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Medical Specialties / Rheumatology / Chronic Inflammation


Axonal Pathology and Demyelination in Viral Models of Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). Monozygotic twin studies suggest that while there is a genetic contribution, genetics alone cannot be the sole determining factor in the development of MS. As the rates of MS are increasing, particularly among women, environmental factors such as viral infections are coming to the foreground as potential agents in triggering disease in genetically susceptible individuals. This review highlights pathological aspects related to two pre-clinical viral models for MS; data are consistent between these two models as experimental infection of susceptible mice can induce axonal degeneration associated with demyelination. These data are consistent with observations in MS that axonal damage or Wallerian degeneration is occurring within the CNS contributing to the disability and disease severity. Such early damage, where axonal damage is primary to secondary demyelination, could set the stage for more extensive immune mediated demyelination arising later. ... Read more

Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

Cholesterol Crystals Induce Inflammatory Cytokines Expression in a Human Retinal Pigment Epithelium Cell Line by Activating the NF-kappaB Pathway

Abstract: Purpose: To investigate the expression of inflammatory cytokines in ARPE-19 cells after stimulation with cholesterol crystals. Methods: APRE-19 cells were cultured, primed with IL-1α, and treated with cholesterol crystals under different concentrations. Inflammatory cytokines (mature-IL-1β, IL-6, and IL-8) in supernatant and inflammatory cytokines (pro-IL-1β, IL-18) in cell lysate were detected by western blot. The NF-κB pathway inhibitor BAY 11-7082 was used to determine the pathway of cytokine expression. Results: Cholesterol crystals did not induce the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, but did increase pro-IL-1β expression in ARPE-19 cells. Cholesterol crystals increased pro-IL-1β expression by activating the NF-κB pathway. Cholesterol crystal activation of the NF-κB pathway also leads to increased IL-6 and IL-8 expression. Conclusion: Cholesterol crystals can induce inflammatory cytokine expression in ARPE-19 cells by activating the NF-κB pathway. ... Read more

Novel Methods of Type 1 Diabetes Treatment

Abstract: Type 1 diabetes is an autoimmune disease characterized by the cell-mediated destruction of insulin-producing β-cells, leading to impaired glucose homeostasis, insulin insufficiency, and other complications. Although classic genetic studies have linked numerous genes to the susceptibility of developing diabetes, the mechanisms by which they influence the disease course remain poorly understood. Epigenetics, inheritable changes in gene expression that occur without accompanying genetic mutation, can both serve as a link between the environment and genetic causes of disease and help explain some of the observed vagaries of diabetes. Elucidation of the epigenetic landscape as it relates to putative treatment modalities is highly warranted. Drugs with histone deacetylase activity are in clinical trials for cancer and certain inflammatory diseases with high safety profiles and they hold similar promise for amelioration of type 1 diabetes with diminished secondary complications. Full-fledged studies on the epigenetics of type 1 diabetes are highly likely to provide novel tools for the manipulation of the disease in the years to come. In this review, epigenetic regulation mediated by small molecular inhibitors of histone deacetylases and their potential for preventing diabetes are discussed. Insights into the nature of the genetic mechanisms unraveled by these studies are also highlighted. ... Read more

Gene Therapy for Obesity: Progress and Prospects

Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ... Read more

A Matrix of Cholesterol Crystals, But Not Cholesterol Alone, Primes Human Monocytes/Macrophages for Excessive Endotoxin-induced Production of Tumor Necrosis Factor-Alpha. Role in Atherosclerotic Inflammation?

Abstract: When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower levels of endotoxin were needed for TNF-α production equivalent to that of unprimed cells. The pro-inflammatory effect was selective as endotoxin-induced production of other pro-inflammatory cytokines was unaffected while production of anti-inflammatory interleukin-10 was diminished. These findings suggest that cholesterol matrix formation may play a pathogenic role in atherosclerotic inflammation, and they indicate a mechanism by which bacteria and/or bacterial products may play a role in processes leading to arteriosclerosis. ... Read more

Novel Therapeutic Approaches for Celiac Disease

Abstract: Celiac disease (CD), which mainly affects the small intestine, is the only systemic autoimmune disorder with an identified environmental trigger which is dietary gluten. Lifelong adherence to a strict gluten free diet (GFD) is currently the only accepted treatment. CD is increasingly diagnosed and the GFD is known to be associated with a large treatment burden. Furthermore, a substantial number of CD patients show an incomplete clinical response to the GFD. These factors have led to demands for the development and testing of novel, non-dietary, therapeutic agents that are both safe and effective. CD pathogenesis is well elucidated which has greatly aided targeted drug development. Compounds currently being tested in phase II clinical trials include glutenase enzymes (to detoxify gluten) and a tight junction modulator (to reduce access of gluten peptides to lamina propria antigen presenting cells). Other promising approaches include inhibition of the transglutaminase 2 enzyme, blocking antigen presentation by HLA-DQ2 or HLA-DQ8, induction of tolerance, and modulation of the inflammatory response. It is hoped that non-dietary therapy for CD will become available in the coming years and can both reduce the burden of treatment of CD and help patients whose symptoms do not respond completely to the GFD. ... Read more

Inflammatory Disease and the Human Microbiome

Abstract: The human body is a superorganism in which thousands of microbial genomes continually interact with the human genome. A range of physical and neurological inflammatory diseases are now associated with shifts in microbiome composition. Seemingly disparate inflammatory conditions may arise from similar disruption of microbiome homeostasis. Intracellular pathogens long associated with inflammatory disease are able to slow the innate immune response by dysregulating activity of the VDR nuclear receptor. This facilitates the ability of other species to gradually accumulate in tissue and blood, where they generate proteins and metabolites that significantly interfere with the body’s metabolic processes. The microbes that contribute to this dysfunction are often inherited from family members. Immunosuppressive therapies for inflammatory disease allow pathogens driving these processes to spread with greater ease. In contrast to immunosuppression, treatments that stimulate the immune system seem to allow for reversal of this pathogen-induced genomic dysregulation. ... Read more

Advances in Mechanisms of Systemic Lupus Erythematosus

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with hormonal, environmental, and genetic factors and linked to the tolerance breakdown of B and T cells to self-antigens. SLE is characterized by the presence in patient serum of autoantibodies raised against nuclear components. Association of these antibodies to self-antigens, complement factors, DNA, and particular proteins will form circulating immune complexes (CIC) which can deposit in several organs, causing tissue damage and clinical manifestations. Historically, SLE is considered as an adaptive immune system disorder. Over the past decade, advances in the understanding of SLE pathogenesis placed the innate immune system as a key player in perpetuating and amplifying this systemic disease. In this review, we summarize some recent key advances in understanding the SLE immune-pathogenesis with a particular focus on newly discovered key factors from the innate immune system and how they influence the pathogenic adaptive immune system: neutrophils and neutrophil extracellular traps (NETs), plasmacytoid dendritic cells (pDCs) and type I interferons, basophils and autoreactive IgE, monocytes/macrophages and the inflammasome. Recent advances on B and T cell involvement in the SLE pathogenesis mechanisms are also discussed. Although the disease is clinically, genetically, and immunologically heterogeneous between affected individuals, the latest discoveries are offering new promising therapeutic strategies. ... Read more

Understanding Autoimmunity in the Eye: From Animal Models to Novel Therapies

Abstract: In recent years considerable headway has been made on understanding the mechanisms underlying inflammatory diseases of the eye. This includes the role of the innate vs. adaptive arms of the immune systems in disease, the concept that distinct immune pathways can drive end-organ pathology, and the role as well as limitations of immune privilege in controlling the innate and adaptive effector responses that lead to eye pathology and loss of vision. These insights have largely been derived from basic studies in established and in newly developed animal models of uveitis. The increased understanding of disease mechanisms has the potential to guide development of rational therapies for human uveitis. Many novel biologics currently in use or being evaluated have been developed, or validated, in animal models of autoimmune and inflammatory disease, including experimental uveitis. Paradoxically, and fueled in part by dwindling research budgets, a campaign has been gathering momentum against use of animal models in preclinical research, as being poorly representative of responses in humans. Given the extensive genetic similarity between humans and laboratory rodents as revealed by the Human, Mouse and Rat Genome Projects, and the finding that almost all known disease-associated genes have orthologs in mice and rats, perhaps the problem is our still-insufficient understanding of mechanisms and inadequate knowledge of species differences, resulting in poor choice of models, rather than in an inherent unsuitability of animal models to represent human disease. ... Read more

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