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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.

PubMed | Biochemical and Cellular Pharmacology;, Immunology Preclinical and Translational Pharmacokinetics., Pathology., Genentech and 5 more.
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2016

CRTh2 is expressed on immune cells that drive asthma pathophysiology. Current treatment options for severe asthma are inadequate and therapeutic antibody-mediated depletion of CRTh2-expressing cells represents a promising new therapeutic strategy. Here we report for the first time that CRTh2 is not only expressed on immune cells, but also on microvasculature in the central nervous system (CNS) and gastric mucosa in humans. Microvascular expression of CRTh2 raises a safety concern because a therapeutic antiCRTh2 antibody with enhanced depletion capacity could lead to vascular damage. To evaluate this safety risk, we characterized microvascular expression in human and in transgenic mice expressing human CRTh2 protein (hCRTh2.BAC.Tg) and found that CRTh2 is not localized to microvascular endothelium that is directly exposed to circulating therapeutic antibody, but rather, to pericytes that in the CNS are shielded from direct circulatory exposure by the blood-brain barrier. Immunohistochemical visualization of an intravenously administered antiCRTh2 antibody in transgenic mice revealed localization to microvascular pericytes in the gastric mucosa but not in the CNS, suggesting the blood-brain barrier effectively limits pericyte exposure to circulating therapeutic antibody in the CNS. Repeated dosing with a depleting antiCRTh2 antibody in hCRTh2.BAC.Tg mice revealed linear pharmacokinetics and no drug-related adverse findings in any tissues, including the CNS and gastric mucosa, despite complete depletion of CRTh2 expressing circulating eosinophils and basophils. Collectively, these studies demonstrate that the likelihood of drug-related CNS or gastrointestinal toxicity in humans treated with a therapeutic depleting antiCRTh2 antibody is low despite pericyte expression of CRTh2 in these tissues.

PubMed | Papworth Hospital, Immunology, UK PIN UKPID Registry Team, the Royal Hospitals and 10 more.
Type: Journal Article | Journal: Clinical and experimental immunology | Year: 2016

Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8(+) T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T cells, might contribute to the increased risk of cancers as individuals age.

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.

Foocharoen C.,Immunology | Pussadhamma B.,Khon Kaen University | Mahakkanukrauh A.,Immunology | Suwannaroj S.,Immunology | Nanagara R.,Immunology
Rheumatology (Oxford, England) | Year: 2015

OBJECTIVE: To determine the prevalence of asymptomatic cardiac involvement and its correlation with non-cardiac manifestation in Thai SSc patients.METHODS: A cross-sectional study was carried out between January 2012 and June 2013 at Srinagarind Hospital, Khon Kaen University, Thailand, on adult SSc patients without signs or symptoms suggestive of cardiac involvement. We excluded those with overlap syndrome, having serum creatinine >123.8 µmol/l, history of cardiac diseases, any atherosclerosis risk factors and receiving angiotensin-converting enzyme inhibitors. Non-invasive tests related to cardiac involvement were performed, including: echocardiography, ECG, chest X-ray, inflammatory biomarkers, cardiac enzymes and N-terminal prohormone of brain natriuretic peptide.RESULTS: A total of 103 SSc patients were enrolled, 61.2% of whom were in the subset. Of these, 63 patients had at least one test abnormality (prevalence 61.2%; 95% CI 51.6, 70.7). The two leading cardiac abnormalities were diastolic dysfunction (44.7%) and elevation of cardiac enzymes (36.9%). The only predictor for cardiac involvement per multivariate analysis was the dcSSc subtype with a higher modified Rodnan skin score, and shorter disease duration (odds ratio = 3.37; 95% CI 1.07, 10.65). Compared with the limited subtype, dcSSc was also significantly associated with elevated cardiac enzyme and prolonged distance between a Q wave and T wave in an ECG (QT interval).CONCLUSION: Asymptomatic cardiac involvement in Thai SSc was not uncommon, and the most common finding was diastolic dysfunction. Elevated cardiac enzymes were found in one-third of the patients, which correlated with the dcSSc subtype with a higher modified Rodnan skin score and shorter disease duration, suggestive of early myocardial microcirculation disruption. Long-term follow-up was performed to elucidate the clinical implication of these abnormalities. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email:

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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