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T Cell Costimulation and Coinhibition: Genetics and Disease


Genetic Progress Towards the Molecular Basis of Common Autoimmunity

Abstract: Identification of the genetic determinants that underlie autoimmune diseases implicates new biochemical pathways in disease pathogenesis. The authors describe how recent advances in genetic knowledge of autoimmunity have pointed to aberrant negative regulation of autoreactive T-cells as a key step in autoimmunity. The tissue specificity of autoimmune attack is also under genetic control and variations in tissue-specific factors also appear to have a role. ... Read more

miRNAs at the Crossroad Between Hematopoietic Malignancies and Autoimmune Pathogenesis

Abstract: The study of microRNA (miRNA) regulation in the pathogenesis of autoimmune diseases and hematopoietic malignancies provides new understanding of the mechanisms of disease and is currently the focus of many researchers in the field. Autoimmune disorders and cancers of immune system comprise a wide range of genetically complex diseases that share certain aspects of dysregulated genetic networks, most notably deactivation of apoptosis. miRNA mechanisms control gene expression at the post-transcriptional level, linking mRNA processing and gene function. Considerable amount of data have been accumulated that indicate that the alteration of miRNA expression closely mirrors the development of immune system diseases and is likely to play a role in their pathogenesis. However, a knowledge gap remains in our understanding of how miRNA dysregulation and the specific effects of miRNAs on target gene expression underlay the disease phenotype. Here we review a number of studies describing miRNA alterations in autoimmune diseases and hematopoietic cancers and discuss potential miRNA-regulated mechanisms that differentially influence the development of autoimmunity as compared to cancer progression. ... Read more

Autoantigen Based Vaccines for Type 1 Diabetes

Abstract: Type 1 diabetes is an organ-specific autoimmune disease caused by chronic inflammation (insulitis), which damages the insulin producing β-cells of the pancreatic Islets of Langerhans. Dendritic cells (DCs) are generally the first cells of the immune system to process β-cell autoantigens and, by promoting autoreactivity, play a major role in the onset of insulitis. Although no cure for diabetes presently exists, the onset of insulitis can be diminished in the non-obese diabetic (NOD) mouse type 1 diabetes model by inoculation with endogenous β-cell autoantigens. These include the single peptide vaccines insulin, GAD65 (glutamic acid decarboxylase), and DiaPep277 (an immunogenic peptide from the 60-kDa heat shock protein). DiaPep277 is the only autoantigen so far to demonstrate positive results in human clinical trials. Diamyd (an alum adjuvant + recombinant GAD65 protein formulation) has shown great promise for suppressing β-cell autoreactivity in phase I and II clinical trials. While Diamyd preserved residual insulin secretion in early-onset type 1 diabetes patients, it did not reduce the amounts of insulin required to maintain euglycemia. Recently, multi-component vaccines composed of the anti-inflammatory cytokine (IL-10) and insulin or GAD55 linked to an immunostimulatory molecule, the cholera toxin B subunit, were shown to safely and completely inhibit diabetes onset in NOD mice. This result suggests that multi-component vaccine strategies are promising for prevention and reversal of diabetes autoimmunity in humans. Here we focus on the development of autoantigen vaccines for type 1 diabetes and demonstrate that multi-component vaccines are promising candidates for type 1 diabetes clinical studies. ... Read more

New Insight in the Mechanism of Action of Rituximab: The Interferon Signature Towards Personalized Medicine

Abstract: Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder of the musculoskeletal system that may cause permanent joint damage. The disease has a major impact on the quality of life of affected individuals, costs for the health care system, and society. Currently, no curative treatment is available, and patients are subjected to a prolonged course of treatment. Due to their role in the pathogenesis of RA, B cells have become an attractive target for therapy. Rituximab (Mabthera®/Rituxan®) is a therapeutic monoclonal antibody against CD20 expressed on B cells, which is effective in depleting B cells and approved worldwide for the treatment of RA. Rituximab was shown to be highly beneficial in decreasing clinical symptoms, safe, and well tolerated. However, clinical experience revealed that approximately 30-40% of RA patients do not respond to it. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for therapy, there is a strong need to make predictions on the clinical outcome before the start of therapy. Since nearly all treated patients experience an effective depletion of circulating B cells, questions have been raised concerning the mechanism of action. In this review, novel developments, in particular the findings on the role of the interferon system, will be highlighted. This may add new and important information to our understanding of the mechanism that underlies the clinical outcome of rituximab treatment and may lead to the identification of biomarkers to predict the response. ... Read more

Environmental Triggers and Epigenetic Deregulation in Autoimmune Disease

Abstract: The study of epigenetic mechanisms in the pathogenesis of autoimmune diseases is receiving unprecedented attention from clinicians and researchers in the field. Autoimmune disorders comprise a wide range of genetically complex diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Together they affect a significant proportion of the population and have a great economic impact on public health systems. Epigenetic mechanisms control gene expression and are influenced by external stimuli, linking environment and gene function. A variety of environmental agents, such as viral infection, hormones, certain drugs, and pollutants, have been found to influence the development of autoimmune diseases. On the other hand, there is considerable evidence of epigenetic changes, particularly DNA methylation alterations, in diseases like systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. However, the gap in our understanding between the specific effects of external agents and the influence on epigenetic profiles has not yet been filled. Here we review a number of studies describing epigenetic alterations in autoimmune diseases and a range of environmental factors that influence the development of autoimmune diseases. We also discuss potential mechanisms linking environment and epigenetics, consider the prospects for future epigenetic studies addressing the relationship between environment and epigenetics, and comment on the use of drugs with an epigenetic-reversing effect in the clinical management of these diseases. ... Read more

The Busy Life of Regulatory T Cells in Systemic Lupus Erythematosus

Abstract: CD4+CD25+Foxp3+ regulatory T (Treg) cells suppress the proliferation and release of cytokines in several subsets of immune cells. By doing so and by maintaining immune tolerance in peripheral tissues, Treg cells contribute to avert autoimmunity. Many studies have investigated how Treg cells operate in autoimmune diseases, and which cellular and molecular pathways are targeted by Treg cells. This review provides an update on the activities of Treg cells in systemic lupus erythematosus (SLE), an autoimmune disease characterized by the presence of hyperactive immune cells and aberrant antibody responses to multiple nuclear and cytoplasmic antigens. ... Read more

Crypticity of Self Antigenic Determinants Is the Cornerstone of a Theory of Autoimmunity

Abstract: Self antigens can have dominant and cryptic (hidden) antigenic determinants. T cells that can see the dominant antigenic determinants are tolerized and "disarmed." T cells that may still see the cryptic determinants are active and become a part of the T cell repertoire. Under certain circumstances when these T cells are more capable of "seeing" the cryptic antigenic determinants or the cryptic determinants unveil themselves, autoimmunity ensues. ... Read more

B-cell Lymphomagenesis in Autoimmune Diseases: the Missing Links

Abstract: Patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome have an increased risk of developing B-cell non-Hodgkin's lymphomas but the mechanisms behind this phenomenon remain unknown. By focusing on recent research reports we explore and discuss some of the proposed mechanisms that contribute to this link. The complexity is enormous and can involve genetic and environmental factors, chronic immune stimulation by antigens, and even the treatment for these autoimmune diseases. These mechanisms can be combined in different ways causing great variability in one's predisposition to lymphomagenesis. Knowing more about these pathways is urgent. The more we know about autoimmune diseases the better we can treat our patients effectively and the more we can prevent lymphomas from developing. ... Read more

Vitamin D Supplementation, Moderate Sun Exposure, and Control of Immune Diseases

Abstract: There is considerable debate about the benefits of vitamin D supplementation for multiple sclerosis, allergic asthma, and type 1 diabetes. This has been driven mainly by observational studies linking vitamin D deficiency and insufficiency with increased prevalence of autoimmune and other diseases driven by immune processes. Randomized controlled trials of vitamin D supplementation to treat these (and other) diseases have been disappointing. This review examines the evidence that circulating vitamin D levels provide a surrogate measure of sun exposure and that it is the other molecules and pathways induced by sun exposure, rather than vitamin D-driven processes, that explain many of the benefits often attributed to vitamin D. ... Read more

GM-CSF-Secreting Vaccines for Solid Tumors: Moving Forward

Abstract: Cancer vaccines consisting of intact tumor cells genetically modified to secrete the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have undergone extensive preclinical development. These vaccines induce the massive accumulation of dendritic cells at the intradermal injection site, which engulf, process, and present tumor antigens to activate tumor-specific T cells. Early phase clinical testing demonstrated promising evidence of safety and bioactivity, although initial phase III clinical trials were unsuccessful. Together, the preclinical and clinical data argue for the continued clinical development of these vaccines, integrating them with standard and novel cancer therapeutics that enhance vaccine activity by overcoming immune tolerance and suppression, and/or augmenting co-stimulatory pathways of T cell activation. ... Read more

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