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| Open AccessA comprehensive genetic map of cytokine responses in Lyme borreliosis
Common genetic variants can affect an individual’s immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.
- Javier Botey-Bataller
- , Hedwig D. Vrijmoeth
- & Yang Li
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Article
| Open AccessEvolution of T cells in the cancer-resistant naked mole-rat
Naked mole-rats are long-lived rodents with remarkable resistance to cancer. Here authors show that their T-cell compartment is different from that of mice in that they have a large population of circulating cytotoxic γδ T cells harboring a dominant clonotype, and the clonotypic diversity of their conventional cytotoxic αβ T cells is more modest than that of mice.
- Tzuhua D. Lin
- , Nimrod D. Rubinstein
- & Rochelle Buffenstein
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Article
| Open AccessNon-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
Fine-mapping has previously implicated the non-coding single nucleotide polymorphism rs117701653 as a risk variant for rheumatoid arthritis and type 1 diabetes, however its function remained unclear. Here the authors show that this variant decreases binding of the inhibitory factor SMCHD1 to enhance expression of ICOS, promoting development of potentially pathogenic T peripheral helper cells.
- Taehyeung Kim
- , Marta Martínez-Bonet
- & Peter A. Nigrovic
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessGWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Article
| Open AccessHuman and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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Article
| Open AccessThe structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function
The formation of polymeric Ig complexes is important for the function of IgM and can vary between species. Here the authors structurally analyse IgM from a teleost species that doesn’t encode a joining chain, which results in a different 3D structure compared to mammalian IgM where other parts of the protein associate to form polymeric complexes.
- Mengfan Lyu
- , Andrey G. Malyutin
- & Beth M. Stadtmueller
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Article
| Open AccessDe novo genome assembly depicts the immune genomic characteristics of cattle
The genomic organisation of the cattle genome has been assembled to a limited level of resolution. Here using long range nanopore sequencing the authors present a cattle genome assembly concentrating on characterising the immunogenomic loci, particularly T cell receptor (TR), immunoglobulin (IG) and MHC genes, from one animal.
- Ting-Ting Li
- , Tian Xia
- & Tao Li
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Article
| Open AccessSystematic identification of gene combinations to target in innate immune cells to enhance T cell activation
Determining targets for genetic engineering of immune cells remains a challenge. Here, we apply genome-wide CRISPR screens with a high-order Perturb-seq (named HMPCITE-seq) to identify gene combinations whose joint targeting improves innate immune cell function.
- Lei Xia
- , Anastasia Komissarova
- & Oren Parnas
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Article
| Open AccessGenetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire
Haplotype diversity in the human immunoglobulin heavy chain (IGH) locus is poorly characterized. Here, the authors use long-read sequencing to discover extensive IGH diversity and link germline variants to variation in the antibody repertoire.
- Oscar L. Rodriguez
- , Yana Safonova
- & Corey T. Watson
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Article
| Open AccessNBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
NBEAL2 loss of function mutations lead to grey platelet syndrome, a condition characterised by α-granule-deficient platelets and, in a proportion of cases, by autoimmunity. Here authors show that NBEAL2 physically interacts with CTLA-4 in human T cells, and NBEAL2 deficiency leads to reduced CTLA-4 surface expression in effector T cells, but not regulatory T cells, thus tipping the balance towards autoimmunity.
- Laure Delage
- , Francesco Carbone
- & Frédéric Rieux-Laucat
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Article
| Open AccessTnpo3 controls splicing of the pre-mRNA encoding the canonical TCR α chain of iNKT cells
iNKT cells recognise glycolipids via their T cell receptors. Here the authors implicate tnpo3 in the regulation of splicing of pre-mRNA encoding cognate TCR α chain for iNKT cells.
- Norimasa Iwanami
- , Andreas S. Richter
- & Thomas Boehm
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| Open AccessSEC-seq: association of molecular signatures with antibody secretion in thousands of single human plasma cells
Linking proteins secreted from individual cells with other cellular information is challenging. Here, authors report a high-throughput method which uses hydrogel nanovials loaded with single cells to link the secretion profile of individual cells with their surface markers and transcriptomic data.
- Rene Yu-Hong Cheng
- , Joseph de Rutte
- & Richard G. James
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Article
| Open AccessPathogen-specific innate immune response patterns are distinctly affected by genetic diversity
Looking at genes that are differentially responsive to pathogens depending on the genetic background may help in the identification of therapeutic targets in personalized medicine. Here, using challenge of monocytes with three pathogens the authors identified eQTL that are shared between pathogens and loci that are pathogen specific.
- Antje Häder
- , Sascha Schäuble
- & Oliver Kurzai
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Article
| Open AccessCross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways
Immune related diseases have been found to have overlapping genetic susceptibility loci. Here the authors perform cross-disorder genetic analysis to uncover three genetic groups of immune diseases that converge on the same immune cells and pathways.
- Pietro Demela
- , Nicola Pirastu
- & Blagoje Soskic
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| Open AccessPrioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection
Immune genes under selection can shed light on phenotypes contributing to survival and modern inflammatory conditions. Here, the authors prioritize adaptive disease variants in 535 risk loci for 21 inflammatory conditions and report promising SNPs for functional studies with predictions of cell context and function.
- Vasili Pankratov
- , Milyausha Yunusbaeva
- & Bayazit Yunusbayev
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Article
| Open AccessBrain milieu induces early microglial maturation through the BAX-Notch axis
The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
- Fangying Zhao
- , Jiangyong He
- & Li Li
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Article
| Open AccessGenetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells
The role of the immune system in the pathogenesis of psychiatric disorders is unclear. Here, the authors show that genetic risk variants for multiple psychiatric disorders are enriched in regions of the genome active in the brain and in lymphoid cells, especially stimulated T cells, but not in myeloid cells.
- Mary-Ellen Lynall
- , Blagoje Soskic
- & Ed Bullmore
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| Open AccessCircular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription
Innate lymphoid cells (ILC) have been shown to be involved in a range of inflammatory contexts but how their cellular lineage is regulated is not fully established. Here the authors show a role for circular RNA circTmem241 in the differentiation of ILC3 via initiation of Elk3 transcription.
- Nian Liu
- , Jiacheng He
- & Zusen Fan
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| Open AccessMouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade
Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.
- Gurman Kaur
- , Caroline B. M. Porter
- & Lars Fugger
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Article
| Open AccessNatural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
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Article
| Open AccessEfficient human-like antibody repertoire and hybridoma production in trans-chromosomic mice carrying megabase-sized human immunoglobulin loci
Trans-chromosomic (Tc) mice have helped the development of therapeutic antibodies, but chromosome instability limits its application. Here the authors develop a new line of Tc mice with full human Ig heavy and kappa loci integrated into the mouse artificial chromosome for stable passage, and confirm efficient generation of B cell responses and specific antibodies.
- Hiroyuki Satofuka
- , Satoshi Abe
- & Yasuhiro Kazuki
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Article
| Open AccessHeterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency
Genetic variants of proteasome subunit genes have been shown to associate with perturbed immune function. Here authors show that a heterozygous missense variant of the immunoproteasome subunit β-type 9 causes an autoinflammatory/immune deficiency syndrome in humans and in a mouse model.
- Nobuo Kanazawa
- , Hiroaki Hemmi
- & Tsuneyasu Kaisho
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| Open AccessCOVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types
Immune cells are important in the pathogenesis of COVID-19. Here the authors assessed the effects of COVID-19-risk variants on gene expression in a range of immune cell types, highlighting their potential to impact the function of diverse immune cell types and influence severe disease.
- Benjamin J. Schmiedel
- , Job Rocha
- & Pandurangan Vijayanand
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Article
| Open AccessSingle cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy
The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.
- Hussein A. Abbas
- , Dapeng Hao
- & Andrew Futreal
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Article
| Open AccessTcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture
How CD8+ T cell identity is maintained after exit from the thymus is not fully established. Here the authors use multiomics approaches including Hi-C to show that Tcf1 and Lef1 prevent aberrant expression of lineage-inappropriate genes by organizing three-dimensional genomic architecture in CD8+ T cells.
- Qiang Shan
- , Xiang Li
- & Hai-Hui Xue
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Article
| Open AccessPolymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases
The Cia21 locus on chromosome 3 has been associated with rheumatoid arthritis severity in females. Here the authors show this locus houses a non-coding polymorphic estrogen receptor binding site and how it regulates neighbouring gene expression of CD2, implicating CD2 signalling in the sexual dimorphism of a variety of T cell-dependent autoimmune diseases.
- Gonzalo Fernandez Lahore
- , Michael Förster
- & Rikard Holmdahl
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Article
| Open AccessImmunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model
Dengue virus causes a range of inflammatory pathology but understanding critical phases of the infection during human infection has been challenging. Here the author’s present immunotranscriptomic changes during the acute and clearance phases of a dengue virus serotype 2 human challenge model.
- John P. Hanley
- , Huy A. Tu
- & Sean A. Diehl
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| Open AccessCD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph
The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.
- Luca Hensen
- , Patricia T. Illing
- & Katherine Kedzierska
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Article
| Open AccessThe neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments
Differentiating neutrophil functional states is difficult. Here the authors show, using single cell RNA-sequencing and trajectory analyses, that mouse neutrophils can be presented as a transcriptome continuum rather than discrete subsets, but are affected by inflammation to express distinct transcriptional states.
- Ricardo Grieshaber-Bouyer
- , Felix A. Radtke
- & Hideyuki Yoshida
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Article
| Open AccessAtlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling
Immune cells infiltrating the tumour microenvironment play critical roles in disease pathogenesis and the immune response. Here the authors present the characterisation of infiltrating B cells in breast tumours by the formation of an atlas created from paired RNA sequence and antigen receptor profiling.
- Qingtao Hu
- , Yu Hong
- & Yu Zhang
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Article
| Open AccessDeepTCR is a deep learning framework for revealing sequence concepts within T-cell repertoires
The advent of high-throughput T-cell receptor sequencing has allowed for the rapid and thorough characterization of the adaptive immune response. Here the authors show how deep learning can reveal both descriptive and predictive sequence concepts within the immune repertoire.
- John-William Sidhom
- , H. Benjamin Larman
- & Alexander S. Baras
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Article
| Open AccessAccurate imputation of human leukocyte antigens with CookHLA
Human leukocyte antigen (HLA) genes influence many immune phenotypes, however methods to impute HLA type have been limited in accuracy. Here, the authors present an HLA imputation method, CookHLA, which uses locally embedded prediction markers to adaptively impute HLA genes across a range of scenarios.
- Seungho Cook
- , Wanson Choi
- & Buhm Han
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Article
| Open AccessGWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).
- Daniel Eriksson
- , Ellen Christine Røyrvik
- & Eystein Sverre Husebye
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| Open AccessThe aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2
Age is one of the strongest risk factors for severe illness from COVID-19. By integrating human lung transcriptomes with experimental data on SARS-CoV-2, the authors pinpoint specific age-associated factors that could contribute to the heightened severity of COVID-19 in older populations.
- Ryan D. Chow
- , Medha Majety
- & Sidi Chen
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Article
| Open AccessEarly-onset autoimmunity associated with SOCS1 haploinsufficiency
SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.
- Jérôme Hadjadj
- , Carla Noemi Castro
- & Frédéric Rieux-Laucat
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Article
| Open AccessDistinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections
Disease prognosis after infection with Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission.
- Neneh Sallah
- , Wendell Miley
- & Inês Barroso
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Article
| Open AccessIgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms
Immunoglobulin (Ig) rearrangement and translocation information are usually obtained by targeted sequencing of the respective loci. Here, the authors present the IgCaller algorithm, which extracts Ig heavy and light chain genetic properties from short-read whole-genome sequencing results to provide a feasible alternative to direct sequencing.
- Ferran Nadeu
- , Rut Mas-de-les-Valls
- & Elías Campo
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Article
| Open AccessProfiling immunoglobulin repertoires across multiple human tissues using RNA sequencing
Information on immune receptor repertoire provides important insights on disease progression and therapy development, but can be expensive and time-consuming to obtain. Here the authors report ImReP, a computational method that can extract detailed immune repertoire information from existing tissue-specific RNA sequencing data.
- Igor Mandric
- , Jeremy Rotman
- & Serghei Mangul
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Article
| Open AccessPhagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity
Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.
- Samuel M. Gonçalves
- , Cláudio Duarte-Oliveira
- & Agostinho Carvalho
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Article
| Open AccessDemographic and genetic factors influence the abundance of infiltrating immune cells in human tissues
Immune infiltration provides critical information for health and disease, yet it is unclear what factors influence infiltration levels. Here, the authors analyze human tissue transcriptomes from the Genotype-Tissue Expression project to find infiltration patterns regulated by age, sex and host genetic information.
- Andrew R. Marderstein
- , Manik Uppal
- & Olivier Elemento
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Article
| Open AccessGenome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.
- Yi Han
- , Qiong Jia
- & Hooman Allayee
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Article
| Open AccessThe genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.
- Jingyuan Xie
- , Lili Liu
- & Krzysztof Kiryluk
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Article
| Open AccessPrioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
While genome-wide association studies have yielded thousands of trait-associated loci, identifying causal variants remains challenging. Here, the authors perform seven genomics assays in various cell types to prioritize genetic variants in the TNFAIP3 locus, and report high-priority variants within disease-associated haplotypes.
- John P. Ray
- , Carl G. de Boer
- & Nir Hacohen
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Article
| Open AccessSomatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.
- Eva Gonçalves Serra
- , Tobias Schwerd
- & Carl A. Anderson
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Article
| Open AccessImmunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma
The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.
- Shelly Kalaora
- , Joo Sang Lee
- & Yardena Samuels
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Article
| Open AccessSexual-dimorphism in human immune system aging
Whether the immune system aging differs between men and women is barely known. Here the authors characterize gene expression, chromatin state and immune subset composition in the blood of healthy humans 22 to 93 years of age, uncovering shared as well as sex-unique alterations, and create a web resource to interactively explore the data.
- Eladio J. Márquez
- , Cheng-han Chung
- & Duygu Ucar
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Article
| Open AccessEighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.
- Thorunn A. Olafsdottir
- , Fannar Theodors
- & Kari Stefansson
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| Open AccessCold-induced urticarial autoinflammatory syndrome related to factor XII activation
Systemic autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS) are rare and often involve genes related to the inflammasome. Here, the authors report a syndrome characterised by systemic inflammation and cold-induced urticarial rash associated with a Factor XII-activating mutation.
- Jörg Scheffel
- , Niklas A. Mahnke
- & Karoline Krause