DOCSLIB.ORG

Modulated in Intestinal Inflammation A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Modulated in Intestinal Inflammation A BTNL2, a Butyrophilin/B7-Like Molecule, Is a Negative Costimulatory Molecule Modulated in Intestinal Inflammation This information is current as Heather A. Arnett, Sabine S. Escobar, Eva Gonzalez-Suarez, of September 28, 2021. Alison L. Budelsky, Lori A. Steffen, Norman Boiani, Ming Zhang, Gerald Siu, Avery W. Brewer and Joanne L. Viney J Immunol 2007; 178:1523-1533; ; doi: 10.4049/jimmunol.178.3.1523 http://www.jimmunol.org/content/178/3/1523 Downloaded from References This article cites 40 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/178/3/1523.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology BTNL2, a Butyrophilin/B7-Like Molecule, Is a Negative Costimulatory Molecule Modulated in Intestinal Inflammation Heather A. Arnett,1* Sabine S. Escobar,1* Eva Gonzalez-Suarez,* Alison L. Budelsky,* Lori A. Steffen,* Norman Boiani,† Ming Zhang,§ Gerald Siu,§ Avery W. Brewer,‡ and Joanne L. Viney2* Butyrophilin-like 2 (BTNL2) is a butyrophilin family member with homology to the B7 costimulatory molecules, polymorphisms of which have been recently associated through genetic analyses to sporadic inclusion body myositis and sarcoidosis. We have characterized the full structure, expression, and function of BTNL2. Structural analysis of BTNL2 shows a molecule with an extracellular region containing two sets of two Ig domains, a transmembrane region, and a previously unreported cytoplasmic tail. Unlike most other butyrophilin members, BTNL2 lacks the prototypical B30.2 ring domain. TaqMan and Northern blot analysis indicate BTNL2 is predominantly expressed in digestive tract tissues, in particular small intestine and Peyer’s patches. Immunohisto- Downloaded from chemistry with BTNL2-specific Abs further localizes BTNL2 to epithelial and dendritic cells within these tissues. Despite its homology to the B7 family, BTNL2 does not bind any of the known B7 family receptors such as CD28, CTLA-4, PD-1, ICOS, or B and T lymphocyte attenuator. Because of its localization in the gut and potential role in the immune system, BTNL2 expression was analyzed in a mouse model of inflammatory bowel disease. BTNL2 is overexpressed during both the asymptomatic and symptomatic phase of the Mdr1a knockout model of spontaneous colitis. In functional assays, soluble BTNL2-Fc protein inhibits the proliferation of murine CD4؉ http://www.jimmunol.org/ T cells from the spleen, mesenteric lymph node, and Peyer’s patch. In addition, BTNL2-Fc reduces proliferation and cytokine produc- tion from T cells activated by anti-CD3 and B7-related protein 1. These data suggest a role for BTNL2 as a negative costimulatory molecule with implications for inflammatory disease. The Journal of Immunology, 2007, 178: 1523–1533. he regulation of T cell responses is achieved through Ag- (4–8) is expressed in both lymphoid and nonlymphoid cells (9). A specific TCRs acting together with coreceptors that can second inhibitory receptor PD-1 (10, 11) binds to either of two T modulate activation. One of the principal costimulatory B7-related ligands PD-L1 (also known as B7-H1) (12, 13) and pathways for naive T cells is initiated when CTLA-4 and CD28 PD-L2 (or B7-DC) (14, 15). Another inhibitory receptor, B and T engage B7 class molecules during TCR engagement by a primary lymphocyte attenuator (BTLA), binds to HVEM, previously iden- by guest on September 28, 2021 signal (1). These secondary costimulatory signals can either inhibit tified as a binding partner for LIGHT and lymphotoxin ␣. B7-H3, or promote T cell responses, depending on the receptor they en- another B7 homolog (16, 17), binds an unidentified receptor on gage. For example, B7-1 and B7-2 can bind either CD28, resulting activated T cells and serves as a negative regulator of T cell acti- in T cell stimulation, or CTLA-4, resulting in T cell inhibition (2). vation (18). A more recently described B7 family member, B7-H4 Negative signals can contribute to the attenuation of T cell re- (also called B7S1 or B7x) (19–21), acts as a novel costimulator sponses and so are important in regulating T cell tolerance. The and regulates the threshold of T cell activation. balance between stimulatory and inhibitory signals is critical to an Butyrophilin-like 2 (BTNL2) has been identified as a B7-like effective immune response. molecule within the butyrophilin gene family, located in the MHC In the past several years, new members of the B7 ligand and the locus in mice and humans (22). Recently, several studies have corresponding CD28/CTLA-4 receptor families have been identi- linked the gene for BTNL2 to two inflammatory diseases, sporadic fied, increasing our understanding of immune cell function. A sec- inclusion body myositis and sarcoidosis (23–25); however, no ond activating receptor in T cells is ICOS (3); its ligand B7-related function has been demonstrated for BTNL2. Although the buty- protein 1 (B7RP1)3 (also known as LICOS, GL50, B7-H2, or B7h) rophilin family of proteins share homology with the B7 family, no immune responses have been associated with BTNL1, the first and most broadly expressed butyrophilin. Because of its close struc- *Inflammation, †Protein Sciences, and ‡Pathology, Amgen, Seattle, WA 98119; and §Inflammation, Amgen, Thousand Oaks, CA 91320 tural homology to B7-1, BTNL2 has been hypothesized to have T cell costimulatory properties (25). Received for publication December 7, 2005. Accepted for publication October 17, 2006. In this study we characterize the expression of BTNL2 in normal The costs of publication of this article were defrayed in part by the payment of page and diseased tissue, and show evidence that BTNL2 down-regulates charges. This article must therefore be hereby marked advertisement in accordance T cell activation and may play a role in maintaining tolerance and with 18 U.S.C. Section 1734 solely to indicate this fact. resetting the balance of the immune response in the gut. 1 H.A.A. and S.S.E. contributed equally to this work. 2 Address correspondence and reprint requests to Dr. Joanne L. Viney, Department of Inflammation, Amgen, 1201 Amgen Court West, Seattle, WA 98119. E-mail address: Materials and Methods [email protected] Cloning 3 Abbreviations used in this paper: B7RP1, B7-related protein 1; BTLA, B and T lymphocyte attenuator; BTNL, butyrophilin-like; MLN, mesenteric lymph node; PP, Murine and human BTNL2 (accession nos. NM_023145 and NM_019602, Peyer’s patch; CHO, Chinese hamster ovary. respectively) were originally identified from the National Center for Bio- technology Information (NCBI) database based on homology to other B7 Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 family molecules. RACE PCR was performed to confirm 5Ј and 3Ј ends of www.jimmunol.org 1524 BTNL2 DOWN-REGULATES T CELL ACTIVATION the human and mouse BTNL2 genes based on the original deposits using 1% Triton X-100, with a protease inhibitor mixture (Boehringer Mann- RACE-Ready Marathon cDNA from human colon and mouse spleen (BD heim). Proteins were separated on 4–20% reducing Tris-glycine gel, trans- Clontech). In addition, cDNAs from human T84 (colon carcinoma) cells, ferred to nitrocellulose, and blocked overnight at 4°C in TBST plus 3% Caco2 (colon carcinoma) cells, and mouse colon were also used to confirm nonfat milk. After washing in TBST, the membranes were incubated with the final cDNA sequences. The final full-length coding region cDNAs of the murine BTNL2–77p polyclonal antisera or control sera for1hat4°C, human and mouse BTNL2 were then amplified as single cDNA contigs, followed by goat anti-rabbit HRP (1/5000; Amersham Biosciences) and with the new additional 3Ј sequence, and then subcloned into pCR4-Topo developed by chemiluminescence (Amersham Biosciences). (Invitrogen Life Technologies) and appropriate mammalian expression vectors. Independent PCR analyses were performed to confirm each final Immunohistochemistry murine and human BTNL2 sequence. The sequence results were compared with both the predicted sequence published by Stammers et al. (22) and the Frozen sections were fixed in acetone at 4°C for 10 min, washed in TBS NCBI database. Transmembrane and signal peptide predictions were predicted (pH 8.0; Sigma-Aldrich) three times, then blocked for endogenous perox- ϩ with TMHMM and SignalP (www.cbs.dtu.dk/services/TMHMM-2.0 and idase in glucose oxidase solution (b-D glucose (G-5250; Sigma-Aldrich), www.cbs.dtu.dk/services/SignalP). glucose oxidase (Sigma-Aldrich), sodium azide (Sigma-Aldrich), and TBS (pH 8.0)) for 30 min at 37°C. Sections were then treated with avidin and Quantitative real-time PCR biotin blocking solutions (Vector Laboratories) for 15 min each, rinsed in TBST and blocked in Tris/NaCl/blocking solution (TNB; PerkinElmer) Expression of murine BTNL2 was measured by quantitative real-time RT- for 30 min. Primary Ab was applied using anti-BTNL2 at 19.5 ␮g/ PCR using the ABI PRISM 7900HT sequence detection system (Applied Bio- ml (xmuRIBD006, rat IgG2a, clone M517; Amgen) or 20 ␮g/ml systems) and normalized to the expression of a housekeeping gene (HPRT).
Load more

Recommended publications
  • 1 Table S1. Outlier Loci Detected by Deepgenomescan Using
    Table S1. Outlier loci detected by DeepGenomeScan using geographic coordinates. Loci highlighted in red are detected by DeepGenomeScan but are not listed in Yang et al. (2012; Supplementary Table 4). RsID is annotated according to the dbSNP database released on 21st April, 2020. CHR BP (Grch37) BP (Grch38) rsID p.value Genes 1 1:4208918 1:4148858 rs9426495 3.8582E-104 1 1:175738168 1:175769032 rs6425357 2.0088E-105 2 2:20310668 2:20110907 rs11679737 1.2002E-111 LAPTM4A-DT 2 2:40289267 2:40062127 rs759361 5.5658E-104 SLC8A1-AS1 2 2:82495127 2:82268003 rs6726401 3.9451E-103 2 2:96660300 2:95994552 rs2579520 1.8176E-127 2 2:96672001 2:96006253 rs1917890 3.7698E-104 2 2:134333012 2:133575441 rs17816830 9.702E-105 NCKAP5 2 2:134350570 2:133592999 rs6715224 5.8745E-111 NCKAP5 2 2:134912243 2:134154672 rs2139309 1.7418E-191 MGAT5 2 2:134917005 2:134159434 rs11692586 9.2121E-151 MGAT5 2 2:134972732 2:134215161 rs11679218 0 MGAT5 2 2:134979966 2:134222395 rs1965183 5.3171E-107 MGAT5 2 2:135260071 2:134502500 rs503562 2.057E-153 TMEM163 2 2:135280039 2:134522468 rs579670 3.1477E-118 TMEM163 2 2:135285279 2:134527708 rs512375 0 TMEM163 2 2:135290221 2:134532650 rs655472 0 TMEM163 2 2:135290453 2:134532882 rs666614 0 TMEM163 2 2:135340840 2:134583270 rs842361 5.6717E-237 TMEM163 2 2:135393110 2:134635540 rs11684785 2.2164E-276 TMEM163 2 2:135430709 2:134673139 rs6745983 0 TMEM163 2 2:135469769 2:134712199 rs6747870 9.6117E-114 TMEM163 2 2:135483381 2:134725811 rs3739034 5.0357E-154 2 2:135483534 2:134725964 rs3739036 3.7269E-156 2 2:135539967 2:134782397
    [Show full text]
  • Next Generation Exome Sequencing of Paediatric Inflammatory Bowel Disease Patients Identifies Rare and Novel Variants in Candida
    Gut Online First, published on April 28, 2012 as 10.1136/gutjnl-2011-301833 Inflammatory bowel disease ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2011-301833 on 28 April 2012. Downloaded from Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes Katja Christodoulou,1 Anthony E Wiskin,2 Jane Gibson,1 William Tapper,1 Claire Willis,2 Nadeem A Afzal,3 Rosanna Upstill-Goddard,1 John W Holloway,4 Michael A Simpson,5 R Mark Beattie,3 Andrew Collins,1 Sarah Ennis1 < Additional materials are ABSTRACT published online only. To view Background Multiple genes have been implicated by Significance of this study these files please visit the association studies in altering inflammatory bowel journal online (http://gut.bmj. com/content/early/recent). disease (IBD) predisposition. Paediatric patients often What is already known on this subject? manifest more extensive disease and a particularly < For numbered affiliations see Genome-wide association studies have impli- end of article. severe disease course. It is likely that genetic cated numerous candidate genes for inflamma- predisposition plays a more substantial role in this group. tory bowel disease (IBD), but evidence of Correspondence to Objective To identify the spectrum of rare and novel causality for specific variants is largely absent. Dr Sarah Ennis, Genetic variation in known IBD susceptibility genes using exome Furthermore, by design, genome-wide associa- Epidemiology and Genomic sequencing analysis in eight individual cases of childhood Informatics Group, Human tion studies are limited to the study of Genetics, Faculty of Medicine, onset severe disease.
    [Show full text]
  • Familial Vs. Sporadic Sarcoidosis: BTNL2 Polymorphisms, Clinical
    Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort Yves Pacheco, Alain Calender, Dominique Israël-Biet, Pascal Roy, Serge Lebecque, Vincent Cottin, Diane Bouvry, Hilario Nunes, Pascal Sève, Laurent Pérard, et al. To cite this version: Yves Pacheco, Alain Calender, Dominique Israël-Biet, Pascal Roy, Serge Lebecque, et al.. Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort. Orphanet Journal of Rare Diseases, BioMed Central, 2016, 11 (1), 10.1186/s13023-016-0546-4. hal- 01595465 HAL Id: hal-01595465 https://hal.archives-ouvertes.fr/hal-01595465 Submitted on 26 Sep 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - ShareAlike| 4.0 International License Pacheco et al. Orphanet Journal of Rare Diseases (2016) 11:165 DOI 10.1186/s13023-016-0546-4 RESEARCH Open Access Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort Yves Pacheco1,11*, Alain Calender2, Dominique Israël-Biet3, Pascal Roy4, Serge Lebecque5, Vincent Cottin6, Diane Bouvry7, Hilario Nunes7, Pascal Sève8, Laurent Pérard9, Gilles Devouassoux8, Nathalie Freymond1, Chahira Khouatra6, Benoît Wallaert10, Raphaelle Lamy2, Mad-Hélénie Elsensohn4, Claire Bardel4, Dominique Valeyre7 and GSF group Abstract Background: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition.
    [Show full text]
  • 2027.Full.Pdf
    Butyrophilin-like 2 Modulates B7 Costimulation To Induce Foxp3 Expression and Regulatory T Cell Development in Mature T Cells This information is current as of September 28, 2021. Ryan M. Swanson, Marc A. Gavin, Sabine S. Escobar, James B. Rottman, Brian P. Lipsky, Shishir Dube, Li Li, Jeannette Bigler, Martin Wolfson, Heather A. Arnett and Joanne L. Viney J Immunol 2013; 190:2027-2035; Prepublished online 28 Downloaded from January 2013; doi: 10.4049/jimmunol.1201760 http://www.jimmunol.org/content/190/5/2027 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/01/28/jimmunol.120176 Material 0.DC1 References This article cites 40 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/190/5/2027.full#ref-list-1 by guest on September 28, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
    [Show full text]
  • Functions to Inhibit T Cell Activation BTNL2, a Butyrophilin-Like
    BTNL2, a Butyrophilin-Like Molecule That Functions to Inhibit T Cell Activation Thang Nguyen, Xikui K. Liu, Yongliang Zhang and Chen Dong This information is current as of October 2, 2021. J Immunol 2006; 176:7354-7360; ; doi: 10.4049/jimmunol.176.12.7354 http://www.jimmunol.org/content/176/12/7354 Downloaded from References This article cites 40 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/176/12/7354.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology BTNL2, a Butyrophilin-Like Molecule That Functions to Inhibit T Cell Activation1 Thang Nguyen,2* Xikui K. Liu,2† Yongliang Zhang,† and Chen Dong3† B7 family members regulate T cell activation and tolerance. Although butyrophilin proteins share sequence homology with the B7 molecules, it is unclear whether they have any function in immune responses.
    [Show full text]
  • FARE2017 WINNERS Sorted by Institute/Center
    FARE2017 WINNERS Sorted By Institute/Center NIH Clinical Center (CC) Zachary Lerner Postdoctoral FellowPostdoctoral Fellow Clinical and Translational Research A Robotic Exoskeleton to Treat Crouch Gait from Cerebral Palsy: Design and Initial Clinical Evaluation Cerebral palsy (CP) is the most prevalent childhood physical disability and adversely affects walking and other motor abilities. Crouch gait, a pathological walking pattern characterized by excessive knee flexion, is one of the most common gait disorders observed in children with CP. Effective treatment of crouch during childhood is critical to maintain mobility into adulthood, yet current interventions do not adequately eliminate or alleviate crouch in most patients. Wearable robotic exoskeletons have the potential to improve crouch gait by providing on demand assistance during walking. However, no exoskeletons suitable to treat children are commercially available, and no evidence exists regarding the feasibility or efficacy of utilizing motorized assistance to alleviate knee flexion from crouch gait. Enhanced knowledge of neuromuscular adaptations to powered assistance in children with crouch gait is needed to optimize this treatment approach. To meet these needs, we developed the first lower- extremity exoskeleton intended to treat crouch gait by providing powered knee extension assistance at different phases of the gait cycle. We evaluated the effects of powered knee extension assistance on knee motion, and knee flexor and extensor muscle activity in four children with crouch gait from CP. The exoskeleton was effective in reducing crouch in three of the four participants compared to their baseline gait pattern. The reduction in crouch was clinically significant (greater than 10 degrees) in two of the participants.
    [Show full text]
  • Functional Characterization of Potential New Agents for Cancer Immunotherapy
    Functional Characterization of Potential New Agents for Cancer Immunotherapy The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:39010116 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Functional Characterization of Potential New Agents for Cancer Immunotherapy Xiaoxu Wang A Thesis Submitted to the Faculty of The Harvard Medical School in Partial Fulfillment of the Requirements for the Degree of Master of Medical Sciences in Immunology Harvard University Boston, Massachusetts. May, 2018 Thesis Advisor: Dr. Gordon Freeman Xiaoxu Wang Functional Characterization of Potential New Agents for Cancer Immunotherapy Abstract PD-1/PD-L1 checkpoint blockade has demonstrated promise in a variety of malignancies. The blockade of T cell inhibitory molecules PD-1 and PD-L1 can rejuvenate T cells and improve tumor cell killing. However, the overall response rate of PD-1/PD-L1 immunotherapy is only about 20-30%. One promising method to improve cancer immunotherapy is combinatory immunotherapies that target new receptors/ligands regulating T cell activity, so the functional characterization of these new receptors/ligands is urgent. Due to the functional importance of the B7 superfamily in T cell activation, I studied T cell regulating functions of two poorly characterized B7 superfamily members, IgC domain-truncated CD86 and butyrophilin-like 2 (BTNL2).
    [Show full text]
  • Detection of BTNL2 Gene Mutation (Rs2076530 Allele) in Iranian
    icine- O ed pe M n l A Vazifehmand et al., Intern Med 2017, 7:3 a c n c r e e s t DOI: 10.4172/2165-8048.1000239 s n I Internal Medicine: Open Access ISSN: 2165-8048 Research Article Open Access Detection of BTNL2 Gene Mutation (rs2076530 Allele) in Iranian Sarcoidosis Patients: A clinical and Genetic Study Reza Vazifehmand1, Tina Saber2, Hamid Reza Khorram Khorshid3, Dhuha Saeed Ali4, Foroozandeh monem homaie5 and Sassan Saber6* 1Young Researchers and elite Club, Islamic Azad University- Rasht campus, Iran 2Beckman Laser Institute and Medical Clinic, University of California, Irvine, Ca, USA 3Genetic Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran 4Halal Products Research Institute, Universiti Putra Malaysia. Serdang,Selangor-Malaysia 5Departments of Biochemistry, Science and Research University-Fars Branch-Shiraz-Iran 6North Karegar Ave. Shariati Hospital, Faculty of Medicine, Tehran University of Medical Science-Tehran, Iran *Corresponding Author: Sassan Saber, North Karegar Ave. Shariati Hospital, Faculty of Medicine Tehran University of Medical Science, Tel: 00982188220000; E-mail: [email protected] Received date: October 24, 2016; Accepted date: May 05, 2017; Published date: May 15, 2017 Copyright: © 2017 Vazifehmand R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background/Aims: Sarcoidosis is a multiorgan granulomatous inflammatory disease of an unknown cause, probably due to inappropriate T-cell response. Mutation in BTNL2 gene (Butirophylin-like2) which is one of the most important genes in MHC II (complex tissue incompatibility) group is related to sarcoidosis.
    [Show full text]
  • Leveraging Models of Cell Regulation and GWAS Data in Integrative Network-Based Association Studies
    PERSPECTIVE Leveraging models of cell regulation and GWAS data in integrative network-based association studies Andrea Califano1–3,11, Atul J Butte4,5, Stephen Friend6, Trey Ideker7–9 & Eric Schadt10,11 Over the last decade, the genome-wide study of both heritable and straightforward: within the space of all possible genetic and epigenetic somatic human variability has gone from a theoretical concept to a variants, those contributing to a specific trait or disease likely have broadly implemented, practical reality, covering the entire spectrum some coalescent properties, allowing their effect to be functionally of human disease. Although several findings have emerged from these canalized via the cell communication and cell regulatory machin- studies1, the results of genome-wide association studies (GWAS) have ery that allows distinct cells to interact and regulates their behavior. been mostly sobering. For instance, although several genes showing Notably, contrary to random networks, whose output is essentially medium-to-high penetrance within heritable traits were identified by unconstrained, regulatory networks produced by adaptation to spe- these approaches, the majority of heritable genetic risk factors for most cific fitness landscapes are optimized to produce only a finite number common diseases remain elusive2–7. Additionally, due to impractical of well-defined outcomes as a function of a very large number of exog- requirements for cohort size8 and lack of methodologies to maximize enous and endogenous signals. Thus, if a comprehensive and accurate power for such detections, few epistatic interactions and low-pen- map of all intra- and intercellular molecular interactions were avail- etrance variants have been identified9. At the opposite end of the able, then genetic and epigenetic events implicated in a specific trait or germline versus somatic event spectrum, considering that tumor cells disease should cluster in subnetworks of closely interacting genes.
    [Show full text]
  • Use of Deep-Learning Genomics to Discriminate Healthy Individuals from Those with Alzheimer’S Disease Or Mild Cognitive Impairment
    Hindawi Behavioural Neurology Volume 2021, Article ID 3359103, 15 pages https://doi.org/10.1155/2021/3359103 Research Article Use of Deep-Learning Genomics to Discriminate Healthy Individuals from Those with Alzheimer’s Disease or Mild Cognitive Impairment Lanlan Li,1 Yeying Yang,2 Qi Zhang,1 Jiao Wang,3 Jiehui Jiang ,1 and Alzheimer’s Disease Neuroimaging Initiative4 1Institute of Biomedical Engineering, School of Communication and Information Engineering, Shanghai University, Shanghai 200444, China 2LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China 3School of Life Science, Shanghai University, Shanghai 200444, China 4Indiana University School of Medicine, Indianapolis, IN 46202, USA Correspondence should be addressed to Jiehui Jiang; [email protected] Received 14 May 2021; Accepted 11 June 2021; Published 15 July 2021 Academic Editor: Muh-Shi Lin Copyright © 2021 Lanlan Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Certain genes have been identified as important clinical risk factors for AD, and technological advances in genomic research, such as genome-wide association studies (GWAS), allow for analysis of polymorphisms and have been widely applied to studies of AD. However, shortcomings of GWAS include sensitivity to sample size and hereditary deletions, which result in low classification and predictive accuracy. Therefore, this paper proposes a novel deep-learning genomics approach and applies it to multitasking classification of AD progression, with the goal of identifying novel genetic biomarkers overlooked by traditional GWAS analysis.
    [Show full text]
  • A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression
    Supplementary Materials A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression Table S1. Statistically significant DEGs (Adj. p-value < 0.01) derived from meta-analysis for samples irradiated with high doses of HZE particles, collected 6-24 h post-IR not common with any other meta- analysis group. This meta-analysis group consists of 3 DEG lists obtained from DGEA, using a total of 11 control and 11 irradiated samples [Data Series: E-MTAB-5761 and E-MTAB-5754]. Ensembl ID Gene Symbol Gene Description Up-Regulated Genes ↑ (2425) ENSG00000000938 FGR FGR proto-oncogene, Src family tyrosine kinase ENSG00000001036 FUCA2 alpha-L-fucosidase 2 ENSG00000001084 GCLC glutamate-cysteine ligase catalytic subunit ENSG00000001631 KRIT1 KRIT1 ankyrin repeat containing ENSG00000002079 MYH16 myosin heavy chain 16 pseudogene ENSG00000002587 HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 ENSG00000003056 M6PR mannose-6-phosphate receptor, cation dependent ENSG00000004059 ARF5 ADP ribosylation factor 5 ENSG00000004777 ARHGAP33 Rho GTPase activating protein 33 ENSG00000004799 PDK4 pyruvate dehydrogenase kinase 4 ENSG00000004848 ARX aristaless related homeobox ENSG00000005022 SLC25A5 solute carrier family 25 member 5 ENSG00000005108 THSD7A thrombospondin type 1 domain containing 7A ENSG00000005194 CIAPIN1 cytokine induced apoptosis inhibitor 1 ENSG00000005381 MPO myeloperoxidase ENSG00000005486 RHBDD2 rhomboid domain containing 2 ENSG00000005884 ITGA3 integrin subunit alpha 3 ENSG00000006016 CRLF1 cytokine receptor like
    [Show full text]
  • WO 2016/070129 Al 6 May 2016 (06.05.2016) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/070129 Al 6 May 2016 (06.05.2016) W P O P C T (51) International Patent Classification: (74) Agent: BAKER, C , Hunter; Wolf, Greenfield & Sacks, A61K 9/00 (2006.01) C07K 14/435 (2006.01) P.C., 600 Atlantic Avenue, Boston, MA 02210-2206 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 15/058479 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 30 October 2015 (30.10.201 5) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 14/529,010 30 October 2014 (30. 10.2014) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: PRESIDENT AND FELLOWS OF HAR¬ VARD COLLEGE [US/US]; 17 Quincy Street, Cam (84) Designated States (unless otherwise indicated, for every bridge, MA 02138 (US).
    [Show full text]