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Inflammatory disease genetics

Hirofumi Chiba, Yoichi Kakuta, Yoshitaka Kinouchi, Yosuke Kawai, Kazuhiro Watanabe, Munenori Nagao, Takeo Naito, Motoyuki Onodera, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Masao Nagasaki, Michiaki Unno, Tooru Shimosegawa
BACKGROUND: Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs...
2018: PloS One
Zhaodong Li, Ludovica F Buttó, Kristine-Anne Buela, Li-Guo Jia, Minh Lam, John D Ward, Theresa T Pizarro, Fabio Cominelli
Death receptor 3 (DR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, has been implicated in regulating T-helper type-1 (TH 1), type-2 (TH 2), and type-17 (TH 17) responses as well as regulatory T cell (Treg ) and innate lymphoid cell (ILC) functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD) is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represents a potential therapeutic target in human inflammatory diseases, including Crohn's disease (CD)...
2018: Frontiers in Immunology
Manuel Fresno, Núria Gironès
Chagas disease is a multisystemic disorder caused by the protozoan parasite Trypanosoma cruzi , which affects ~8 million people in Latin America, killing 7,000 people annually. Chagas disease is one of the main causes of death in the endemic area and the leading cause of infectious myocarditis in the world. T. cruzi infection induces two phases, acute and chronic, where the infection is initially asymptomatic and the majority of patients will remain clinically indeterminate for life. However, over a period of 10-30 years, ~30% of infected individuals will develop irreversible, potentially fatal cardiac syndromes (chronic chagasic cardiomyopathy [CCC]), and/or dilatation of the gastro-intestinal tract (megacolon or megaesophagus)...
2018: Frontiers in Microbiology
Holger Winkels, Erik Ehinger, Melanie Vassallo, Konrad Buscher, Huy Dinh, Kouji Kobiyama, Anouk Hamers, Clément Cochain, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Alma Zernecke, Akula Pramod, Amlan Ghosh, Nathaly Anto Michel, Natalie Hoppe, Ingo Hilgendorf, Andreas Zirlik, Catherine Hedrick, Klaus Ley, Dennis Wolf
<u>Rationale:</u> Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is only poorly understood. <u>Objective:</u> We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single cell RNA-sequencing (scRNAseq) and mass cytometry (CyTOF) to define an atlas of the immune cell landscape in atherosclerosis...
March 15, 2018: Circulation Research
Fawaz Awad, Eman Assrawi, Camille Louvrier, Claire Jumeau, Irina Giurgea, Serge Amselem, Sonia-Athina Karabina
Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)-1β and IL-18 cytokines, and an inflammatory form of death named pyroptosis...
March 12, 2018: Mechanisms of Ageing and Development
Christoph Niemietz, Christoph Röcken, Matthias Schilling, Jörg Stypman, Constantin E Uhlig, Hartmut H-J Schmidt
Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated...
March 2018: Deutsche Medizinische Wochenschrift
K Soelberg, A C Nilsson, C Nielsen, S Jarius, M Reindl, B Wildemann, S T Lillevang, N Asgari
BACKGROUND: Optic neuritis (ON) is an inflammatory optic neuropathy, where the genetic and autoimmune dependency remains poorly characterized. OBJECTIVE: To investigate autoimmune and immunogenetic aspects of ON. METHOD: In a prospective population-based cohort 51 patients with ON were included. At follow up 20 patients had progressed to multiple sclerosis (MS-ON). All patients were screened for neuronal and systemic autoantibodies. HLA genotypes and allele and genotype frequencies of the PTPN22 C1858T and the PD-1...
March 7, 2018: Multiple Sclerosis and related Disorders
Dragana Mijac, Irena Vukovic-Petrovic, Vera Mijac, Vladimir Perovic, Natasa Milic, Srdjan Djuranovic, Daniela Bojic, Dragan Popovic, Djordje Culafic, Miodrag Krstic, Goran Jankovic, Vera Pravica, Milos Markovic
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology in which genetic factors contribute to development of disease. Single nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDR1) gene encoding transporter P-glycoprotein have been associated with IBD, but their role in disease susceptibility remains unclear. Therefore, the aim of this study was to investigate the association of three MDR1 polymorphisms, C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642), with Serbian IBD patients...
2018: PloS One
Kurt A Zimmerman, Cheng Jack Song, Nancy Gonzalez-Mize, Zhang Li, Bradley K Yoder
Hepatorenal fibrocystic disease (HRFCD) is characterized by cysts in the kidney and liver with associated fibrosis and is the result of defects in proteins required for cilia function or assembly. Previous reports indicate that macrophages, mainly M2-like macrophages, contribute to HRFCD, although the origin (yolk-sac derived resident macrophages vs bone-marrow derived infiltrating macrophages) and contribution of these cells to the observed phenotypes is unknown. Herein, we utilize a congenital model of cilia dysfunction (IFT88Orpk ) to study the importance of macrophages in HRFCD...
March 15, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Francesco Caso, Marco Tasso, Pasquale Ambrosino, Matteo Nicola, Dario Di Minno, Roberta Lupoli, Livio Criscuolo, Paolo Caso, Francesco Ursini, Antonio Del Puente, Raffaele Scarpa, Luisa Costa, Rosario Peluso
BACKGROUND: Psoriatic arthritis is a chronic inflammatory arthropathy that affects 14%-30% of patients with skin and/or nail psoriasis and leading to severe physical limitations and disability. It has been included in the group of spondyloarthropathy with which it shares clinical, radiologic, and serologic features in addition to familial and genetic relationship. Beyond skin and joint involvement, psoriatic arthritis is characterized by a high prevalence of extra-articular manifestation and comorbidities, such as autoimmune, infectious and neoplastic diseases...
March 13, 2018: Reviews on Recent Clinical Trials
Christian Schwedler, Thomas Häupl, Ulrich Kalus, Véronique Blanchard, Gerd-Rüdiger Burmester, Denis Poddubnyy, Berthold Hoppe
BACKGROUND: Galactosylation of immunoglobulin G (IgG) is reduced in rheumatoid arthritis (RA) and assumed to correlate with inflammation and altered humoral immunity. IgG hypogalactosylation also increases with age. To investigate dependencies in more detail, we compared IgG hypogalactosylation between patients with RA, patients with axial spondyloarthritis (axSpA), and healthy control subjects (HC), and we studied it in RA on the background of HLA-DRB1 shared epitope (SE), anticitrullinated protein antibodies (ACPA), and/or rheumatoid factor (RF) status...
March 14, 2018: Arthritis Research & Therapy
Phoebe Lin
PURPOSE OF REVIEW: The intestinal commensal microbiota are important in shaping immune cell repertoire and are influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This review summarizes the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit. RECENT FINDINGS: Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis...
March 13, 2018: Current Opinion in Ophthalmology
Rene Y Choi, Mark Asquith, James T Rosenbaum
PURPOSE OF REVIEW: The intestinal microbiome is thought to play a role in the pathogenesis of inflammatory bowel disease (IBD). There are many shared clinical manifestations between IBD and spondyloarthritis (SpA), of which the most common are peripheral arthritis and uveitis. Clinical overlap along with similar genetics between these diseases suggests a possible shared pathogenetic mechanism, which might center on the intestinal microbiota. In this review, we discuss the available evidence that SpA is a microbiome-driven disease and indicate how SpA-associated uveitis could be tied to gut dysbiosis...
March 13, 2018: Current Opinion in Rheumatology
Michelle Chang, Lin He, Lei Cai
Genome-wide association study (GWAS) is a powerful study design to identify genetic variants of a trait and, in particular, detect the association between common single-nucleotide polymorphisms (SNPs) and common human diseases such as heart disease, inflammatory bowel disease, type 2 diabetes, and psychiatric disorders. The standard strategy of population-based case-control studies for GWAS is illustrated in this chapter. We provide an overview of the concepts underlying GWAS, as well as provide guidelines for statistical methods performed in GWAS...
2018: Methods in Molecular Biology
Andrew Leber, Raquel Hontecillas, Nuria Tubau-Juni, Victoria Zoccoli-Rodriguez, Vida Abedi, Josep Bassaganya-Riera
Interactions among the gut microbiome, dysregulated immune responses, and genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Nlrx1 -/- mice have exacerbated disease severity, colonic lesions, and increased inflammatory markers. Global transcriptomic analyses demonstrate enhanced mucosal antimicrobial defense response, chemokine and cytokine expression, and epithelial cell metabolism in colitic Nlrx1 -/- mice compared to wild-type (WT) mice. Cell-specificity studies using cre-lox mice demonstrate that the loss of NLRX1 in intestinal epithelial cells (IEC) recapitulate the increased sensitivity to DSS colitis observed in whole body Nlrx1 -/- mice...
2018: Frontiers in Immunology
Laura Watts, Tugce Karaderi, Amity Roberts, Louise Appleton, Tom Wordsworth, Carla Cohen, Paul Wordsworth, Matteo Vecellio
Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy...
March 10, 2018: Genes and Immunity
Tingting Zheng, Weiheng Zhao, Hongjin Li, Shuxiu Xiao, Ran Hu, Miaomiao Han, Heng Liu, Yeqiang Liu, Kinya Otsu, Xinguang Liu, Gonghua Huang
Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38α activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38α in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38α in LCs specifically promoted IL-17 production from γδ and CD4+ T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion...
March 13, 2018: Science Signaling
Robert P Dickson, John R Erb-Downward, Nicole R Falkowski, Ellen M Hunter, Shanna L Ashley, Gary B Huffnagle
RATIONALE: The "gut-lung axis" is commonly invoked to explain the microbiome's influence on lung inflammation. Yet the lungs harbor their own microbiome which is altered in respiratory disease. The relative influence of gut and lung bacteria on lung inflammation is unknown. OBJECTIVES: To determine if baseline lung immune tone reflects local (lung-lung) or remote (gut-lung) microbe-host interactions. METHODS: We compared lung, tongue, and cecal bacteria in forty healthy, genetically-identical 10-week old mice using 16S rRNA gene quantification and sequencing...
March 13, 2018: American Journal of Respiratory and Critical Care Medicine
You-Hong Fang, You-You Luo, Jin-Dan Yu, Jin-Gan Lou, Jie Chen
AIM: To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease (VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS: A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing...
March 7, 2018: World Journal of Gastroenterology: WJG
Jia-Yue Zhang, Minxian Wang, Lei Tian, Giulio Genovese, Paul Yan, James G Wilson, Ravi Thadhani, Amy K Mottl, Gerald B Appel, Alexander G Bick, Matthew G Sampson, Seth L Alper, David J Friedman, Martin R Pollak
People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1 -associated kidney disease...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
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