DOCSLIB.ORG

IL2RA and IL7RA Genes Confer Susceptibility for Multiple Sclerosis in Two Independent European Populations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IL2RA and IL7RA Genes Confer Susceptibility for Multiple Sclerosis in Two Independent European Populations Genes and Immunity (2008) 9, 259–263 & 2008 Nature Publishing Group All rights reserved 1466-4879/08 $30.00 www.nature.com/gene ORIGINAL ARTICLE IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations F Weber1,10, B Fontaine2,3,4,10, I Cournu-Rebeix2,3,4, A Kroner5, M Knop1, S Lutz1,FMu¨ ller-Sarnowski1, M Uhr1, T Bettecken1, M Kohli1, S Ripke1, M Ising1, P Rieckmann5,11, D Brassat6, G Semana7, M-C Babron8,9, S Mrejen2,3,4, C Gout2,3,4, O Lyon-Caen2,3,4, J Yaouanq7, G Edan7, M Clanet6, F Holsboer1, F Clerget-Darpoux8,9,12 and B Mu¨ ller-Myhsok1,12 1Max Planck Institute of Psychiatry, Munich, Germany; 2Fe´de´ration des Maladies du Syste`me Nerveux, Assistance Publique-Hoˆpitaux de Paris, G.H. Pitie´-Salpeˆtrie`re, Paris, France; 3UMR546, INSERM, Paris, France; 4UMR S546, University Pierre et Marie Curie-Paris 6, Paris, France; 5Department of Neurology, University of Wu¨rzburg, Wu¨rzburg, Germany; 6Fe´de´ration de Neurologie, University of Toulouse, Toulouse, France; 7Department of Neurology, CHU Pontchaillou, Rennes, France; 8U535, INSERM, Villejuif, France and 9UMRS535, Univ Paris Sud, Villejuif, France Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated. Genes and Immunity (2008) 9, 259–263; doi:10.1038/gene.2008.14; published online 20 March 2008 Keywords: multiple sclerosis; genetics; interleukin-2 receptor a-subunit; interleukin-7 receptor a-subunit; risk factors; genetic predisposition to disease Introduction descendants which strengthens the hypothesis of genetic factors contributing to MS.2 Multiple sclerosis (MS)—the most common cause of Epidemiological studies performed in twins and chronic neurologic disability beginning in early to siblings clearly indicate the impact of genetic factors.3,4 middle adult life—is considered to be a multifactorial In addition, the geographical distribution of MS and disease involving both genetic and environmental studies of migrants also suggest a considerable contribu- factors. Evidence of genetic contribution to MS suscept- tion of environmental factors that may not be evenly ibility arose from familial aggregation, twin studies and distributed over the world. high incidence in populations of northern European Current evidence indicates that there is not only one origin, when compared with African and Asian groups.1 gene conferring susceptibility, but rather a number of The prevalence pattern may be explained, at least in part, genes—each contributing only a small amount.5 A large by migrations of northern European groups and their number of studies performed so far confirmed HLA- DRB1 on chromosome 6p21 to represent a major risk 6 Correspondence: Professor Dr med F Weber, Max Planck Institute factor for MS in all populations tested. However, it does of Psychiatry, Kraepelinstr. 2-10, Munich D-80804, Germany. not fully explain the genetic basis of the disease.7,8 Other E-mail: [email protected] loci outside the human leukocyte antigen (HLA) region 10These are the equal first authors. were suspected by the results of several candidate genes 11 Current address: MS Clinic, Division of Neurology, UBC Hospital, or genome-wide approaches, but could not be validated Vancouver, Canada. 12These are the equal last authors. in other samples—until recently. Variations in the Received 10 December 2007; revised 5 February 2008; accepted 7 interleukin-2 receptor-a gene (IL2RA) and the interleu- February 2008; published online 20 March 2008 kin-7 receptor-a chain (IL7RA) were demonstrated to IL2RA and IL7RA as risk factors for MS F Weber et al 260 confer a risk for MS in candidate gene approaches and a positive trend in the French trios (Table 2). Linkage whole genome screen.9–11 disequilibrium between these two SNPs is strong (D0 ¼ 1 The association of MS with IL7RA was originally in the German cases, German controls, and French case reported in a candidate gene approach by Zhang et al.12 2 chromosomes, with D0 estimated at 0.989 in the French years ago, and is now replicated on large additional control chromosomes), but far from perfect (r2 ¼ 0.500, samples.9–11 Interestingly, linkage to chromosome 5p13, 0.552, 0.555 and 0.417, for the above-mentioned samples, precisely where IL7RA is located, was also reported in a respectively). The SNP rs6897932 located within the Canadian MS cohort with a maximum logarithm (base IL7RA gene exhibits a significant association in the 10) of odds score of 4.2413 and supported later by French trios and a positive trend in the German sample. others.14 With respect to IL2RA, genome-wide linkage Combining the results of both samples a significant P- analysis has shown potential linkage on chromosome value is obtained (Table 2). 10p15, which contains the IL2RA gene.15 Subsequently, a candidate approach on this gene first suggested an association between MS and IL2RA.16 This result was strongly supported by the whole genome approach on Discussion extremely large samples.11 This study reports the results obtained in two The identification of non-HLA genes conferring suscept- independent European MS samples (French and Ger- ibility for MS is difficult. Linkage analysis in nuclear man) by genotyping the three single nucleotide poly- families failed to identify additional loci with genome- morphisms (SNPs) showing the strongest association wide significance,8,17 but highlighted the IL2R and IL7R with MS in the study of the International Multiple regions13–15 and the involvement of these two genes were Sclerosis Genetics Consortium.11 Two SNPs are within suggested by candidate gene approaches.12,16 Recent the IL2RA gene (rs12722489, rs2104286) and one in the work9–11 on extremely large samples rendered IL2RA IL7RA gene (rs6897932). and IL7RA highly attractive and motivated further investigations. The risks associated to the SNPs of IL2RA and IL7RA however are modest at best (odds ratios Results between 1.1 and 1.5), so that only replications in a large number of different samples will make their involvement The three SNPs (rs12722489, rs2104286 and rs6897932) in MS susceptibility convincing. were typed in the German sample, consisting of 206 MS We confirm here the positive association with the same patients and 605 age and sex-matched controls, and in risk alleles within the IL2RA and the IL7RA genes in two the French sample, consisting of 540 MS trios. Basic independent European samples. The odds ratios are demographics of both samples are given in Table 1. A consistent with those previously published.9–11 The two statistical comparison showed significant difference SNPs typed in the IL2RA gene are in strong, but not between the samples for age at time of analysis, disease perfect, linkage disequilibrium, which could explain the course and Expanded Disability Status Scale (EDSS). observed difference in P-values and odds ratios ob- However, these differences do not alter the overall tained. Therefore, our findings convincingly corroborate genetic findings discussed below. the recently published results. Risk allele frequency (RAF) for the three SNPs, given In the meantime, another independent replication on a in Table 2, were estimated from the German control Canadian sample18 published similar results. In addition, sample and from the French untransmitted allele sample, association of IL2RA with MS susceptibility was also respectively. No significant difference was found be- recently concluded by Matesanz et al.16 with other SNPs tween our two populations, and the RAFs are very located within the IL2RA gene. Further studies on this similar to that of the original report.11 gene are needed to make a link between those different We first estimated the expected power of our two signals.19 In addition, it will be very important to take samples, under two scenarios (see Materials and meth- advantage of both the linkage and association informa- ods section) represented by the allele frequencies (0.75 tion for a better understanding and a refined modeliza- for the two first SNPs and 0.85 for the third one) and the tion of the effects of both the IL2RA and IL7RA genes.20,21 corresponding odds ratio (1.2 and 1.25 respectively) Together with the well-known HLA association these given in the original report. In both scenarios, the results fit very well the assumption that MS is an expected power for the French trio sample and the autoimmune disease caused by lymphocytes and mono- German sample was 56 and 38%, respectively. This cytes infiltrating the central nervous system.22 Both clearly demonstrates the interest in the joint analysis of cytokines are of central importance in promoting the samples.
Load more

Recommended publications
  • ENSG Gene Encodes Effector TCR Pathway Costimulation Inhibitory/Exhaustion Synapse/Adhesion Chemokines/Receptors
    ENSG Gene Encodes Effector TCR pathway Costimulation Inhibitory/exhaustion Synapse/adhesion Chemokines/receptors ENSG00000111537 IFNG IFNg x ENSG00000109471 IL2 IL-2 x ENSG00000232810 TNF TNFa x ENSG00000271503 CCL5 CCL5 x x ENSG00000139187 KLRG1 Klrg1 x ENSG00000117560 FASLG Fas ligand x ENSG00000121858 TNFSF10 TRAIL x ENSG00000134545 KLRC1 Klrc1 / NKG2A x ENSG00000213809 KLRK1 Klrk1 / NKG2D x ENSG00000188389 PDCD1 PD-1 x x ENSG00000117281 CD160 CD160 x x ENSG00000134460 IL2RA IL-2 receptor x subunit alpha ENSG00000110324 IL10RA IL-10 receptor x subunit alpha ENSG00000115604 IL18R1 IL-18 receptor 1 x ENSG00000115607 IL18RAP IL-18 receptor x accessory protein ENSG00000081985 IL12RB2 IL-12 receptor x beta 2 ENSG00000186810 CXCR3 CXCR3 x x ENSG00000005844 ITGAL CD11a x ENSG00000160255 ITGB2 CD18; Integrin x x beta-2 ENSG00000156886 ITGAD CD11d x ENSG00000140678 ITGAX; CD11c x x Integrin alpha-X ENSG00000115232 ITGA4 CD49d; Integrin x x alpha-4 ENSG00000169896 ITGAM CD11b; Integrin x x alpha-M ENSG00000138378 STAT4 Stat4 x ENSG00000115415 STAT1 Stat1 x ENSG00000170581 STAT2 Stat2 x ENSG00000126561 STAT5a Stat5a x ENSG00000162434 JAK1 Jak1 x ENSG00000100453 GZMB Granzyme B x ENSG00000145649 GZMA Granzyme A x ENSG00000180644 PRF1 Perforin 1 x ENSG00000115523 GNLY Granulysin x ENSG00000100450 GZMH Granzyme H x ENSG00000113088 GZMK Granzyme K x ENSG00000057657 PRDM1 Blimp-1 x ENSG00000073861 TBX21 T-bet x ENSG00000115738 ID2 ID2 x ENSG00000176083 ZNF683 Hobit x ENSG00000137265 IRF4 Interferon x regulatory factor 4 ENSG00000140968 IRF8 Interferon
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0070450 A1 Ishikawa Et Al
    US 20120070450A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0070450 A1 Ishikawa et al. (43) Pub. Date: Mar. 22, 2012 (54) LEUKEMA STEM CELLMARKERS Publication Classification (51) Int. Cl. A 6LX 39/395 (2006.01) (75) Inventors: Fumihiko Ishikawa, Kanagawa CI2O I/68 (2006.01) (JP): Osamu Ohara, Kanagawa GOIN 2L/64 (2006.01) (JP); Yoriko Saito, Kanagawa (JP); A6IP35/02 (2006.01) Hiroshi Kitamura, Kanagawa (JP); C40B 30/04 (2006.01) Atsushi Hijikata, Kanagawa (JP); A63L/7088 (2006.01) Hidetoshi Ozawa, Kanagawa (JP); C07K 6/8 (2006.01) Leonard D. Shultz, Bar Harbor, C7H 2L/00 (2006.01) A6II 35/12 (2006.01) ME (US) CI2N 5/078 (2010.01) (52) U.S. Cl. .................. 424/173.1; 424/178.1; 424/93.7: (73) Assignee: RIKEN, Wako-shi (JP) 435/6.14; 435/723; 435/375; 506/9: 514/44 A: 530/389.6; 530/391.7:536/24.5 (57) ABSTRACT (21) Appl. No.: 13/258,993 The invention provides a test method for predicting the initial onset or a recurrence of acute myeloid leukemia (AML) com PCT Fled: prising (1) measuring the expression level of human leukemic (22) Mar. 24, 2010 stem cell (LSC) marker genes in a biological sample collected from a Subject for a transcription product or translation prod uct of the gene as an analyte and (2) comparing the expression (86) PCT NO.: PCT/UP2010/0551.31 level with a reference value; an LSC-targeting therapeutic agent for AML capable of Suppressing the expression of a S371 (c)(1), gene selected from among LSC marker genes or a Substance (2), (4) Date: Dec.
    [Show full text]
  • A1068-CD86 Polyclonal Antibody
    BioVision 05/16 For research use only CD86 Polyclonal Antibody CATALOG NO: A1068-100 ALTERNATIVE NAMES: T-lymphocyte activation antigen CD86, Activation B7-2 antigen, B70, BU63, CTLA-4 counter-receptor B72, FUN-1, CD86, CD86, CD28LG2 Western blot analysis of CD86 in NCI-H292 cell line lysate AMOUNT: 100 µl IMMUNOGEN: KLH conjugated synthetic peptide between 269-298 amino acids from the C-terminal region of human CD86. MOLECULAR WEIGHT: 37 kDa HOST/ISOTYPE: Rabbit IgG SPECIES REACTIVITY: Human PURIFICATION: This antibody is purified through a protein A column, followed by peptide affinity purification. FORM: Liquid FORMULATION: Supplied in PBS with 0.09% (W/V) sodium azide. STORAGE CONDITIONS: Maintain refrigerated at 2-8°C for up to 6 months. For long term RELATED PRODUCTS storage store at -20°C in small aliquots to prevent freeze-thaw cycles. DESCRIPTION: This gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily. This protein is expressed by Human CellExp™ B7-2 /CD86, human recombinant (Cat. No. 7496-10, -50) antigen-presenting cells, and it is the ligand for two proteins at the CD86 (Human) ELISA Kit (Cat. No. K4175-100) cell surface of T cells, CD28 antigen and cytotoxic T-lymphocyte- Human CellExp™LAG3 /CD223, human recombinant (Cat. No. 7278-10, -50) associated protein 4. Binding of this protein with CD28 antigen is a costimulatory signal for activation of the T-cell. Binding of this CD223 (LAG3) Polyclonal Antibody (Cat. No. A1067-100) protein with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response.
    [Show full text]
  • Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples
    Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples Qiang Liu Chinese Academy of Medical Sciences & Peking Union Medical College Yihang Qi ( [email protected] ) Chinese Academy of Medical Sciences and Peking Union Medical College https://orcid.org/0000-0001- 7589-0333 Jie Zhai Chinese Academy of Medical Sciences & Peking Union Medical College Xiangyi Kong Chinese Academy of Medical Sciences & Peking Union Medical College Xiangyu Wang Chinese Academy of Medical Sciences & Peking Union Medical College Yi Fang Chinese Academy of Medical Sciences & Peking Union Medical College Jing Wang Chinese Academy of Medical Sciences & Peking Union Medical College Research Keywords: Cancer immunotherapy, CD223, LAG3, Immune response, Inammatory activity Posted Date: June 19th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-36422/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/33 Abstract Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer.
    [Show full text]
  • Diabetes in the Absence of LAG-3 Cutting Edge
    Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3 Maria Bettini, Andrea L. Szymczak-Workman, Karen Forbes, Ashley H. Castellaw, Mark Selby, Xiaoyu Pan, This information is current as Charles G. Drake, Alan J. Korman and Dario A. A. Vignali of September 24, 2021. J Immunol 2011; 187:3493-3498; Prepublished online 26 August 2011; doi: 10.4049/jimmunol.1100714 http://www.jimmunol.org/content/187/7/3493 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/08/26/jimmunol.110071 Material 4.DC1 http://www.jimmunol.org/ References This article cites 25 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/187/7/3493.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3 Maria Bettini,* Andrea L.
    [Show full text]
  • Point Mutation in CD19 Facilitates Immune Escape of B Cell Lymphoma from CAR-­T Cell Therapy
    Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001150 on 6 October 2020. Downloaded from Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR- T cell therapy 1 1 1 1 1 1 Zhen Zhang, Xinfeng Chen, Yonggui Tian, Feng Li , Xuan Zhao, Jinyan Liu, 1 1,2,3,4 Chang Yao, Yi Zhang To cite: Zhang Z, Chen X, ABSTRACT relapses after CD19 CAR-T cell therapy are Tian Y, et al. Point mutation Background Tumor relapse due to mutation in CD19 can attributed to the antigen loss, indicating an in CD19 facilitates immune hinder the efficacy of chimeric antigen receptor (CAR)- T urgent need for investigating the mechanisms escape of B cell lymphoma from cell therapy. Herein, we focused on lymphoma patients CAR- T cell therapy. Journal underlying recurrence and for improving whose B cells exhibited a point mutation in CD19 of B cells 4 5 for ImmunoTherapy of Cancer the efficacy of CAR- T cell therapy. Inter- 2020; :e001150. doi:10.1136/ after CAR-T cell infusion. 8 + estingly, one of the specific mechanisms jitc-2020-001150 Methods The CAR- T and CD19 B cells from peripheral blood or bone marrow were assessed using flow of tumor escape that has been reported cytometry. Genome sequencing was conducted to identify suggests that exon mutations affecting the ► Additional material is + published online only. To view, the molecular characteristics of CAR- T and CD19 B cells CD19 gene and its splicing isoforms, leading please visit the journal online from pre-rela pse and postrelapse samples.
    [Show full text]
  • LAG-3: from Molecular Functions to Clinical Applications
    Open access Review J Immunother Cancer: first published as 10.1136/jitc-2020-001014 on 13 September 2020. Downloaded from LAG-3: from molecular functions to clinical applications Takumi Maruhashi , Daisuke Sugiura , Il- mi Okazaki , Taku Okazaki To cite: Maruhashi T, Sugiura D, ABSTRACT (PD-1) and cytotoxic T lymphocyte antigen Okazaki I, et al. LAG-3: from To prevent the destruction of tissues owing to excessive 4 (CTLA-4) significantly improved the molecular functions to clinical and/or inappropriate immune responses, immune outcomes of patients with diverse cancer applications. Journal for cells are under strict check by various regulatory ImmunoTherapy of Cancer types, revolutionizing cancer treatment. The mechanisms at multiple points. Inhibitory coreceptors, 2020;8:e001014. doi:10.1136/ success of these therapies verified that inhib- including programmed cell death 1 (PD-1) and cytotoxic jitc-2020-001014 itory coreceptors serve as critical checkpoints T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against for immune cells to not attack the tumor Accepted 29 July 2020 self- tissues and tumor cells. Immune checkpoint inhibitors cells as well as self-tissues. However, response that block PD-1 and CTLA-4 pathways significantly rates are typically lower and immune-related improved the outcomes of patients with diverse cancer adverse events (irAEs) are also observed in types and have revolutionized cancer treatment. However, patients administered with immune check- response rates to such therapies are rather limited, and point inhibitors. This is indicative of the immune-rela ted adverse events are also observed in a continued need to decipher the complex substantial patient population, leading to the urgent need biology of inhibitory coreceptors to increase for novel therapeutics with higher efficacy and lower response rates and prevent such unwanted toxicity.
    [Show full text]
  • Contribution of IL9, IL2RA and IL2RB Genetic Polymorphisms in Coronary Heart Disease in Chinese Han Population
    Contribution of IL9, IL2RA and IL2RB genetic polymorphisms in coronary heart disease in Chinese Han population Xianghong Chen The Second Aliated Hospital of Hainan Medical University Xingfan Wang The Second Aliated Hospital of Hainan Medical University Zaozhang q Zhang The second Aliated Hospital of Hainan Medical University Yuewu Chen The Second Aliated Hospital of Hainan Medical University Chao Wang ( [email protected] ) The Second Aliated Hospital of Hainan Medical Universiy https://orcid.org/0000-0001-5632-9778 Research article Keywords: Posted Date: December 9th, 2019 DOI: https://doi.org/10.21203/rs.2.18401/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/11 Abstract Background: Coronary heart disease (CHD) is one of the leading causes of disability and death worldwide. In the pathogenesis of CHD, inammatory cytokines take an essential part. This study was designed to detect the potential association between IL-9, IL-2RA and IL-2RB variants and CHD in Chinese Han population. Methods: This case-control study conducted 499 CHD patients and 496 healthy controls. Seven selected SNPs were genotyped to investigate the possible association between the polymorphisms and the CHD risk. The interaction of SNP-SNP in the CHD risk was analyzed by Multifactor dimensionality reduction (MDR). Results: We observed an association between IL-9 rs55692658 (OR = 1.72, p = 0.003) and the increased CHD risk. The stratication analysis by age indicated that no matter participants who were older or younger than 61 years, IL-9 rs55692658 and IL-2RB rs1573673 contributed to the CHD susceptibility signicantly (p < 0.05, respectively).
    [Show full text]
  • An Ontogenetic Switch Drives the Positive and Negative Selection of B Cells
    An ontogenetic switch drives the positive and negative selection of B cells Xijin Xua, Mukta Deobagkar-Lelea, Katherine R. Bulla, Tanya L. Crockforda, Adam J. Meadb, Adam P. Cribbsc, David Simsc, Consuelo Anzilottia, and Richard J. Cornalla,1 aMedical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom; bMedical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom; and cMedical Research Council, Weatherall Institute of Molecular Medicine, Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom Edited by Michael Reth, University of Freiburg, Freiburg, Germany, and approved January 6, 2020 (received for review September 3, 2019) + Developing B cells can be positively or negatively selected by self- BM HSCs increased CD5 B-1a B cell development (15), while antigens, but the mechanisms that determine these outcomes are expression of let-7b in FL pro-B cells blocked the development of incompletely understood. Here, we show that a B cell intrinsic B-1 B cells (17). These findings support the notion of hard-wired switch between positive and negative selection during ontogeny differences during ontogeny, but possibly downstream of the HSC is determined by a change from Lin28b to let-7 gene expression. commitment stage. Ectopic expression of a Lin28b transgene in murine B cells restored Several lines of evidence also suggest that B-1 B cells can un- the positive selection of autoreactive B-1 B cells by self-antigen in dergo positive selection, which is linked to their B cell receptor adult bone marrow.
    [Show full text]
  • Lymphocyte Activation Gene-3 – the Expression and Function in the Immune System
    Lymphocyte Activation Gene-3 – the expression and function in the immune system Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-naturwissenschaftlichen Fakultät der Universität Basel von Malgorzata Kisielow aus Edmonton, Kanada Basel, 2006 Genehmigt von der Philosphisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Antonius Rolink und PD. Dr. Patrick Matthias Basel, den 24 Mai 2005 Prof. Dr. Hans-Jakob Wirz 2 Mojej Mamie Mojemu Tacie 3 TABLE OF CONTENTS ABBREVIATIONS 7 SUMMARY 9 1. INTRODUCTION 11 1.1. The immune system 11 1.1.1. Players of adaptive immunity 12 1.1.1.1. B lymphocytes 12 - B2 B cells 13 - B1 B cells 13 - Marginal zone B cells 14 1.1.1.2. T lymphocytes 14 - αβ T cells 15 Helper T cells 15 Cytotoxic T cells 16 Regulatory T cells 16 NK T cells 17 - γδ T cells 18 1.1.1.3. Antigen Presenting Cells 18 - Denritic cells 19 1.1.1.4. Natural Killer Cells 21 1.1.2. Lymphocyte homeostasis 21 1.1.3. T cell responses 22 1.1.4. T cell-B cell collaboration in B cell responses 24 - Germinal Center reaction 27 1.2. Lymphocyte Activation Gene-3 28 1.2.1. Identification and the predicted structure 28 1.2.2. LAG-3 expression pattern 31 1.2.3. Regulation of Lag-3 expression 33 1.2.4. Suggested function of LAG-3 35 1.2.5. Mode of action of LAG-3 36 1.2.6. LAG-3 and cancer 38 2. THESIS OBJECTIVES 40 3.
    [Show full text]
  • Impact of IL-27 on Regulatory T Cell Responses
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Impact of IL-27 on regulatory T cell responses Aisling Catherine O'Hara University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation O'Hara, Aisling Catherine, "Impact of IL-27 on regulatory T cell responses" (2013). Publicly Accessible Penn Dissertations. 906. https://repository.upenn.edu/edissertations/906 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/906 For more information, please contact [email protected]. Impact of IL-27 on regulatory T cell responses Abstract Interleukin (IL)–27 is a heterodimeric cytokine with potent inhibitory properties. Thus, mice that lack IL–27–mediated signaling develop exaggerated inflammatory responses during toxoplasmosis as well as other infections or autoimmune processes. While regulatory T (Treg) cells are critical to limit inflammation, their oler during toxoplasmosis is controversial because this infection results in a dramatic decrease in the total numbers of these cells associated with reduced levels of IL–2. Because IL–27 suppresses IL–2, we initially hypothesized that it was responsible for the Treg cell “crash”. Thus, we examined the role of IL–27 and IL–2 and their effects on Treg cells during toxoplasmosis. We observed that although IL–2 production is enhanced in the absence of IL–27, this was not sufficiento t rescue Treg cell frequencies during infection. Rather, our data indicated that IL–27 promoted an immunosuppressive Treg cell population that displayed a T helper 1 (TH1) phenotype, characterized by the expression of T–bet, CXCR3, IL–10 and interferon (IFN)–γ.
    [Show full text]
  • Circulating Exosomes Inhibit B Cell Proliferation and Activity
    cancers Article Circulating Exosomes Inhibit B Cell Proliferation and Activity Jan C. Schroeder , Lisa Puntigam, Linda Hofmann , Sandra S. Jeske, Inga J. Beccard, Johannes Doescher, Simon Laban, Thomas K. Hoffmann, Cornelia Brunner , , Marie-Nicole Theodoraki y and Patrick J. Schuler * y Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University, 89075 Ulm, Germany; [email protected] (J.C.S.); [email protected] (L.P.); [email protected] (L.H.); [email protected] (S.S.J.); [email protected] (I.J.B.); [email protected] (J.D.); [email protected] (S.L.); T.hoff[email protected] (T.K.H.); [email protected] (C.B.); [email protected] (M.-N.T.) * Correspondence: [email protected]; Tel.: +49-731-500-59501 These authors contributed equally. y Received: 23 June 2020; Accepted: 24 July 2020; Published: 29 July 2020 Abstract: (1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography.
    [Show full text]