Th17 cells and their associated cytokines in liver diseases

T helper 17 (Th17) cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease. The functions of Th17 cells are mediated via the production of several cytokines including interleukin (IL)-17 and IL-22. Recent studies show that the frequency of IL-17⁺ cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease, viral hepatitis and hepatocellular carcinoma. IL-17 receptor is expressed virtually on all types of liver cells, while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver. IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines, while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.     

IL-17: A new actor in IFN-driven systemic autoimmune diseases

Systemic autoimmune diseases such as systemic lupus erythematosus are type I IFN-driven diseases with exaggerated B-cell responses and autoantibody production. Th17 cells, a T-helper-cell subset with high inflammatory capacity, was initially discovered and characterized in the context of experimental autoimmune encephalomyelitis - an animal model of multiple sclerosis. There is now emerging evidence that Th17 cells, and more generally IL-17 and IL-17-producing cells, may play a role in the pathogenesis of type I IFN-driven systemic autoimmune diseases such as lupus. Here, we review the different studies suggesting a role for IL-17 and IL-17-producing cells in systemic autoimmune diseases, both in humans and in animal models, and we consider the possible mechanisms by which these cells may contribute to disease. We also discuss the hypothesis that type I IFN and IL-17 act in concert to sustain and amplify autoimmune and inflammatory responses, making them a dangerous combination involved in the pathogenesis of systemic autoimmune diseases.     

Interleukin-17 and its expanding biological functions

Interleukin-17 (IL-17) and IL-17-producing cells have been shown to play important roles in inflammation and the immune response. IL-17 is believed to be mainly produced by T helper 17 (Th17) cells, a unique helper T-cell subset different from Th1 and Th2 cells. Other subsets of T cells such as γδT and natural killer T (NKT) cells have also been found to produce IL-17 in response to innate stimuli. IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines, cytokines, matrix metalloproteinases (MMPs) and antimicrobial peptides from mesenchymal and myeloid cells. This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo. Furthermore, increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies, autoimmune diseases, allograft transplantation and even malignancy. They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte (CTL) responses against cancer. Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.     

自身免疫肝病患者抗中性粒细胞胞浆抗体的检测及临床意义

探讨抗中性粒细胞胞浆抗体(anti-neutrophil cytoplastic antibodies,ANCA)对自身免疫肝病的临床意义。应用间接免疫荧光法和斑点法检测149例自身免疫性肝病患者[自身免疫性肝炎(autoimmune hepatitis,AIH)患者57例,原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)患者42例,不明原因肝损患者50例]的ANCA和抗可提取性核抗原抗体(extract-able nuclear antigen,ENA),进而用ELISA法分析60例ANCA阳性的自身免疫肝病患者的ANCA抗原谱。以200例健康献血员为正常对照。结果ANCA在AIH、PBC、不明原因肝损中的阳性率分别为81%、40%、30%,其中非典型性pANCA的阳性率依次为70%、40%、28%。AIH组与PBC组及AIH组与不明原因肝损组间非典型性pANCA的阳性率有显著性差异(P<0.01),但PBC组与不明原因肝损组间差异不显著(P>0.05)。各疾病组ANCA抗原谱如下:AIH组中,乳铁蛋白3%阳性,MPO 11%阳性,组织蛋白酶G和BPI的阳性率分别为11%、17%;PBC组中,弹性蛋白酶和组织蛋白酶G阳性率均为5%,BPI的阳性率为16%;不明原因肝损组中,BPI阳性率为17%。大多数自身免疫性肝病患者非典型性pANCA为阳性(28%~70%),且伴有特征性自身抗体。注重非典型性pANCA的检测对明确诊断自身免疫肝病及其分类有很大的帮助。     

IL-23/Th17轴与自身免疫性疾病

既往研究认为,自身免疫性疾病主要是Th1/Th2平衡失调所致,但就Th1细胞亚群的研究结果并不能完全解释自身免疫性疾病的发病机制.Th17细胞是新发现的CD4+辅助性T细胞亚群,IL-23是Th17细胞赖以存在,并维持其稳态及扩增,促进其分泌IL-17的必需细胞因子.目前认为,越来越多的研究表明,IL-23/Th17轴参与了多种自身免疫性疾病的病理过程.     

The roles of IL-17A in inflammatory immune responses and host defense against pathogens

Summary: T-helper 17 (Th17) cells are a newly discovered CD4⁺ helper T-cell subset that produces interleukin-17A (IL-17A) and IL-17F. IL-17A plays important roles in allergic responses such as delayed-type hypersensitivity, contact hypersensitivity, and allergic airway inflammation. IL-17A promotes inflammation by inducing various proinflammatory cytokines and chemokines, recruiting neutrophils, enhancing antibody production, and activating T cells. IL-17A expression is also augmented in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Using mouse models of these diseases, we found that IL-17A plays a central role in their development. IL-6 is required for the development of Th17 cells and tumor necrosis factor functions downstream of IL-17A during the effector phase. IL-1 is important both for developing Th17 cells and eliciting inflammation. Th17 cells, like Th1 and Th2 cells, are involved in host defense against infections, but the contribution of these Th subsets to defense mechanisms differs among pathogens. The roles of IL-17F remain largely unknown. In this review, we introduce how IL-17A/IL-17F are involved in inflammatory immune responses and host defense mechanisms and discuss their relationship with other cytokines in the development of inflammatory and infectious diseases.     

Th17细胞与自身免疫性疾病关系的研究进展

CIM+辅助性T细胞(Th)通常可分为Th0、Th1、Th2和Th3等细胞亚群.Th1细胞过去一直被认为是介导迟发型超敏反应、引起组织损伤的主要细胞.近年来发现一群主要分泌白细胞介素-17(IL-17)、不同于Th1/Th2的新型CD4+T细胞亚群-11117细胞.Th17细胞与自身免疫性疾病、肿瘤、炎性反应和移植排斥等的发生发展关系密切.     

Th17细胞与自身免疫性疾病

Th17细胞是近年发现的不同于Th1细胞和Th2细胞的新型CD4^＋T细胞亚群。活化的Th17细胞可分泌IL—17、肿瘤坏死因子-α（TNF—α）、IL-6、粒-单核细胞集落刺激因子（GM—CSF）等多种促炎症因子,Th17细胞不适当的激活与多种自身免疫性疾病和过敏性疾病密切相关。在体内阻断Th17细胞的分化、扩增及其相关细胞因子可预防、延缓或阻止自身免疫性疾病的发生、发展。     

Th17细胞与肝脏疾病的研究进展

机体免疫系统是抵抗外来病原体和各种损害的防御系统,根据CD4^＋T细胞的功能经典地分为辅助性T细胞（Th1、Th2）、细胞毒性T细胞以及调节性T细胞（Treg）3个亚群。Th1介导细胞免疫,Th2介导体液免疫,而Treg则在维护机体免疫平衡中发挥重要作用。然而随着对自身免疫性疾病的研究,发现一群不同于Th1、Th2、Treg的新型CD4^＋T细胞亚群——Th17细胞。已证实Th17细胞与清除胞外病原体、炎症、自身免疫性疾病和肿瘤的发生发展有密切联系。随着人们对肝炎、肝纤维化和肝癌等肝病认识不断加深,这种新型的Th17细胞在这些疾病中发生发展的作用机制也不断的被研究者所关注。     

p19-targeted ABD-derived protein variants inhibit IL-23 binding and exert suppressive control over IL-23-stimulated expansion of primary human IL-17+ T-cells

Interleukin-23 (IL-23), a heterodimeric cytokine of covalently bound p19 and p40 proteins, has recently been closely associated with development of several chronic autoimmune diseases such as psoriasis, psoriatic arthritis or inflammatory bowel disease. Released by activated dendritic cells, IL-23 interacts with IL-23 receptor (IL-23R) on Th17 cells, thus promoting intracellular signaling, a pivotal step in Th17-driven pro-inflammatory axis. Here, we aimed to block the binding of IL-23 cytokine to its cell-surface receptor by novel inhibitory protein binders targeted to the p19 subunit of human IL-23. To this goal, we used a combinatorial library derived from a scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived p19-targeted variants, called ILP binders. From 214 clones analyzed by ELISA, Western blot and DNA sequencing, 53 provided 35 different sequence variants that were further characterized. Using in silico docking in combination with cell-surface competition binding assay, we identified a group of inhibitory candidates that substantially diminished binding of recombinant p19 to the IL-23R on human monocytic THP-1 cells. Of these best p19-blockers, ILP030, ILP317 and ILP323 inhibited IL-23-driven expansion of IL-17-producing primary human CD4^+?T-cells. Thus, these novel binders represent unique IL-23-targeted probes useful for IL-23/IL-23R epitope mapping studies and could be used for designing novel p19/IL-23-targeted anti-inflammatory biologics.     

Interleukin-17 producing mucosal associated invariant T cells - emerging players in chronic inflammatory diseases?

Mucosal associated invariant T (MAIT) cells are a population of evolutionarily conserved T cells, which express an invariant T cell receptor (TCR) and represent a significant subset of innate-like T cells in humans, yet their role in immunity is still emerging. Unlike conventional αβ T cells, MAIT cells are not restricted by MHC molecules, but instead uniquely recognize microbially derived vitamin metabolites presented by the MHC-I like molecule MR1. MAIT cells are enriched in mucosal sites and tissues including liver and adipose tissue where they are thought to play an important role in immunosurveillance and immunity against microbial infection. In addition to their putative role in antimicrobial immunity, recent research on MAIT cells, in particular IL-17 producing MAIT cells, has demonstrated their involvement in numerous chronic inflammatory conditions. In this review, we give an overview of the work to date on the function and subsets of MAIT cells. We also examine the role of IL-17 producing MAIT cells in chronic inflammatory diseases ranging from autoimmune conditions, metabolic diseases to cancer. Furthermore, we discuss the most recent findings from the clinic that might help deepen our understanding about the biology of MAIT cells.     

Interleukin-17 and systemic lupus erythematosus: current concepts

The emerging role of interleukin (IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, produced primarily by a new T helper cell subset termed ‘Th17’, has received considerable attention. Differentiation of Th17 cells is driven by the simultaneous presence of transforming growth factor-β and certain inflammatory cytokines (e.g. IL-6, IL-21), and recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. In this review, we focus on the information regarding IL-17 and systemic lupus erythematosus (SLE), a chronic autoimmune disease. The work that has explored the development and behaviour of IL-17-producing cells in SLE is discussed, and different mechanisms by which IL-17 could potentially augment inflammation and autoantibody production in the context of SLE are proposed.     

Peribiliary capillary plexus around interlobular bile ducts in various chronic liver diseases: An immunohistochemical and morphometric study

Peribiliary capillary plexus (PCP) is a network of capillaries which arise from the hepatic artery surrounding the intrahepatic bile ducts. We immunohistochemically investigated the density of PCP around interlobular bile ducts in various chronic liver diseases including primary biliary cirrhosis (PBC) (n = 47), autoimmune hepatitis (AIH) (n = 12), chronic hepatitis B (n = 16), chronic hepatitis C (n = 19), liver cirrhosis due to hepatitis B virus (n = 13), liver cirrhosis due to hepatitis C virus (n = 20), alcoholic hepatitis (n = 20), alcoholic liver cirrhosis (n = 17), using human liver biopsies fixed in formalin and embedded in paraffin wax. PCP was immunohistochemically detected by an endothelial marker, the CD34 antigen. The number of PCP per duct was 1.21 +/- 0.18 in normal livers. Compared with normal liver, vasopenia was observed in PBC and AIH, the number in which was 0.93 +/- 0.34 (P < 0.0001) and 0.82 +/- 0.38 (P < 0.005) per duct, respectively. In contrast, increased number of PCP was observed in liver cirrhosis due to hepatitis B or C virus, alcoholic hepatitis, and alcoholic liver cirrhosis, the number in which were 1.59 +/- 0.37 (P < 0.005), 1.55 +/- 0.52 (P < 0. 02), 1.38 +/- 0.23 (P < 0.02) and 1.61 +/- 0.33 (P < 0.002) per duct, respectively. These data suggest that PCP may be destroyed in autoimmune liver diseases, including PBC and AIH, but PCP may proliferate in other inflammatory and alcoholic liver diseases.     

IL-17RB enhances thyroid cancer cell invasion and metastasis via ERK1/2 pathway-mediated MMP-9 expression

IL-17RB, a member of the IL-17 receptor family that can be activated by IL-17B, has been proved to be involved in inflammatory diseases and cancers. However, the function of IL-17RB in thyroid cancer is still unknown. In this study, IL-17RB expression in thyroid cancer cell lines and tissues was examined by real-time PCR and western blot. The effects of IL-17RB on cell invasion and migration were determined by in vitro invasion and migration assays, while the effects of IL-17RB on cell metastasis were analyzed by in vivo experiments. The results showed that IL-17RB expression was upregulated in both thyroid cancer cells and tissues. IL–17B dose-dependently promoted the invasion, growth and migration of thyroid cancer cells, whereas knockdown of IL-17RB attenuated the effects of IL–17B in vitro. Moreover, IL-17RB was involved in the metastasis and growth of thyroid cancer cells in vivo. In addition, IL-17RB induced ERK1/2 activation and increased MMP-9 expression in vitro and in vivo. Inhibition of ERK1/2 pathway blocked the IL-17RB-mediated thyroid cancer cell invasion and MMP-9 expression. Together, our findings demonstrate that IL-17RB can enhance thyroid cancer cell invasion and metastasis via ERK1/2 pathway-mediated MMP-9 expression, suggesting that IL-17RB may act as a potential therapeutic target for thyroid cancer therapy.     

Th17与自身免疫性疾病

Th17细胞是新近发现的一类新型的能够分泌白细胞介素17(interleukin 17,IL-17)的CD4+T细胞。在IL-6和TGF-β作用下,初始CD4+T细胞分化为Th17细胞。分化成熟的Th17细胞可以分泌IL-17,IL-17F和IL-22等多种细胞因子,其中IL-17和IL-17F是其主要效应分子。临床前和临床数据均表明:Th17细胞与一些自身免疫性疾病(如系统性红斑狼疮、类风湿性关节炎、多发性硬化、银屑病、炎症性肠病、自身免疫性甲状腺疾病)有关。     

Th17细胞及白细胞介素17A在慢性气道炎症性疾病中的作用

长期以来,人们对于T淋巴细胞的研究集中在辅助性T细胞1型、2型(Th1、Th2)、调节性T细胞(Treg)以及细胞毒性T细胞(Tc)等亚群上。传统理论认为,Th1细胞介导细胞免疫,在抗胞内菌感染的过程中发挥作用;而Th2细胞介导体液免疫,与过敏性疾病以及抗寄生虫感染的过程紧密相关。Th1/Th2失衡被认为是许多疾病产生和发展的重要因素。     

Regulation of IL-10 and IL-17 mediated experimental autoimmune encephalomyelitis by S-nitrosoglutathione

In this study, we investigated IL-10 and IL-17 specific immunomodulatory potential of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in experimental autoimmune encephalomyelitis (EAE). In active EAE model, GSNO treatment attenuated EAE severity and splenic CD4⁺ T cells isolated from these mice exhibited decreased IL-17 expression without affecting the IFN-γ expression compared to the cells from untreated EAE mice. Similarly, adoptive transfer of these cells to nave mice resulted in reduction in IL-17 expression in the spinal cords of recipient mice with milder EAE severity. CD4⁺ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, still expressed lower levels of IL-17 under T_H17 skewing conditions, but expressed similar levels of IFN-γ under T_H1 skewing condition. Interestingly, under both T_H17 and T_H1 skewing condition, CD4⁺ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, expressed higher levels of IL-10 and adoptive transfer of these T_H17 and T_H1 skewed cells seemingly exhibited milder EAE disease. In addition, adoptive transfer of CD4⁺ T cells from GSNO treated EAE mice to active EAE mice also ameliorated EAE disease with induction of spinal cord expression of IL-10 and reduction in of IL-17, thus suggesting the participation of IL-10 mechanism in GSNO mediated immunomodulation. GSNO treatment of mice passively immunized with CD4⁺ T cells either from GSNO treated EAE mice or untreated mice further ameliorated EAE disease, supporting efficacy of GSNO for prophylaxis and therapy in EAE. Overall, these data document a modulatory role of GSNO in IL-17/IL-10 axis of EAE and other autoimmune diseases.     

A novel TH17-type cell is rapidly increased in the liver in response to acetaminophen-induced liver injury: TH17 cells and the innate immune response

Helper T (T_H) cells are an important part of the adaptive immune system. It is hypothesized that one type of helper T-cell, T_H17 cells, play an important role in idiosyncratic drug-induced liver failure, and it was found that interleukin (IL)-17, the signature cytokine of T_H17 cells, was elevated in most patients with idiosyncratic drug-induced liver failure. However, it was also found that IL-17 was elevated in some patients with acetaminophen (APAP)-induced liver failure. It is unlikely that APAP-induced liver failure is mediated by the adaptive immune system, but there are other cells such as macrophages and natural killer (NK) cells that also produce IL-17. Therefore, the phenotype of cells that produce IL-17 was studied in a mouse model of APAP-induced liver toxicity. To the authors’ surprise, it was found that most of the IL-17 producing cells in the liver were T_H17 cells, and they were increased within hours of APAP treatment. This is too fast for a response of the adaptive immune system. These data suggest that T_H17 cells can be part of the innate immune response; however, it is unclear what role they play in the pathogenesis of APAP-induced hepatotoxicity.