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| Open AccessProduction of individualized V gene databases reveals high levels of immunoglobulin genetic diversity
Current databases of V genes for antibody repertoire have limitations. Here Corcoran et al. develop a computational approach named IgDiscover that can identify germline V gene sequences from expressed antibody repertoires to high specificity and completeness.
- Martin M. Corcoran
- , Ganesh E. Phad
- & Gunilla B. Karlsson Hedestam
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| Open AccessIncreased DNA methylation variability in type 1 diabetes across three immune effector cell types
The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.
- Dirk S. Paul
- , Andrew E. Teschendorff
- & R. David Leslie
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| Open Access17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells
Variations in the 17q21 locus are linked to asthma susceptibility and other autoimmune diseases. Here, the authors perform cell type-specific functional genomic analyses of asthma-risk SNPs, and show a genotype specific mechanism of differential gene regulation relevant to immune function.
- Benjamin Joachim Schmiedel
- , Grégory Seumois
- & Pandurangan Vijayanand
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| Open AccessEnvelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus
Infection of African green monkeys with simian immunodeficiency virus is a potential model for HIV vaccine development. Here, Zhang et al. catalogue the immunoglobulin loci present in the genome of these animals, and experimentally study their B-cell response to the viral envelope protein.
- Ruijun Zhang
- , David R. Martinez
- & Sallie R. Permar
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| Open AccessThe elongation factor Spt5 facilitates transcription initiation for rapid induction of inflammatory-response genes
A subset of inflammatory-response NF-κB target genes is activated immediately after proinflammatory stimulation. Here, the authors show that in rapidly induced genes, depletion of the elongation factor Spt5 reduces transcription initiation and TFIID–promoter association without affecting the transcription elongation rate.
- Gil Diamant
- , Anat Bahat
- & Rivka Dikstein
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The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis. Here the authors carry out a fine-mapping analysis of the major histocompatibility complex region and identify amino acids that have a causal role in SLE aetiology.
- Kwangwoo Kim
- , So-Young Bang
- & Sang-Cheol Bae
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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes
Genetic variation in the IFNλ locus has been associated with clearance of hepatitis C virus. Here, the authors show that a single amino-acid variant of IFNλ4 affects its antiviral activity and that patients carrying the impaired variant have better viral clearance rates.
- Ewa Terczyńska-Dyla
- , Stephanie Bibert
- & Rune Hartmann
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Age-related variations in the methylome associated with gene expression in human monocytes and T cells
The functional relevance of age-related variation in DNA methylation is unclear. Here, Reynolds et al. analyze how patterns of genome-wide gene expression and DNA methylation data vary with age in circulating monocytes and T cells, and report age-associated methylation signals that are correlated with cis-gene expression and vascular aging.
- Lindsay M. Reynolds
- , Jackson R. Taylor
- & Yongmei Liu
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| Open AccessCharacterizing the genetic basis of innate immune response in TLR4-activated human monocytes
Toll-like receptors (TLRs) are an essential component of innate immunity. Here, the authors identify expression quantitative trait loci that are unique to TLR4-stimulation and highlight genes that may have a role in innate immune response.
- Sarah Kim
- , Jessica Becker
- & Johannes Schumacher
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Host–parasite network structure is associated with community-level immunogenetic diversity
Genes of the major histocompatibility complex (MHC) are crucial for immune response, yet it is unclear what shapes their diversity at a community level. Here, the authors show that indirect effects among rodent hosts and their helminth parasites can play a crucial role in shaping host MHC diversity.
- Shai Pilosof
- , Miguel A. Fortuna
- & Jordi Bascompte
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Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells
Genetic studies have connected polymorphisms in the IL-2 receptor alpha (IL2RA) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human THcells.
- Felix J. Hartmann
- , Mohsen Khademi
- & Burkhard Becher
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Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
Clozapine-induced agranulocytosis/granulocytopenia, or CIAG, is characterised by a rare and potentially fatal reaction to antipsychotic drugs. Here, the authors identify genetic variants in two immune-related genes that may contribute to the pathophysiology of CIAG.
- Jacqueline I. Goldstein
- , L. Fredrik Jarskog
- & Patrick F. Sullivan
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Jarid2 is induced by TCR signalling and controls iNKT cell maturation
The transcriptional regulator PLZF controls many of the key effector functions of invariant natural killer T (iNKT) cells but it is not clear how PLZF itself is regulated. Here, Pereira et al. demonstrate that a methlytransferase Jarid2 regulates PLZF expression and thus controls iNKT cell maturation.
- Renata M. Pereira
- , Gustavo J. Martinez
- & Anjana Rao
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Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients
Pemphingus vulgaris is known to be caused by anti-desmoglein 3 autoantibodies, but how these antibodies arise is not clear. Here, the authors show that VH gene usage is shared among patients and that few or no somatic mutations are required for these autoantibodies to acquire autoreactivity.
- Michael Jeffrey Cho
- , Agnes S.Y. Lo
- & Aimee S. Payne
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| Open AccessImpact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides
Mass spectrometry (MS) has furthered our understanding of MHC class I-associated peptides (MIPs), but the technique is inadequate for studying MIP-associated polymorphisms. Here, the authors combine high-throughput MS with exome and transcriptome sequencing to identify polymorphic MIPs from two female siblings.
- Diana Paola Granados
- , Dev Sriranganadane
- & Claude Perreault
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A genome-wide regulatory network identifies key transcription factors for memory CD8+ T-cell development
The establishment of a memory phenotype in T cells requires profound changes in their transcriptional profile, but many components of this profile are still not known. Here, the authors perform a systematic study to identify key transcription factors associated with memory CD8+T-cell development.
- Guangan Hu
- & Jianzhu Chen
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| Open AccessGenome-wide mapping of gene–microbiota interactions in susceptibility to autoimmune skin blistering
The pathogenesis of inflammatory disorders afflicting the skin is multifactorial. Srinivas et al. show that diversity of the skin microbiota is a critical factor determining the susceptibility to epidermolysis bullosa acquisita, a chronic mucocutaneous autoimmune skin blistering disease.
- Girish Srinivas
- , Steffen Möller
- & Saleh M. Ibrahim
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| Open AccessIMGT/HighV QUEST paradigm for T cell receptor IMGT clonotype diversity and next generation repertoire immunoprofiling
Dynamic changes in T cell repertoire underlie immune responses during infection, allergy, autoimmunity and cancer. Here, Li et al. present a workflow for high throughput sequencing and analysis of T cell receptor sequences, and use it to monitor the T cell response to influenza vaccination in a human patient.
- Shuo Li
- , Marie-Paule Lefranc
- & Eric J. Gowans
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The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage
Mice lacking the C-terminal non-core domain of RAG2 and ATM mutant mice develop thymic lymphomas harbouring recurrentTcra/d–Ightranslocations. Here the authors show that ATM and the non-core domain of RAG2 prevent bi-locus recombination by modulating higher-order chromatin structure.
- Julie Chaumeil
- , Mariann Micsinai
- & Jane A. Skok
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Extensive diversification of IgH subclass-encoding genes and IgM subclass switching in crocodilians
Different mechanisms for generating antibody diversity have evolved since the emergence of immunoglobulin genes in jawed vertebrates. By sequencing the crocodilian immunoglobulin heavy-chain locus, Chenget al. uncover new insights into the evolutionary origins of adaptive immunity.
- Gang Cheng
- , Yang Gao
- & Yaofeng Zhao