was higher than CHB (P<0.05), the incidence of bile thrombus are 6.92%、44.44%、6.67%, PBC was higher than AIH and CHB(P<0.01、P<0.05); and the incidence of proliferation of small bile duct were different significantly in AIH, PBC and CHB (34.48%、61.11%、13.33%) PBC was higher than AIH and CHB (P<0.05)
2. The expression of CD4 for PBC was higher than CHB(P<0.01),
3. The difference of the expression of CD25 was not statistically significant in above groups (P>0.05),
4. The expression of Foxp3 in bile duct epithelial was significantly different in above groups, PBC are higher than normal (P<0.01) but in cell the difference was not statistically significant (P>0.05).
5. The expression of ERa was significantly different in above 4 groups, AIH、PBC are higher than normal (P<0.01).
6. For PBC, the expression of TGF-β1 was significantly higher in portal area than in hepatic lobule(P<0.05)and also significantly higher than other3group(P<0.01), For normal, the expression of TGF-β1 was significantly higher in hepatic lobule than in portal area (P<0.01)
CONCLUSION
1. Different autoimmune liver disease have different histological features, the feature of AIH is interface hepatitis, the feature of PBC is destructive cholangitis.
2. CD4 regulatory T cells may play a important role in the pathogenesis of PBC.
3. ERa and TGF-B1 may mediate and promote the occurrence and development of autoimmune liver disease.
近年来不同类型肝炎的鉴别诊断是临床迫切需要解决的难题,尤其是各型AILD的诊断更是难中之难,虽然国际自身免疫性肝炎小组(IAIHG)制定了一套诊断标准,并经过多次修订使得诊断率有所提高,诊断也更加可靠,但还会遇到诊断与临床表现不符或是治疗效果不满意的情况。基于此许多临床医生向病理医生寻求帮助,希望通过分析肝穿标本的病理特征能够给于他们更明确的诊断及治疗方向。我们分析,虽然各种肝炎有许多相似的组织学表现,但各自有各自相对的组织学特征,为此我们通过分析几种常见的肝炎(自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)及慢性乙型肝炎(CHB)) HE染色标本的组织学特征,以此来为临床诊断提供帮助,为临床治疗提供依据。此外CD4、CD25、叉头样转录因子Foxp3(foxhead box protein 3)、雌激素受体α(ERa)及转化生长因子β1 (TGF-β1)与自身免疫性疾病的关系倍受关注,尤其是CD4+、CD25+的Treg及Foxp3在自身免疫性疾病发病机制中的作用更是研究焦点中的热中之热。为此我们比较它们在各组肝活检中的表达情况来探讨其作用及意义。
方法
应用HE染色进行29例I型AIH、18例PBC、15例CHB肝穿标本的组织学特征分析,应用免疫组化方法检测各组CD4、CD25、Foxp3、ERa及TGF-β1的表达情况,设8例正常肝组织(非肝病患者尸检来源的肝组织)为对照。
结果
1. AIH、PBC、CHB三组中羽毛状变性发生率分别为3.45%、33.33%、6.67%,PBC组明显高于AIH组(P<0.05)；桥接坏死发生率分别为27.59%、50.00%、13.33%,PBC组明显高于乙肝组(P<0.05)；胆栓发生率分别为6.92%、44.44%、6.67%,PBC组明显高于AIH和CHB组(P<0.01、P<0.05)；胆管增生发生率分别为34.48%、61.11%、13.33%,PBC组明显高于AIH和CHB组(P<0.05)。
2.CD4在各组的表达PBC组高于乙肝组(P<0.01)。
3.CD25在各组的表达差异没有统计学意义(P>0.05)。
4. Foxp3组间阳性胆管数PBC组高于正常组(P<0.01),阳性细胞数各组间差异没有统计学意义(P>0.05)。
5.ERα在各组的表达AIH和PBC组高于正常组(P<0.01)。
6. TGF-B1表达：在PBC组汇管区阳性细胞数高于肝小叶(P<0.05),各组间汇管区阳性细胞数PBC组高于其它三组(P<0.01),在正常组肝小叶内阳性细胞数高于汇管区(P<0.01)。
结论
1.不同类型的自身免疫性肝病的组织学特征有所不同,AIH以肝小叶界板的损伤为主要改变,而PBC以胆管上皮损伤为主要特征,比如羽毛状变性,胆栓及胆管增生。
2. CD4+T细胞可能在PBC发生的免疫机制中起到重要作用。
3.ERa及TGF-β1可能介导和促进了自身免疫性肝病的发生发展。
AIM
In recent years the different type hepatitis's differential diagnosis was the difficult problem which clinical urgent needed to solve, particularly each AILD diagnosis was especially difficult, although the International Immunity Hepatitis Group has formulated a set of diagnosis standard, and after many times revised the diagnosis rate was improved, the diagnosis was also more reliable, but we will also meet the situation which the diagnoses and the clinical manifestation was not correspond, or some other phenomenon could not be explained in the course of treatment. Based on this many clinicians seeked help to pathology doctor and hoped that through analyzing the pathology characteristic of the liver' specimen to be able to give them more explicit diagnosis and guide the treatment direction. We analyzed, although each kind of hepatitis has many similar histology performance, but has respectively the relative different histology characteristic, for this reason we summarized and induced the histology characteristic of the HE stained several kind of common hepatitis (AIH、PBC、CHB),and strived for to provide the help for the clinical diagnosis and the clinical care. In addition the relationship of CD4、CD25、the foxhead box protein 3 (Foxp3)、the estrogen acceptor Alpha (ERa) and the transformation growth factorβ1 (TGF-B 1) with the autoimmune disease was received much attention, Especially the function of the CD4+ CD25+ Treg and Foxp3 in the pathogenesis of the autoimmune disease was the studing focus.For that we explored the expression and significance of them in above the autoimmune liver disease.
METHODS
Histological analysis of liver biopsy specimens from 29 patients with AIH,18 patients with PBC,15 patients with CHB, and immunohistochemistry technique was used to detect the expression of CD4、CD25、FoxP3、ERaand TGF-β1 in above 3 groups and 8 normal. RESULTS
1. The incidence of the feathery degeneration are 3.45%、33.33%、6.67%, PBC
was higher than AIH (P<0.05), the incidence of the bridging necrosis are27.59%、 50.00%、13.33%, PBC was higher than CHB (P<0.05), the incidence of bile thrombus are 6.92%、44.44%、6.67%, PBC was higher than AIH and CHB(P<0.01、P<0.05); and the incidence of proliferation of small bile duct were different significantly in AIH, PBC and CHB (34.48%、61.11%、13.33%) PBC was higher than AIH and CHB (P<0.05)
2. The expression of CD4 for PBC was higher than CHB(P<0.01),
3. The difference of the expression of CD25 was not statistically significant in above groups (P>0.05),
4. The expression of Foxp3 in bile duct epithelial was significantly different in above groups, PBC are higher than normal (P<0.01) but in cell the difference was not statistically significant (P>0.05).
5. The expression of ERa was significantly different in above 4 groups, AIH、PBC are higher than normal (P<0.01).
6. For PBC, the expression of TGF-β1 was significantly higher in portal area than in hepatic lobule(P<0.05)and also significantly higher than other3group(P<0.01), For normal, the expression of TGF-β1 was significantly higher in hepatic lobule than in portal area (P<0.01)
CONCLUSION
1. Different autoimmune liver disease have different histological features, the feature of AIH is interface hepatitis, the feature of PBC is destructive cholangitis.
2. CD4 regulatory T cells may play a important role in the pathogenesis of PBC.
3. ERa and TGF-B1 may mediate and promote the occurrence and development of autoimmune liver disease.
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