Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C

Background and Aim: As a newly identified subset of T helper cells, T‐helper 17 cells (Th17) are major mediators of inflammation‐associated disease. Some reports have revealed significantly increased Th17 cells in hepatitis B virus‐infected patients, and a recent study has demonstrated that hepatitis C virus (HCV)‐specific Th17 cells can be induced in vitro and regulated by transforming growth factor‐β. This study attempted to characterize the role of Th17 cells in the disease progression of chronic hepatitis C (CHC). Methods: The current study enrolled 53 patients with CHC and 23 healthy controls, in which the circulating and liver‐infiltrating Th17 cells were monitored. Results: We found that CHC patients had increased proportions of both circulating and liver‐infiltrating Th17 cells compared to healthy individuals, and both measures of Th17 cells were correlated with severity of liver inflammation. We further demonstrated that the HCV‐specific Th17 cells were correlated with liver damage but not HCV viral replication. Conclusions: Such a correlation between the severity of liver damage of CHC and Th17 cells illustrated in this study sheds some light on the understanding of the pathogenesis of CHC.     

Pivotal roles of the interleukin-23/T helper 17 cell axis in hepatitis B

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. Research interest in these cells was piqued when hepatitis B virus (HBV)-infected patients were found to have significantly elevated Th17 cell frequency, and it was proposed that these proinflammatory effectors may promote the HBV disease process. Subsequent studies have revealed that Th17 cells drive immune-mediated pathology of HBV infection, and that IL-23 amplifies the Th17 cell responses and liver inflammation. As a result, new pathways of HBV-mediated liver damage have been elucidated, along with promising new targets of molecular therapeutic strategies. Ongoing research is also providing significant insights into the target cells and underlying mechanisms of Th17-secreted cytokines, including IL-17A, IL-21 and IL-22. Future studies are expected to fully uncover the cytokine-related mechanisms mediating HBV-induced liver inflammation, and to determine the yet unknown cell source of IL-23. This review will draw upon the most up-to-date available data to discuss the putative roles and detailed mechanisms of IL-23/Th17 cell axis in HBV infection-mediated liver pathogenesis.     

Multiple sclerosis

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.     

The inflammatory and immune response to Helicobacter pylori infection

Lifelong Helicobacter pylori infection and its associated gastric inflammation underlie peptic ulceration and gastric carcinogenesis. The immune and inflammatory responses to H. pylori are doubly responsible: gastric inflammation is the main mediator of pathology, and the immune and inflammatory response is ineffective, allowing lifelong bacterial persistence. However, despite inducing gastric inflammation, most infections do not cause disease, and bacterial, host and environmental factors determine individual disease risk. Although H. pylori avoids many innate immune receptors, specific virulence factors (including those encoded on the cag pathogenicity island) stimulate innate immunity to increase gastric inflammation and increase disease risk. An acquired T helper 1 response upregulates local immune effectors. The extent to which environmental factors (including parasite infection), host factors and H. pylori itself influence T-helper differentiation and regulatory T-cell responses remains controversial. Finally, effective vaccines have still not been developed: a better understanding of the immune response to H. pylori may help.     

Immunology of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelin-reactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by meningeal lymphoid follicles with germinal centers.     

Immune response and tolerance during chronic hepatitis B virus infection

The hepatitis B virus (HBV) is a hepatotropic non-cytopathic DNA virus that despite the presence of an effective prophylactic vaccine is estimated to infect 300 million people, with a particularly high prevalence in Asia and Africa. It causes liver diseases that vary greatly in severity from person to person. Some subjects control infection efficiently and clear the virus from the bloodstream either without clinically evident liver disease or with an acute inflammation of the liver (acute hepatitis) that can resolve without long-term clinical sequelae. Other patients fail to clear the virus and develop chronic infection. Most chronically infected patients remain asymptomatic without life-threatening liver disease but 10–30% develop liver cirrhosis with possible progression to liver cancer . Outcome of infection and the pathogenesis of liver disease are determined by virus and host factors, which have been difficult tofully elucidate because the host range of HBV is limited to man and chimpanzees. However, the study of animal models of related Hepadnavirus infections and transgenic mouse able to express individual HBV genes or replicate the entire viral genome have clarified several aspects connected to HBV infection. Furthermore, the ability to analyze many immunological phenomena ex vivo through direct quantification of Ag-specific T cells in humans and chimps has considerably increased our knowledge of HBV pathogenesis. Here, we will discuss the distinctions of HBV adaptive immunity between resolved and persistently infected patients and the host/viral factors that can cause and maintain them.     

Pathogénie des vascularites associées aux ANCA en 2021 : mise au point

Anticytoplasmic neutrophil antibodies (ANCA)-associated vasculitis (AAV) are rare systemic immune-mediated diseases characterized by small vessel necrotizing vasculitis and/or respiratory tract inflammation. Over the last 2 decades, anti-MPO vasculitis mouse model has enlightened the role of ANCA, neutrophils, complement activation, T helper cells (Th1, Th17) and microbial agents. In humans, CD4T cells have been extensively studied, while the dramatic efficacy of rituximab demonstrated the key role of B cells. Many areas of uncertainty remain, such as the driving force of GPA extra-vascular granulomatous inflammation and the relapse risk of anti-PR3 AAV pathogenesis. Animal models eventually led to identify complement activation as a promising therapeutic target. New investigation tools, which permit in depth immune profiling of human blood and tissues, may open a new era for the studying of AAV pathogenesis.     

Environmental factors in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease more commonly found in women (with most cases being diagnosed in the fourth to fifth decades of life) that share peculiar features. Among these, serum antimitochondrial autoantibodies (AMA), serum hyper-immunoglobulin M, and progressive destruction of intrahepatic bile ducts are the most common clinical findings. The pathogenesis of the selective destruction of small-duct biliary epithelial cells is still unknown, although an autoimmune mechanism appears likely due to the detection of autoreactive T and B cells. Genetic background is critical in determining susceptibility to the disease, despite the limited associations with alleles within the major histocompatibility complex. However, among other observations, incomplete concordance of the disease in monozygotic twins and epidemiology strongly support a role for environmental factors in PBC onset. Molecular mimicry by either infectious agents or chemicals has been proposed to induce breakdown of immune tolerance in genetically predisposed individuals. This hypothesis is further supported by clinical (risk factors) and experimental evidence obtained also in animal models.     

Cytokines and respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a single-stranded negative sense RNA virus in the Paramyxovirus family that is a major cause of morbidity and life-threatening lower respiratory tract disease in infants and young children worldwide. RSV is recognized as a ubiquitous virus having considerable worldwide disease burden. Studies investigating the immune response and disease pathogenesis associated with infection attribute the interplay of the virus with host factors, particularly cytokines and chemokines, in inflammation, disease, and immune effector processes. There is convincing evidence that Th1- and Th2-type cytokine patterns determine the type of immune response to RSV infection, and that the spectrum of cytokine expression affects control mechanisms involved in the regulation of disease pathogenesis and chronicity. Thus, there is a critical need to identify virus and host mechanisms that regulate cytokine expression to allow for intervention strategies to control disease pathogenesis. In this report, we discuss the role of cytokines and chemokines in the response to RSV infection, and the potential role for suppressor of cytokine signaling (SOCS) proteins in regulating these responses.     

T helper type-2 cells induce ileal villus atrophy,goblet cell metaplasia,and wasting disease in T cell-deficient mice

BACKGROUND & AIMS: T helper (Th) 1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4(+)CD45RB(Hi) (RB(Hi)) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2-deficient (RAG(-/-)) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. METHODS: RB(Hi) T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-gamma-defective [IFN-gamma(-/-)]) with or without B cells were transferred to T cell receptor (TCR)-beta and delta-chain-defective (TCR(-/-)) or SCID mice. RESULTS: Transfer of Wt RB(Hi) T cells induced wasting disease with severe colitis in the TCR(-/-) mice. In contrast, IFN-gamma(-/-) RB(Hi) T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-gamma(-/-) RB(Hi) T cells for ileal lesions to develop. Treatment of TCR(-/-) recipients of IFN-gamma(-/-) RB(Hi) T cells with anti-IL-4 mAb abrogated both the wasting disease and the villus atrophy. CONCLUSIONS: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells.     

Hepatocellular carcinoma and hepatitis B virus

Chronic hepatitis B is the most common cause of hepatocellular carcinoma (HCC) in Asia. Integration of hepatitis B virus (HBV) genome is likely an early event of carcinogenesis. The integrated HBV genome may activate neighboring cellular genes directly to offer a selective growth advantage to the liver cells. Production of hepatitis B X protein can act as a transactivator on various cellular genes for tumor development. Hepatic inflammation and cirrhosis also favors the process of carcinogenesis. Various viral factors associated with hepatocellular carcinoma development include HBV genotype, basal core promoter mutations, and high viral load. Polymorphisms at the androgen receptor-regulating genes and cytokine genes are possible host factors associated with HCC. This review article summarizes the pathogenesis of HBV-related carcinogenesis and the viral and host factors that may increase the risk of HCC development.     

Osteoporosis in rheumatic diseases

Rheumatic diseases, characterized by chronic inflammation and damage to various organs and systems, include systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis and other connective tissue diseases. Bone is a target in many inflammatory rheumatic diseases. In recent years, the survival of patients with rheumatic diseases has increased markedly and the relationship between rheumatic diseases and osteoporosis (OP) has become more prominent. OP and related fragility fractures increase the morbidity and mortality of rheumatic disease. The cause of OP in rheumatic diseases is complex. The pathogenesis of OP in rheumatic diseases is multifactorial, including disease and treatment-related factors. Osteoimmunology, a crosstalk between inflammatory and bone cells, provides some insight into the pathogenesis of bone loss in systematic inflammatory diseases. The aim of this article is to review different risk factors in rheumatic diseases. Several factors play a role, such as chronic inflammation, immunological factors, traditional factors, metabolism and drug factors. Chronic inflammation is the most important risk factor and drug treatment is complex in patients with OP and rheumatic disease. Attention should be paid to bone loss in rheumatic disease. Optimal treatment of the underlying rheumatic disease is the first step towards prevention of OP and fractures. Apart from that, a healthy lifestyle is important as well as calcium and vitamin D supplementation. Bisphosphonates or denosumab might be necessary for patients with a low T score.     

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from individuals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8(+) T cells from the liver producing IL-10 (P = 0.044), primarily in hepatitis B e antigen positive (HBeAg(+)) individuals. A positive correlation resulted between the magnitude of HBV-specific TNF-alpha(+) CD4(+) T cells in the liver and the degree of liver inflammation and fibrosis (P = 0.002 and P = 0.006, respectively). Conclusion: The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.     

A new look at viruses in type 1 diabetes

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed.     

Multiple sclerosis

Multiple sclerosis is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs but is not durable. Hence, the early course of disease is characterised by episodes of neurological dysfunction that usually recover. However, over time the pathological changes become dominated by widespread microglial activation associated with extensive and chronic neurodegeneration, the clinical correlate of which is progressive accumulation of disability. Paraclinical investigations show abnormalities that indicate the distribution of inflammatory lesions and axonal loss (MRI); interference of conduction in previously myelinated pathways (evoked electrophysiological potentials); and intrathecal synthesis of oligoclonal antibody (examination by lumbar puncture of the cerebrospinal fluid). Multiple sclerosis is triggered by environmental factors in individuals with complex genetic-risk profiles. Licensed disease modifying agents reduce the frequency of new episodes but do not reverse fixed deficits and have questionable effects on the long-term accumulation of disability and disease progression. We anticipate that future studies in multiple sclerosis will provide a new taxonomy on the basis of mechanisms rather than clinical empiricism, and so inform strategies for improved treatment at all stages of the disease.     

Environmental factors in the pathogenesis of primary Sjögren's syndrome

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease in which exocrine organs, primarily the salivary and lacrimal glands, are targets of chronic inflammation, leading to severe dryness of eyes and mouth. Fatigue and arthralgia are also common, and extraglandular manifestations involving the respiratory, nervous and vascular systems occur in a subset of patients. Persistent activation of the type I interferon system, and autoreactive B and T cells with production of disease‐associated autoantibodies are central to the pathogenesis. Genetic polymorphisms that associate with an increased risk of SS have been described, though the risk‐increase contributed by the respective variant is generally low. It is thus becoming increasingly clear that genetics cannot alone account for the development of SS and that other, presumably exogenous, factors must play a critical role. Relatively few studies have investigated exposure to potential risk factors prior to SS disease onset. Rather, many factors have been studied in prevalent cases. In this review, we summarize current literature on exogenous factors in the pathogenesis of SS including infections, hormones, smoking, solvents and additional compounds. We delineate for which factors there is current evidence of increased disease risk, and for which our present knowledge is confined to suggesting their role in SS pathogenesis. Finally, we outline future perspectives in the continued search for environmental risk factors for SS, a research area of great importance considering the possibilities for preventive measures.     

Th9与支气管哮喘

支气管哮喘（简称哮喘）是一种由多种细胞如淋巴细胞、嗜酸粒细胞、肥大细胞等及其细胞组分参与的气道慢性炎症疾患,Th2细胞被认为是哮喘发病机制中的主要效应细胞。长期以来,白介素9（IL-9）都被认为是Th2类细胞因子,在变应性疾病,尤其是过敏性哮喘、变应性鼻炎等发病机制中起着重要的作用。近年来研究发现,机体内可能存在着一群新型的不同于目前已知Th1、Th2及Th17等效应细胞,被称之为＂Th9＂细胞。Th9细胞在转化生长因子-β及IL-4联合刺激下分化而来,具有分泌IL-9和IL-10的能力。Th9细胞作为效应性T细胞,在促进组织炎症发生的过程中起着重要作用。现就Th9细胞的生物学功能及与哮喘的关系进行简要综述。