Current directions in autoimmunity最新文献

{"title":"TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells.","authors":"Xin Chen,&nbsp;Joost J Oppenheim","doi":"10.1159/000289201","DOIUrl":"https://doi.org/10.1159/000289201","url":null,"abstract":"<p><p>TNF-alpha (TNF) is a pleiotropic cytokine which can have proinflammatory or immunosuppressive effects, depending on the context, duration of exposure and disease state. The basis for the opposing actions of TNF remains elusive. The growing appreciation of CD4+FoxP3+ regulatory T cells (Tregs), which comprise approximately 10% of peripheral CD4 cells, as pivotal regulators of immune responses has provided a new framework to define the cellular and molecular basis underlying the contrasting action of TNF. TNF by itself can overcome the profound anergic state of T cell receptor-stimulated Tregs. Furthermore, in concert with IL-2, TNF selectively activates Tregs, resulting in proliferation, upregulation of FoxP3 expression and increases in their suppressive activity. Both human and mouse Tregs predominantly express TNFR2, making it possible for TNF to enhance Treg activity, which helps limit the collateral damage caused by excessive immune responses and eventually terminates immune response. TNFR2-expressing CD4+FoxP3+ Tregs comprise approximately 40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"119-34"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNF-alpha and obesity.","authors":"T Tzanavari,&nbsp;P Giannogonas,&nbsp;Katia P Karalis","doi":"10.1159/000289203","DOIUrl":"https://doi.org/10.1159/000289203","url":null,"abstract":"<p><p>Obesity, an epidemic of our times with rates rising to alarming levels, is associated with comorbidities including cardiovascular diseases, arthritis, certain cancers, and degenerative diseases of the brain and other organs. Importantly, obesity is a leading cause of insulin resistance and type 2 diabetes. As emerging evidence has shown over the last decade, inflammation is one of the critical processes associated with the development of insulin resistance, diabetes and related diseases, and obesity is now considered as a state of chronic low-grade inflammation. Adipose tissue, apart from its classical role as an energy storage depot, is also a major endocrine organ secreting many factors, whose local and circulating levels are affected by the degree of adiposity. Obesity leads to infiltration of the expanded adipose tissue by macrophages and increased levels in proinflammatory cytokines. The first indication for increased cytokine release in obesity was provided by the identification of increased expression of TNF-alpha, a proinflammatory cytokine, in the adipose tissue of obese mice in the early 1990s. TNF-alpha is expressed in and secreted by adipose tissue, its levels correlating with the degree of adiposity and the associated insulin resistance. Targeting TNF-alpha and/or its receptors has been suggested as a promising treatment for insulin resistance and type 2 diabetes. This review will summarize the available knowledge on the role of TNF-alpha in obesity and related processes and the potential implications of the above in the development of new therapeutic approaches for obesity and insulin resistance. Recent data from clinical studies will also be described together with late findings on the pathogenesis of obesity and insulin resistance.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"145-56"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type I interferon: a new player in TNF signaling.","authors":"Anna Yarilina,&nbsp;Lionel B Ivashkiv","doi":"10.1159/000289199","DOIUrl":"https://doi.org/10.1159/000289199","url":null,"abstract":"<p><p>TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-beta-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"94-104"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional control of the TNF gene.","authors":"James V Falvo,&nbsp;Alla V Tsytsykova,&nbsp;Anne E Goldfeld","doi":"10.1159/000289196","DOIUrl":"https://doi.org/10.1159/000289196","url":null,"abstract":"<p><p>The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor kappaB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"27-60"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNF and bone.","authors":"Jean-Pierre David,&nbsp;Georg Schett","doi":"10.1159/000289202","DOIUrl":"https://doi.org/10.1159/000289202","url":null,"abstract":"<p><p>Bone is subject to permanent remodeling during development and through life. This activity is essential for (a) proper shaping and growth of each bone during development; (b) maintenance of bone mass as well as structural integrity of the micro architecture of bone through adult life, and (c) tissue repair needed for healing of fracture as well as of micro-damage. In addition to genetically linked rare developmental diseases, disturbances in bone remodeling are causing common bone pathologies, which severely impair the quality of life of patients. Among them are postmenopausal osteoporosis and local as well as systemic bone loss observed in chronic inflammatory diseases such as rheumatoid arthritis. The role of TNF-alpha in mediating bone remodeling will be presented and discussed in this chapter.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"135-44"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions.","authors":"Petros P Sfikakis","doi":"10.1159/000289205","DOIUrl":"https://doi.org/10.1159/000289205","url":null,"abstract":"<p><p>Results from clinical trials of biologic anti-TNF drugs performed in the late 1990s confirmed the biological relevance of TNF function in the pathogenesis of chronic noninfectious inflammation of joints, skin and gut, which collectively affects 2-3% of the population. Up to April 2009, more than two million patients worldwide have received the first marketed drugs, namely the monoclonal anti-TNF antibodies infliximab and adalimumab and the soluble TNF receptor etanercept. All three are equally effective in rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, but, for not clearly defined reasons, only the monoclonal antibodies are effective in inflammatory bowel disease. About 60% of patients who do not benefit from standard nonbiologic treatments for these diseases respond to TNF antagonists. Less than half of responding patients achieve complete remission of disease. Importantly, some of those patients with rheumatoid arthritis in whom long-term anti-TNF therapy induced disease remission remain disease-free after discontinuation of any kind of treatment. There are not yet reliable predictors of which patients will or will not respond on anti-TNF therapy, whereas subsequent loss of an initial clinical response occurs frequently. The spectrum of efficacy anti-TNF therapies widens to include diseases such as systemic vasculitis and sight-threatening uveitis. While paradoxical new adverse effects are recognized, i.e. exacerbation or development of new onset psoriasis, reactivation of latent tuberculosis remains the most important safety issue of anti-TNF therapies. Clinical practice guidelines and consensus statements on the criteria of introduction, duration of treatment and cessation of TNF antagonists, including safety issues, are under constant revision as data from longer periods of patient exposure accumulate. It is hoped that more efficacious drugs that will ideally target the deleterious proinflammatory properties of TNF without compromising its protective role in host defense and (auto)immunity will be available in the near future.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"180-210"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms of TNF function in models of inflammation and autoimmunity.","authors":"Maria Apostolaki,&nbsp;Maria Armaka,&nbsp;Panayiotis Victoratos,&nbsp;George Kollias","doi":"10.1159/000289195","DOIUrl":"https://doi.org/10.1159/000289195","url":null,"abstract":"<p><p>The TNF/TNF receptor (TNFR) system has a prominent role in the pathogenesis of chronic inflammatory and autoimmune disorders. Extensive research in animal models with deregulated TNF expression has documented that TNF may initiate or sustain inflammatory pathology, while at the same time may exert immunomodulatory or disease-suppressive activities. The TNF/TNFR system encompassing both the soluble and the transmembrane form of TNF with differential biological activities, as well as the differential usage of its receptors, mediating distinct functions, appears to confer complexity but also specificity in the action of TNF. The inherent complexity in TNF-mediated pathophysiology highlights the requirement to address the role of TNF taking into account both proinflammatory tissue-damaging and immunomodulatory functions in a cellular and receptor-specific manner. In this review, we discuss our current understanding of the involvement of TNF in chronic inflammation and autoimmunity, focusing on TNF-mediated cellular pathways leading to the pathogenesis or progression of joint and intestinal inflammatory pathology. Knowledge of the mechanisms by which TNF either initiates or contributes to disease pathology is fundamentally required for the design of safe and effective anti-TNF/TNFR therapies for human inflammatory and autoimmune disorders.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"1-26"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28728882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Posttranscriptional regulation of TNF mRNA: a paradigm of signal-dependent mRNA utilization and its relevance to pathology.","authors":"Panagiota Stamou,&nbsp;Dimitris L Kontoyiannis","doi":"10.1159/000289197","DOIUrl":"https://doi.org/10.1159/000289197","url":null,"abstract":"<p><p>The relationship between TNF and immune pathology forced an intense research into the regulation of its biosynthesis that extends to multiple mechanisms controlling the utilization of its mRNA. These posttranscriptional mechanisms gradually and variably impose a series of flexible rate-limiting controls to modify the abundance of the TNF mRNA and the rate of its translation in response to environmental signals. Mechanistically, these controls consist of signaling networks converging to RNA-binding proteins and microRNAs, which in turn target a code of secondary or tertiary ribonucleotide structures located on the TNF mRNA. The outcome of these interactions is the stringent control of this mRNA's maturation, localization, turnover and translation. A wealth of molecular and genetic data highlighted that if these posttranscriptional interactions fail, they perturb cellular responses to provide the impetus for TNF-mediated inflammatory disease. Here, we highlight the parameters guiding the posttranscriptional regulation of TNF mRNA and their relevance to homeostasis and pathology.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"61-79"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28728883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of TNF in pathologies induced by nuclear factor kappaB deficiency.","authors":"Katerina Vlantis,&nbsp;Manolis Pasparakis","doi":"10.1159/000289198","DOIUrl":"https://doi.org/10.1159/000289198","url":null,"abstract":"<p><p>TNF is a potent cytokine with an important role in the regulation of a multitude of cellular responses and in coordinating immune and inflammatory reactions. TNF exerts its effects by binding to the TNFR1- and TNFR2-specific cell surface receptors, which activate a number of intracellular signaling cascades including the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways. Activation of NF-kappaB mediates many of the functions of TNF by transmitting information from the cell surface TNF receptors to the nucleus, where it coordinates a gene expression program that allows the cell to survive and elicit its responses. The intimate interplay of TNF with the NF-kappaB signaling pathway is highlighted by results obtained in transgenic and knockout mice with defects in NF-kappaB signaling components, where TNF has been shown to contribute to different pathologies observed in these mice. This chapter focuses on the function of TNF in pathologies induced by NF-kappaB deficiency and discusses the implications of these findings for our understanding of inflammatory diseases.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"80-93"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cells as sources and targets of TNF: implications for immunity and autoimmunity.","authors":"Ioannis Chatzidakis,&nbsp;Clio Mamalaki","doi":"10.1159/000289200","DOIUrl":"https://doi.org/10.1159/000289200","url":null,"abstract":"<p><p>TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"11 ","pages":"105-18"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000289200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28729930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}