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Yang C.-Y.,University of California at Davis | Ma X.,Shanghai JiaoTong University | Tsuneyama K.,University of Toyama | Huang S.,Shanghai JiaoTong University | And 9 more authors.
Hepatology | Year: 2014

The interleukin (IL)-12/IL-23-mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, interferon-gamma (IFN-γ), IL-12RB2, IL-23p40, IL-23p19, IL-17, and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining was detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most important, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance profibrotic Th17 signaling and proinflammatory IFN-γ production that contribute to PBC pathology. Conclusion: Our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention. © 2014 by the American Association for the Study of Liver Diseases.

Over the past decade, the introduction of biologic therapies has had a profound impact for millions of patients with immune-mediated arthritides, inflammatory bowel diseases and plaque psoriasis. Today, five anti-Tumor Necrosis Factor (TNF) therapies are approved in the United States and many countries around the world, and innovations in the TNF class continue more than a decade after the initial approval. Several other biologic therapies targeting distinct immune cell receptors or cytokines have been approved for immunologically mediated diseases, and many promising new biologic medicines are in various stages of clinical development.

Menendez C.M.,Immunology | Carr D.J.J.,Immunology | Carr D.J.J.,The University of Oklahoma Health Sciences Center
Journal of Neuroinflammation | Year: 2017

Background: Herpes simplex virus 1 (HSV-1) infection can result in a life-threatening condition known as herpes simplex encephalitis (HSE). Trafficking patterns by which the virus reaches the central nervous system (CNS) following ocular infection are unresolved. We evaluated early viral dissemination pathways following ocular infection that involve trafficking to the olfactory bulb (OB). Additionally, we have characterized the capacity of HSV-1 to establish latency within OB tissue and profiled the local T lymphocyte response over the course of the acute infection into latency. Methods: Scarified corneas of C57BL/6 or reporter-inducible Rosa mice (RosaTd/Tm) were inoculated with HSV-1 and assessed for viral dissemination into the peripheral nervous system (PNS) and CNS by RT-PCR and confocal microscopy. T cells and the resident microglia activation signatures were analyzed by flow cytometry. T cell effector function in the form of IFN-γ secretion was measured by T cells isolated from OB in comparison to T cells from other nervous system sites known to harbor HSV-1-specific memory T cells. Results: Following ocular infection, HSV-1 viral titers from nasal secretions were detected as early as 48 h through 8 days post infection (8 DPI). HSV-1 gene expression was expressed as early as 2 days following ocular infection in the OB and was consistent with an enhanced expression in the ophthalmic, maxillary, and mandibular branch of the trigeminal nerve ganglia (TG). Rosa fluorescence protein expression (RFP+) representing HSV-1-infected cells from RosaTd/Tm mice was detected in the OB before other areas of the CNS (2 DPI). Additionally, during acute infection, most infected cells appeared to be anatomically distributed within the OB rather than other regions of the CNS. During latency (i.e., 30 DPI and beyond) despite no detectable infectious virus or lytic gene expression and low levels of latency associated transcripts, total effector (CD44+ CD62-) CD4+ T, CD8+ T, HSV-1-specific CD8+ T cells, and MHC class II positive resident microglia numbers continued to increase. CD4+ and CD8+ T cell populations isolated from the OB during latency were capable of responding to PMA/ionomycin in the production of IFN-γ similar to T cells from other tissue that possess latent virus including the TG and brain stem. Conclusions: It is currently understood that HSV-1 traffics to the TG following ocular infection. We have identified a second conduit by which HSV-1 can directly access the CNS bypassing the brain stem. We have also recognized that the OB is unique in that during HSV-1 latency, latency-associated transcripts levels were marginally above uninfected controls. Despite these findings, the local immune response mimicked the phenotype of an active infection during latency. © 2017 The Author(s).

Vashisht P.,Immunology | O'dell J.,Internal Medicine
Expert Opinion on Biological Therapy | Year: 2017

Introduction: Anti-TNF therapy has dramatically changed how we manage rheumatoid arthritis. There are many similarities among the five approved agents but also some important differences. Rheumatologists have 5 different options to choose from when they are ready to commence anti-TNF therapy. Although all block the TNF cytokine, there are important critical differences among them that affect their safety profile and clinical utility in certain scenarios. Unfortunately, there are no head to head trials to compare the different anti-TNF agents and none appear to be in the horizon. Areas covered: This article reviews the various clinical situations where it may be important to use a particular anti-TNF agent. The authors also give their expert opinion and future perspectives on the area. Expert opinion: Although there are many similarities among the five different TNFi that are clinically available, there are important clinical niches, where the limited data that are available, that clearly support the preferential use of a particular agent or class of agents. Assays or tests that allow us to find the ‘sweet spot’ of TNF inhibition at the level of each patient are long overdue. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Baer G.,Immunology | Lameire N.,Ghent University | Van Biesen W.,Ghent University
NDT Plus | Year: 2010

Late referral of patients with chronic kidney disease (CKD) is a known problem and a major challenge for practising nephrologists since decades. In this review we report about the reasons for late referral, its epidemiology and socioeconomic impact and the medical particularities of late referred patients. We furthermore highlight on the efforts which have been undertaken so far to avoid late referral and should be undertaken in future to face the ever growing numbers of chronic kidney disease patients. © The Author 2009. Published by Oxford University Press.

Diogo D.,Immunology | Diogo D.,Harvard University | Diogo D.,Cambridge Broad Institute | Okada Y.,Immunology | And 6 more authors.
Current Opinion in Rheumatology | Year: 2014

PURPOSE OF REVIEW: A significant number of loci implicated in rheumatoid arthritis (RA) susceptibility have been highlighted by genome-wide association studies (GWAS). Here, we review the recent advances of GWAS in understanding the genetic architecture of RA, and place these findings in the context of RA pathogenesis. RECENT FINDINGS: Although the interpretation of GWAS findings in the context of the disease biology remains challenging, interesting observations can be highlighted. Integration of GWAS results with cell-type specific gene expression or epigenetic marks have highlighted regulatory T cells and CD4 memory T cells as critical cell types in RA. In addition, many genes in RA loci are involved in the nuclear factor-kappaB signaling pathway or the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The observation that these pathways are targeted by several approved drugs used to treat the symptoms of RA highlights the promises of human genetics to provide insights in the disease biology, and help identify new therapeutic targets. SUMMARY: These findings highlight the promises and need of future studies investigating causal genes and underlined mechanisms in GWAS loci to advance our understanding of RA. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.

Rivas Bejarano J.J.,Immunology | Rivas Bejarano J.J.,LoneStar College | Valdecantos W.C.,Immunology
Dermatologic Clinics | Year: 2013

This article presents a summary of the evidence for a link between autoinflammatory diseases and psoriasis. The main concepts regarding the disease state of psoriasis are discussed and these lead to a change in the perspective on the clinical and pathophysiologic nature of psoriasis as a chronic, recurrent disease with important genetically defined features, and an associated or concomitant systemic inflammatory state that involves a multifactorial cellular and molecular network, transforming the old perception of psoriasis as a localized autoimmune skin disease, to one of psoriasis as a systemic inflammatory disease with autoinflammatory features and severe associated comorbid conditions. © 2013 Elsevier Inc.

Vogt W.B.,University of Georgia | Joyce G.,University of Southern California | Xia J.,Harvard University | Dirani R.,Health Economics and outcomes Research | And 2 more authors.
Health Affairs | Year: 2011

"Atypical" or second-generation antipsychotics are a class of drug introduced in the 1990s for the treatment of schizophrenia. Given their growing use and rising cost, these and other psychotherapeutic drugs are increasingly subject to prior authorization and other restrictions in state Medicaid programs. To evaluate the effects of these policies, we collected drug-level information on their use and on utilization management strategies-for example, requirements for prior authorization, quantity limits, and so-called step therapy-in thirty state Medicaid programs between 1999 and 2008. In the eleven states that instituted prior authorization during that period, use of atypicals per enrollee rose by 14 percent, versus 19 percent in the other nineteen states. Prior authorization also had spillover effects, in that reduced use of drugs subject to this requirement was not fully offset by the substitution of other atypicals or of typical antipsychotics. To understand the impact on patients and the resulting use of health services, studies should be undertaken of a large, national sample of Medicaid enrollees being treated with atypical antipsychotics. Comparative effectiveness research should guide physicians and health plans on appropriate first treatments, while prior authorization policies should focus on moving patients to appropriate second-line therapies when necessary.

Doreswamy V.,Immunology | Peden D.B.,University of North Carolina at Chapel Hill
Clinical and Experimental Allergy | Year: 2011

Asthma is a common inflammatory disease triggered by both allergic and non-allergic stimuli. The most common risk factor in the development of asthma is induction of IgE against indoor allergens and imbalance in the T-helper type 1 (Th1) and Th2 with skewing towards Th2 response. Interplay of genetic and environmental factors is involved in induction and propagation of asthma. Endotoxin is a common environmental pollutant and elicits a Th1 response. The amount of endotoxin varies with several factors but of significant interest has been the role of pets. Endotoxin not only protects against the development of asthma but also enhances an already established inflammation. The difference of outcomes is likely not only due to the time and dose of exposure but also as we discuss the variable interaction of genes with environment. We focus on studies since 2001 that have explored the role of endotoxin in asthma and the gene-environment interactions of the endotoxin effect. © 2010 Blackwell Publishing Ltd.

Rao N.L.,Immunology | Riley J.P.,Immunology | Banie H.,Immunology | Xue X.,Immunology | And 7 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Allergic asthma is characterized by reversible airway obstruction, lung inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene B4 (LTB4) receptor 1-deficient mice and adoptive transfer experiments have suggested that LTB4 plays a role in lung inflammation and AHR. Objectives: In this study, we used a leukotriene A4 hydrolase (LTA4H) inhibitor as a pharmacological tool to directly examine the role of LTB4 in a mast cell-dependent murine model of allergic airway inflammation. Methods: We used the forced oscillation technique to test the effects of an LTA4H inhibitor dosed during the challenge phase on AHR. Lung tissue and lavage were collected for analysis. Measurements and Main Results: Treatment with an LTA4H inhibitor improved multiple parameters encompassing AHR and lung function. Significant decreases in inflammatory leukocytes, cytokines, and mucin wereobserved in the lung lumen. Serum levels of antigen-specific IgE and IgG1 were also decreased. Labeled antigen uptake by lung dendritic cells and subsequent trafficking to draining lymph nodes and the lung were decreased on LTA4H inhibitor treatment. Provocatively, inhibition of LTA 4H increased lipoxin A4 levels in lung lavage fluid. Conclusions: These data suggest that LTB4 plays a key role in driving lung inflammation and AHR. Mechanistically, we provide evidence that inhibition of LTA4H, affects recruitment of bothCD4+ and CD8 + T cells, as well as trafficking of dendritic cells to draining lymph nodes, and may beneficially modulate other pro- and antiinflammatory eicosanoids in the lung. Inhibition of LTA4H is thus a potential therapeutic strategy that could modulate key aspects of asthma.

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