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IL21R (interleukin 21 receptor)

Written2008-10Silvano Ferrini, Marina Fabbi
Lab of Immunotherapy Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy
Updated2012-05Silvano Ferrini, Marina Fabbi
Lab of Immunotherapy Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)CD360
Other aliasIL-21R
MGC10967
NILR
HGNC (Hugo) IL21R
LocusID (NCBI) 50615
Atlas_Id 40955
Location 16p12.1  [Link to chromosome band 16p12]
Location_base_pair Starts at 27438579 and ends at 27463363 bp from pter ( according to hg19-Feb_2009)  [Mapping IL21R.png]
Local_order The human IL21R gene maps on 16p11 between the IL4R and the GTF3C1 loci.
Fusion genes
(updated 2016)
BCL6 (3q27.3) / IL21R (16p12.1)IL21R (16p12.1) / BCL6 (3q27.3)
Note The gene for interleukin 21 receptor is the partner of BCL6 in t(3;16)(q27;p11) translocation, which is recurrently observed in diffuse large B-cell lymphoma (Ueda et al., 2002).

DNA/RNA

 
  Diagram of IL21R gene organization and of the encoded transcripts. The IL21R gene is comprised of 11 exons and encodes for three alternatively spliced transcript variants that use a different first exon. As the first exon is contained within the 5' UTR region the three transcripts encode for the same protein.
Description The IL21R gene is comprised of 9 exons (+2 alternative first exons), spanning 48.4kb on chromosome 16p11 (Parrish-Novak et al., 2000).
The human IL21R promoter region, contained within nucleotides -789 to +195 (relative to the start of exon 1a) induces the high levels of transcription in reporter assays (Ueda et al., 2002). A critical SP1 binding site is contained in the region from -80 to -20 and is essential for gene expression in human T cells (Wu et al., 2005).
The DNA region (12MB) containing the IL21R gene contains multiple copies of large, duplicated segments (duplicons) originating in other regions of the genome (Loftus et al., 1999), which may predispose to additional duplications or deletions.
Transcription Three alternatively spliced transcript variants of 3248, 3361 and 3263 bp, each comprising 9 exons, have been described. They differ only for the alternative usage of a different first exon, which is contained within the 5' UTR region. Therefore these transcript variants encode for the same protein.

Protein

 
  The IL21R requires interaction with the common-gamma chain (γc) for mediating signal transduction upon IL21 binding. The tyrosine kinases JAK1 and JAK3 associate with the receptor complex and mediate receptor chain phosphorylation, recruitment and activation of downstream STAT1 and STAT3 molecules.
Description The IL21R gene encodes for a 538 aminoacid precursor protein with a 19 aminoacid signal peptide. The mature IL21R protein is a transmembrane glycoprotein with a molecular mass of approximately 75 kDa. IL21R is a type I cytokine receptor with an extracellular domain involved in cytokine binding, which contains one copy of the conserved WSXWS (Trp-Ser-X-Trp-Ser) motif, two fibronectin type-III domains of about 100 amino acids each, and conserved cysteine residues (Parrish-Novak, 2000). IL21R has a transmembrane domain followed by a large intracellular domain that contains the Box 1 and Box 2 elements shown to be important in signal transduction, and six tyrosine residues. The IL-21R also displays a consensus motif for STAT3 binding in its C-terminal tail. IL21R forms a heterodimeric receptor complex with the common gamma-chain (CD132) (Asao et al., 2001), which is also shared as subunit by the receptors for interleukin 2, interleukin 4, interleukin 7, interleukin 9, and interleukin 15.
The crystal structure of IL21 bound to IL21R revealed that the IL21R WSXWS motif is C-mannosylated at the first tryptophan. A sugar chain bridges the two fibronectin domains of the IL21R extracellular portion and anchors at the WSXWS motif through hydrogen bonds (Hamming et al., 2012).
Expression IL21R is expressed on normal B, T and NK lymphoid cells and also on monocyte/macrophages and dendritic cells.
It is of note that also certain lymphoid neoplasias, such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, B-chronic lymphocytic leukemia and acute T cell leukemia express IL21R.
IL21R expression has been reported on other non-immune cell types such as intestinal epithelium in inflammatory bowel disease (Caruso et al., 2007a), gastric epithelium in Helicobacter pylori infection (Caruso et al., 2007b) and rheumatoid synovium (Jungel et al., 2004).
Localisation IL21R protein is localized at the cell membrane.
Function The IL21R mediates the pleiotropic biological activities of IL21, the lastly identified member of the IL2 family (Parrish-Novak et al., 2000). IL21 co-stimulates mature T and B cell proliferation and differentiation and also potentiate NK cytolytic functions, inducing NK terminal differentiation (Kasaian et al., 2002). IL21 also promotes proliferation, cytotoxic function and IFN-gamma production by murine and human CD8+ effector T cells (Parrish-Novak et al., 2000; Strengell et al., 2003; Di Carlo et al., 2004). IL21R signaling may mediate B cell proliferation and survival or B-cell apoptosis, in relationship to the activation status of the B cells (Ozaki et al., 2004; Metha et al., 2003; Jin et al., 2004). Mice deficient of IL21R (IL21R -/-) show defects in antibody production (in particular decreased IgG1 and increased IgE production in response to antigen stimulation) and reduced CTL responses, although their CD8+ T cell numbers are normal (Ozaki et al., 2002). The IL21/IL21R system is also a regulator of Th17 development and activity (Wei et al., 2007).
The IL21R/common gamma chain complex, upon engagement of its specific ligand IL21, mediates signal transduction through the activation of downstream signaling molecules. These include the tyrosine kinases JAK1 and JAK3, which phosphorylate STAT1 and STAT3 (Zeng et al., 2007; de Totero et al., 2008). Differently from IL2 and IL15, which also use the common gamma chain and JAK3 for signaling and are strong inducers of STAT5 activation, IL21 is a weak inducer of STAT5 activation.
IL21R signaling also leads to weak activation of both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase pathways (PI3K) (Zeng et al., 2007).
Homology IL21R displays structural homologies with other members of the type I cytokine receptor family, such as the IL2Rbeta chain (29% identity, 46% similarity), IL9R, IL4R and IL7R. It has been initially described as an orphan cytokine receptor, structurally related to the IL2Rbeta (Parrish-Novak et al., 2000; Ozaki et al., 2000).

Mutations

Note Not yet described. Genetic polymorphisms of IL21R have been described (Heckert et al., 2003). The IL21 variant bearing the (T-83C) genetic polymorphism has been associated with increased IgE levels in females, suggesting a possible role of this IL21R polymorphism in allergy.

Implicated in

Note
  
Entity Multiple myeloma (MM)
Disease IL21R is expressed on MM cell lines and primary cells. IL21 induced proliferation and inhibited apoptosis of IL6-dependent human myeloma cell lines. Tumor necrosis factor (TNF) up-regulated the expression of IL21R and combinations of TNF and IL21 synergistically mediated myeloma cell proliferation. Four out of 9 purified primary myeloma cells showed increased DNA synthesis in response to IL21 (Brenne et al., 2002).
  
  
Entity HTLV-I-infected cell lines and Acute T cell leukemia (ATL)
Disease HTLV-I-infected cell lines and primary ATL cells expressed IL21R mRNA and surface protein. IL21 induced the proliferation of ATL cell lines and activated the phosphorylation of the STAT3 and STAT5. These findings suggest that the IL21/IL21R system may represent a target for the treatment of ATL (Ueda et al., 2005).
  
  
Entity Hodgkin lymphoma (HL)
Disease IL21R as well as IL21 are expressed by HL cells. IL21 activates STAT3 and STAT5 in HL cell lines. Expression of a constitutively active STAT5 molecule in normal human B cells immortalized them. These data suggest that the IL21/IL21R system may activate auto/para-crine loops involved in HL genesis via STAT5 activation (Sheeren et al., 2008).
IL21 also protects HRS cells from CD95 death receptor-induced apoptosis and up-regulates the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha), which attracts regulatory T cells towards HL cells (Lamprecht et al., 2008).
  
  
Entity Sézary syndrome (SS)
Disease SS is a cutaneous CD4+ T-cell lymphoma. IL21 and IL21R are expressed by skin SS cells and STAT3 is constitutively activated. In vitro experiments showed that IL21 itself and the IL2R α-chain are STAT3 target genes in SS cells. These data indicate the existence of an autocrine feedback loop involving IL21/IL21R in the pathogenesis of SS and suggest that IL21 and IL21R are potential therapeutic targets (van der Fits et al., 2012).
  
  
Entity Anaplastic large cell lymphoma (ALKL)
Disease ALKL primary tumors and cell lines express IL21R. IL21 induces JAK3/STAT3 signaling and increases growth of ALKL cell lines. Small interfering RNA down-regulation of IL21R decreased both STAT3 activation and cell growth, further supporting a role for IL21/IL21R in ALKL (Dien Bard et al., 2009).
  
  
Entity B-Chronic Lymphocytic Leukemia (B-CLL)
Disease B-CLL cells express IL21R at variable levels and stimuli such as CpG-ODN (Jahrsdorfer et al., 2006) or CD40L (de Totero et al., 2006) induce up-regulation of IL-21R expression. IL21 mediates apoptosis in B-CLL acting in synergy with these stimuli and may also cooperate with chemotherapy (fludarabine) or anti-CD20 therapeutic antibodies (Gowda et al., 2008).
IL21 may limit the expansion of the CLL clone by inducing apoptosis and counteracting the mitogenic growth factors, such as IL15 (de Totero et al., 2008) and is being considered as a possible therapeutic agent in CLL (Gowda et al., 2008).
  
  
Entity Follicular lymphoma (FL)
Disease IL21R is expressed on FL cell lines and primary cells, and IL21 induces apoptosis in some FL cell lines and in primary FL cells at diagnosis (Akamatsu et al., 2007; de Totero et al., 2011). However, other FL cell lines or primary cells from patients in progression express low IL21R and are insensitive to IL21-mediated apoptosis (de Totero et al., 2011).
  
  
Entity Diffuse large B-cell lymphoma (DLBCL)
Disease DLBCL cell lines and primary cells express IL21R and IL21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis. These effects are STAT3-dependent and involve up-regulation of c-Myc expression. Up-regulated c-Myc decreases the expression of antiapoptotic Bcl-2 and Bcl-X(L) proteins and results in cell death (Sarosiek et al., 2010).
DLBCL is associated in about 28.6-35.5% with BCL6 translocation, which can involve either one of the immunoglobulin genes (IGs) but also other non-IG partners. IL21R gene represents one of such non-Ig fusion partners of BCL6 in the t(3;16) translocation (Ueda et al., 2002).
Cytogenetics FISH of lymphoma metaphase cells revealed fusion signals that contained both the BCL6 and IL21R sequences on the der(3)t(3;16) chromosome.
Hybrid/Mutated Gene As a result of the t(3;16) translocation, the promoter region of IL21R was substituted for the regulatory sequences of BCL6. RT-PCR analyses revealed the presence of a chimeric mRNA consisting of two non-coding exons 1a/1b of IL21R and coding exons of BCL6 in the two lymphoma cells. BCL6 was moderately expressed at the mRNA and protein level under the control of IL21R promoter (Ueda et al., 2002).
Abnormal Protein None.
Oncogenesis Unknown role.
  
  
Entity Autoimmune diseases, allergy and neoplasia
Note Several evidences in experimental murine models indicate that the IL21/IL21R system may be involved in immune-mediated disorders, such as autoimmune diabetes (Spolski et al., 2008), arthritis (Jungel et al., 2004), uveitis (Wang et al., 2011), Sjogren's syndrome (Kang et al., 2011), and systemic lupus erythematosus (SLE) (Herber et al., 2007). The study of the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE showed a correlation with rs3093301, suggesting that IL21R is a novel susceptibility gene for SLE (Webb et al., 2009). In view of the role of the IL21/IL21R system in autoimmune disorders, anti-IL21 (Maurer et al., 2012) and anti-IL21R (Arai et al., 2010) human antibodies capable of inhibiting IL21 activity are under development for therapy.
In view of its immune-enhancing activities IL21 has been regarded as a suitable molecule for cancer immunotherapy (reviewed in Di Carlo et al., 2007; Sploski and Leonard, 2008; Skak et al., 2008) and clinical phase I clinical trials in melanoma and renal carcinoma have shown acceptable toxicities and clinical activity (Thompson et al., 2008; Schmidt et al., 2010).
In addition, the IL21/IL21R system may play a role in several hematological neoplasias that express the IL21R. The effects of IL21R signaling may however be strikingly different in different neoplastic conditions, as it may transduce mitogenic or survival signals or on the opposite trigger apoptotic cell death. Thus the IL21/IL21R system may represent a therapeutic target for inhibitory molecules in certain hematologic neoplasias, whereas in others IL21 may represent a possible therapeutic agent.
  
  
Entity Graft verus host disease (GVHD)
Disease Abrogation of IL21 signaling reduces GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses (Hanash et al., 2009). In a murine MHC-mismatched bone marrow transplantation model IL21R-/- donor T cells mediated decreased systemic and gastrointestinal GVHD in transplant recipients. IL21R-/- T cells showed decreased inflammatory cytokine production within the mesenteric lymph nodes, in association with increased regulatory T cell expansion. However, Th-cell cytokine production was maintained peripherally, and IL21R-/- T cells mediated equivalent GVL against hematopoietic tumors. Therefore IL21 is a potential target for therapeutic intervention in bone marrow transplantation (Bucher et al., 2011).
  
  
Entity Inflammatory bowel disease (IBD)
Disease IL21R is expressed at high levels on intestinal epithelial cells and stomal fibroblasts in IBD. IL21 induced macrophage inflammatory protein-3 alpha (MIP-3alpha), a T-cell chemoattractant in epithelial cells. Therefore IL21 has been involved in the cross-talk between epithelial and immune cells in the gut (Caruso et al., 2007b).
  
  
Entity Rheumatoid Arthritis (RA)
Disease Both synovial macrophages and synovial fibroblasts expressed IL21R in synovial biopsy samples from RA patients. IL21R is associated with the activated phenotype of fibroblasts (Jungel et al., 2004).
  
  
Entity Helicobacter pylori (HP) gastritis
Disease Hp infection is associated with gastric inflammation. IL21R is expressed by primary gastric epithelial cells and cell lines, which respond to IL21 by increasing production of MMP-2 and MMP-9. Since IL21 is overexpressed in Hp-infected gastric mucosa it could contribute to increased epithelial gelatinase production (Caruso et al., 2007a).
  

Breakpoints

Note Two t(3;16)(q27;p11) breakpoints on 16p11 are both localized within the intron 1 of IL-21R gene in two different DLBCL (Ueda et al., 2002).

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PMID 17447063
 
Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sezary syndrome.
van der Fits L, Out-Luiting JJ, van Leeuwen MA, Samsom JN, Willemze R, Tensen CP, Vermeer MH.
J Invest Dermatol. 2012 Feb;132(2):440-7. doi: 10.1038/jid.2011.293. Epub 2011 Sep 22.
PMID 21938013
 

Citation

This paper should be referenced as such :
Ferrini, S ; Fabbi, M
IL21R (interleukin 21 receptor)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):716-722.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IL21RID40955ch16p12.html
History of this paper:
Ferrini, S ; Fabbi, M. IL21R (interleukin 21 receptor). Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):634-638.
http://documents.irevues.inist.fr/bitstream/handle/2042/44554/10-2008-IL21RID40955ch16p12.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(3;16)(q27;p11) IL21R/BCL6


External links

Nomenclature
HGNC (Hugo)IL21R   6006
LRG (Locus Reference Genomic)LRG_731
Cards
AtlasIL21RID40955ch16p12
Entrez_Gene (NCBI)IL21R  50615  interleukin 21 receptor
AliasesCD360; NILR
GeneCards (Weizmann)IL21R
Ensembl hg19 (Hinxton)ENSG00000103522 [Gene_View]  chr16:27438579-27463363 [Contig_View]  IL21R [Vega]
Ensembl hg38 (Hinxton)ENSG00000103522 [Gene_View]  chr16:27438579-27463363 [Contig_View]  IL21R [Vega]
ICGC DataPortalENSG00000103522
TCGA cBioPortalIL21R
AceView (NCBI)IL21R
Genatlas (Paris)IL21R
WikiGenes50615
SOURCE (Princeton)IL21R
Genetics Home Reference (NIH)IL21R
Genomic and cartography
GoldenPath hg19 (UCSC)IL21R  -     chr16:27438579-27463363 +  16p11   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)IL21R  -     16p11   [Description]    (hg38-Dec_2013)
EnsemblIL21R - 16p11 [CytoView hg19]  IL21R - 16p11 [CytoView hg38]
Mapping of homologs : NCBIIL21R [Mapview hg19]  IL21R [Mapview hg38]
OMIM147050   605383   615207   
Gene and transcription
Genbank (Entrez)AA354979 AF254067 AF269133 AK292663 AK312825
RefSeq transcript (Entrez)NM_021798 NM_181078 NM_181079
RefSeq genomic (Entrez)NC_000016 NC_018927 NG_012222 NT_187260 NW_004929400
Consensus coding sequences : CCDS (NCBI)IL21R
Cluster EST : UnigeneHs.210546 [ NCBI ]
CGAP (NCI)Hs.210546
Alternative Splicing GalleryENSG00000103522
Gene ExpressionIL21R [ NCBI-GEO ]   IL21R [ EBI - ARRAY_EXPRESS ]   IL21R [ SEEK ]   IL21R [ MEM ]
Gene Expression Viewer (FireBrowse)IL21R [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)50615
GTEX Portal (Tissue expression)IL21R
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9HBE5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9HBE5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9HBE5
Splice isoforms : SwissVarQ9HBE5
PhosPhoSitePlusQ9HBE5
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    HEMATOPO_REC_S_F1 (PS01355)   
Domains : Interpro (EBI)FN3_dom    Hempt_rcpt_S_F1_CS    Ig-like_fold   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)FN3 (SM00060)  
Conserved Domain (NCBI)IL21R
DMDM Disease mutations50615
Blocks (Seattle)IL21R
PDB (SRS)3TGX    4NZD   
PDB (PDBSum)3TGX    4NZD   
PDB (IMB)3TGX    4NZD   
PDB (RSDB)3TGX    4NZD   
Structural Biology KnowledgeBase3TGX    4NZD   
SCOP (Structural Classification of Proteins)3TGX    4NZD   
CATH (Classification of proteins structures)3TGX    4NZD   
SuperfamilyQ9HBE5
Human Protein AtlasENSG00000103522
Peptide AtlasQ9HBE5
HPRD05649
IPIIPI00034249   IPI00643921   
Protein Interaction databases
DIP (DOE-UCLA)Q9HBE5
IntAct (EBI)Q9HBE5
FunCoupENSG00000103522
BioGRIDIL21R
STRING (EMBL)IL21R
ZODIACIL21R
Ontologies - Pathways
QuickGOQ9HBE5
Ontology : AmiGOinterleukin-21 receptor activity  integral component of membrane  natural killer cell activation  interleukin-21-mediated signaling pathway  
Ontology : EGO-EBIinterleukin-21 receptor activity  integral component of membrane  natural killer cell activation  interleukin-21-mediated signaling pathway  
Pathways : KEGGCytokine-cytokine receptor interaction    Jak-STAT signaling pathway    Inflammatory bowel disease (IBD)   
NDEx NetworkIL21R
Atlas of Cancer Signalling NetworkIL21R
Wikipedia pathwaysIL21R
Orthology - Evolution
OrthoDB50615
GeneTree (enSembl)ENSG00000103522
Phylogenetic Trees/Animal Genes : TreeFamIL21R
HOVERGENQ9HBE5
HOGENOMQ9HBE5
Homologs : HomoloGeneIL21R
Homology/Alignments : Family Browser (UCSC)IL21R
Gene fusions - Rearrangements
Fusion : MitelmanIL21R/BCL6 [16p12.1/3q27.3]  
Fusion : TICdbIL21R [16p12.1]  -  BCL6 [3q27.3]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIL21R [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IL21R
dbVarIL21R
ClinVarIL21R
1000_GenomesIL21R 
Exome Variant ServerIL21R
ExAC (Exome Aggregation Consortium)IL21R (select the gene name)
Genetic variants : HAPMAP50615
Genomic Variants (DGV)IL21R [DGVbeta]
DECIPHER (Syndromes)16:27438579-27463363  ENSG00000103522
CONAN: Copy Number AnalysisIL21R 
Mutations
ICGC Data PortalIL21R 
TCGA Data PortalIL21R 
Broad Tumor PortalIL21R
OASIS PortalIL21R [ Somatic mutations - Copy number]
Cancer Gene: CensusIL21R 
Somatic Mutations in Cancer : COSMICIL21R  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIL21R
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch IL21R
DgiDB (Drug Gene Interaction Database)IL21R
DoCM (Curated mutations)IL21R (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IL21R (select a term)
intoGenIL21R
NCG5 (London)IL21R
Cancer3DIL21R(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM147050    605383    615207   
Orphanet22220   
MedgenIL21R
Genetic Testing Registry IL21R
NextProtQ9HBE5 [Medical]
TSGene50615
GENETestsIL21R
Huge Navigator IL21R [HugePedia]
snp3D : Map Gene to Disease50615
BioCentury BCIQIL21R
ClinGenIL21R
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD50615
Chemical/Pharm GKB GenePA29821
Clinical trialIL21R
Miscellaneous
canSAR (ICR)IL21R (select the gene name)
Probes
Litterature
PubMed50 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIL21R
EVEXIL21R
GoPubMedIL21R
iHOPIL21R
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:33:32 CEST 2017

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