Cutting Edge Issues in Autoimmune Gastritis

Autoimmune gastritis is the outcome of a pathological CD4 T cell-mediated autoimmune response directed against the gastric H/K-ATPase. Silent initially, the gastric lesion becomes manifest in humans by the development of megaloblastic pernicious anemia arising from vitamin B12 deficiency. Cutting edge issues in this disease relate to its epidemiology, immunogenetics, a role for Helicobacter pylori as an infective trigger through molecular mimicry, its immunopathogenesis, associated organ-specific autoimmune diseases, laboratory diagnosis, and approaches to curative therapy.     

Cutting Edge Issues in Autoimmune Hepatitis

Autoimmune hepatitis is an inflammatory liver disease affecting mainly females and characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by circulating autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Seropositivity for smooth muscle and/or antinuclear antibody defines type 1 autoimmune hepatitis, while positivity for liver kidney microsomal type 1 antibody defines type 2 autoimmune hepatitis. The aetiology of autoimmune hepatitis is unknown, though both genetic and environmental factors are involved in its expression. The major mechanism of liver damage involves immune reactions against host liver antigens that are not adequately controlled by defective regulatory T cells. Current research aiming at potentiating regulatory T cell function in vitro to reconstitute tolerance in vivo has given promising results.     

Autoimmune Hepatitis and Sclerosing Cholangitis

Immune senescence is associated with a decline in T- and B-cell immune responses. It is, therefore, perhaps surprising that aging is linked to the appearance of serological and clinical autoimmunity. Here we review the mechanisms that contribute to the increase in inflammatory and autoimmune responses in aging. The bulk of this review will focus on aging-associated changes in epigenetic mechanisms, and in particular DNA methylation, as this has emerged as an attractive mechanistic link between aging and autoimmunity.     

Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis

1. Download : Download high-res image (271KB)
2. Download : Download full-size image

     

原发性硬化性胆管炎伴溃疡性结肠炎和克罗恩病患者的回顾性比较分析

目的 回顾性比较分析原发性硬化性胆管炎伴溃疡性结肠炎和克罗恩病患者的相关指标,为临床诊治提供依据.方法 选取2005年1月至2015年12月间我院收治的原发性硬化性胆管炎患者257例,原发性硬化性胆管炎伴克罗恩病患者72例.回顾性分析这两组患者的病历资料等信息并做统计分析.结果 两组患者的吸烟史、参与的胆总管数、生物制剂、结肠切除术、不典型增生、结肠癌、进展不良和/或癌组间比较具有统计学差异.CD患者与结肠切除术风险降低密切相关;Mayo评分是结肠切除术的保护性因素;而UC或CD诊断为PSC前持续时间、进展不良和/或癌及结肠癌是结肠切除术的危险因素.CD患者与结肠不典型增生和/或癌风险降低密切相关;而UC或CD诊断为PSC前持续时间是结肠不典型增生和/或癌的危险因素.结论 原发性硬化性胆管炎伴克罗恩病患者结肠切除术、结肠不典型增生及结肠癌风险比原发性硬化性胆管炎伴溃疡性结肠炎患者显著降低.     

The Immunophysiology and Apoptosis of Biliary Epithelial Cells: Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.     

Immunomodulatory Effect of Vancomycin on Treg in Pediatric Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin’s therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-β) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4?+?CD25hiCD127lo and CD4?+?FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC?+?IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC?+?IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.     

Development of Scaffold-Free Three-Dimensional Cholangiocyte Organoids to Study the Progression of Primary Sclerosing Cholangitis

1. Download : Download high-res image (186KB)
2. Download : Download full-size image

     

DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis

Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight‐junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in‐frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.     

Dysregulation of antioxidant responses in patients diagnosed with concomitant Primary Sclerosing Cholangitis/Inflammatory Bowel Disease

Objective

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease that is characterized by severe peri-biliary tract inflammation and fibrosis, elevated oxidative stress and hepatocellular injury. A hallmark of PSC patients is the concurrent diagnosis of Inflammatory Bowel Disease occurring in approximately 70%–80% of PSC patients (PSC/IBD). The objective of this study was to determine the impact of end stage PSC/IBD on cellular antioxidant responses and the formation of protein carbonylation.

Evaluation of the Role of MHC Class II Alleles,Haplotypes and Selected Amino Acid Sequences in Primary Sclerosing Cholangitis

Background and Aims: Genetic susceptibility to primary sclerosing cholangitis is associated with several different HLA haplotypes, though a single "shared" susceptibility allele has yet to be identified. Most recently, attention has focussed on the MICA alleles in close proximity to the HLA class I, B locus. However, although there are strong associations with MICA*008, implicating this or a closely linked allele as major risk factors, this explanation alone does not account for all of the MHC-encoded susceptibility and resistance to PSC. The present study re-examines HLA class II associations in a large single centre series of well-characterised PSC patients. The specific aims of the study were to test existing associations and to develop hypotheses which together may account for all, or the majority, of the MHC-encoded susceptibility in PSC. Methods: A total of 148 adult white northern European patients and 134 control subjects were studied. HLA DRB1, DQA1, DQB1 alleles and DRB1*04, DRB1*13 and DRB3 subtypes were determined by standard PCR-genotyping. Results: The primary associations with the DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*1301-DQA1*0103-DQB1*0603 haplotypes were confirmed (O.R.=2.69, p <0.0000025 and O.R.=3.8, p <0.0005). In addition the strong protective influence of the DRB1*04-DQB1*0302 haplotype was reaffirmed (O.R.=0.26, p <0.000025) and a previously unreported negative (i.e. protective) association with the DRB1*0701-DQB1*0303 haplotype was also demonstrated (O.R.=0.15, p <0.005). Further analysis suggested that susceptibility/resistance encoded by the second and third susceptibility haplotypes and by the two resistance haplotypes may be determined by specific amino acids at DQ&#103 -87 and DQ&#103 -55, respectively.     

原发性胆汁性胆管炎抗体及肝外疾病研究

原发性胆汁性胆管炎（PBC）是一种以胆汁淤积为特点的慢性自身免疫性肝病,可发展至肝硬化甚至肝衰竭,早期诊断PBC十分重要。PBC患者多数合并自身免疫性相关肝外疾病,包括干燥综合征、系统性硬化症、甲状腺疾病等。本文总结了PBC相关抗体及相关肝外疾病的研究,帮助临床医生对PBC的诊断及治疗。     

A Cutting Edge Overview: Psoriatic Disease

Psoriasis is a lifelong skin disease, affecting about 2% of the global population. Generalized involvement of the body (erythroderma), extensive pustular lesions, and an associated arthritis known as psoriatic arthritis (PsA) are severe complications of psoriasis. Genetic, immunologic, and environmental factors contribute to its pathogenesis. A complete understanding of the pathogenesis of psoriasis and psoriatic arthritis is lacking. Cytokines, chemokines, adhesion molecules, growth factors like NGF, neuropeptides, and T cell receptors all act in an integrated way to evolve into unique inflammatory and proliferative processes typical of psoriasis and PsA. Management of psoriasis requires exemplary skin care along with careful monitoring of arrays of comorbidities which includes arthritis and coronary artery disease. In many ways, psoriasis can be considered a model autoimmune disease. This statement itself is ironic considering that it was not recognized as immune mediated until relatively recently. Fortunately, the immunobiology has made enormous strides and there are now excellent therapeutic options for patients. In this thematic review, we have attempted to provide summaries of not only basic science and clinical research, but also an overview of future research directions.