RESUMEN
We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.
Asunto(s)
Anticuerpos Monoclonales Humanizados , COVID-19 , Miocarditis , Miositis , SARS-CoV-2 , Humanos , Miocarditis/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Miositis/inducido químicamente , COVID-19/prevención & control , COVID-19/inmunología , Masculino , SARS-CoV-2/inmunología , Femenino , Persona de Mediana Edad , Anciano , Vacunas contra la COVID-19/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Vacunación/efectos adversosRESUMEN
To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.
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Islas de CpG , Metilación de ADN , Epigénesis Genética , Monocitos , Adulto , Femenino , Humanos , Masculino , Islas de CpG/genética , Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Lipopolisacáridos/farmacología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/inmunología , Persona de Mediana Edad , AncianoRESUMEN
Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.
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Predisposición Genética a la Enfermedad , Hipersensibilidad , Inflamación , Humanos , Estudio de Asociación del Genoma Completo , Hipersensibilidad/genética , Inflamación/genética , Subunidad p50 de NF-kappa B/genética , Biobanco del Reino UnidoRESUMEN
IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor ß chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.
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Melanoma , Linfocitos T Citotóxicos , Ratones , Animales , Linfocitos T Citotóxicos/metabolismo , Linfocitos T CD8-positivos , Melanoma/terapia , Melanoma/tratamiento farmacológico , Células Clonales/metabolismoRESUMEN
Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.
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Interleucina-7 , Melanoma , Humanos , Interleucina-7/genética , Interleucina-7/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Melanoma/genética , Linfocitos T CD8-positivos , Variación GenéticaRESUMEN
Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.
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Enfermedades Inflamatorias del Intestino , Lepra , Humanos , Niño , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Malaui , Malí , Lepra/genética , Proteínas de Transporte de Nucleósidos/genéticaRESUMEN
Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.
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Enfermedades Autoinmunes , Transcriptoma , Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Proteínas Portadoras , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Células Asesinas Naturales , Polimorfismo de Nucleótido SimpleRESUMEN
The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8+ T cells. How sensitivity to ICB varies across CD8+ T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8+ T cell clones, identify baseline markers of CD8+ T cell clonal sensitivity, and chart how CD8+ T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8+ T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8+ T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8+ effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8+ T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8+ immune landscape in determining ICB response in metastatic melanoma.
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Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Ipilimumab/farmacología , Nivolumab/farmacología , Linfocitos T CD8-positivos/inmunología , Humanos , Supervivencia sin ProgresiónRESUMEN
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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Proteínas Sanguíneas/genética , Regulación de la Expresión Génica/genética , Sitios de Carácter Cuantitativo/genética , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genéticaRESUMEN
BACKGROUND & AIMS: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. METHODS: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. RESULTS: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.
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Linfocitos T CD8-positivos/efectos de los fármacos , Colitis/inducido químicamente , Colon/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Memoria Inmunológica/efectos de los fármacos , Interferón gamma/metabolismo , Células T de Memoria/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Estudios de Casos y Controles , Colitis/tratamiento farmacológico , Colitis/inmunología , Colitis/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Colon/inmunología , Colon/metabolismo , Estudios Transversales , Perfilación de la Expresión Génica , Humanos , Estudios Longitudinales , Activación de Linfocitos/efectos de los fármacos , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Fenotipo , Piperidinas/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Prospectivos , Pirimidinas/uso terapéutico , RNA-Seq , Análisis de la Célula Individual , TranscriptomaRESUMEN
We present EPISPOT, a fully joint framework which exploits large panels of epigenetic annotations as variant-level information to enhance molecular quantitative trait locus (QTL) mapping. Thanks to a purpose-built Bayesian inferential algorithm, EPISPOT accommodates functional information for both cis and trans actions, including QTL hotspot effects. It effectively couples simultaneous QTL analysis of thousands of genetic variants and molecular traits with hypothesis-free selection of biologically interpretable annotations which directly contribute to the QTL effects. This unified, epigenome-aided learning boosts statistical power and sheds light on the regulatory basis of the uncovered hits; EPISPOT therefore marks an essential step toward improving the challenging detection and functional interpretation of trans-acting genetic variants and hotspots. We illustrate the advantages of EPISPOT in simulations emulating real-data conditions and in a monocyte expression QTL study, which confirms known hotspots and finds other signals, as well as plausible mechanisms of action. In particular, by highlighting the role of monocyte DNase-I sensitivity sites from >150 epigenetic annotations, we clarify the mediation effects and cell-type specificity of major hotspots close to the lysozyme gene. Our approach forgoes the daunting and underpowered task of one-annotation-at-a-time enrichment analyses for prioritizing cis and trans QTL hits and is tailored to any transcriptomic, proteomic, or metabolomic QTL problem. By enabling principled epigenome-driven QTL mapping transcriptome-wide, EPISPOT helps progress toward a better functional understanding of genetic regulation.
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Algoritmos , Simulación por Computador , Epigenoma , Modelos Genéticos , Mutación , Fenotipo , Sitios de Carácter Cuantitativo , Teorema de Bayes , Mapeo Cromosómico , HumanosRESUMEN
BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Linfocitos T CD8-positivos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Autoinmunidad/efectos de los fármacos , Autoinmunidad/genética , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/efectos adversos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Transcriptoma/efectos de los fármacos , Transcriptoma/inmunología , Resultado del Tratamiento , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Pneumococcal infections are a major cause of morbidity and mortality in young children and immaturity of the immune system partly underlies poor vaccine responses seen in the young. Emerging evidence suggests a key role for epigenetics in the maturation and regulation of the immune system in health and disease. The study aimed to investigate epigenetic changes in early life and to understand the relationship between the epigenome and antigen-specific antibody responses to pneumococcal vaccination. METHODS: The epigenetic profiles from 24 healthy children were analyzed at 12 months prior to a booster dose of the 13-valent pneumococcal conjugate vaccine (PCV-13), and at 24 months of age, using the Illumina Methylation 450 K assay and assessed for differences over time and between high and low vaccine responders. RESULTS: Our analysis revealed 721 significantly differentially methylated positions between 12 and 24 months (FDR < 0.01), with significant enrichment in pathways involved in the regulation of cell-cell adhesion and T cell activation. Comparing high and low vaccine responders, we identified differentially methylated CpG sites (P value < 0.01) associated with HLA-DPB1 and IL6. CONCLUSION: These data imply that epigenetic changes that occur during early childhood may be associated with antigen-specific antibody responses to pneumococcal vaccines.
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Sistema Inmunológico/metabolismo , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/genética , Reacciones Antígeno-Anticuerpo/inmunología , Estudios de Casos y Controles , Competencia Celular/inmunología , Preescolar , Islas de CpG/inmunología , Metilación de ADN , Epigénesis Genética , Femenino , Cadenas beta de HLA-DP/inmunología , Cadenas beta de HLA-DP/metabolismo , Humanos , Sistema Inmunológico/inmunología , Lactante , Interleucina-6/inmunología , Interleucina-6/metabolismo , Masculino , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/mortalidad , Vacunas Neumococicas/administración & dosificación , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
The immune system is paradigmatic for a complex arrangement of heterogenous cells performing distinct, frequently temporally and anatomically dissociated, functions. Immune dysfunction is a common characteristic across most diseases and human genetic approaches have revealed that many disease risk loci are associated with expression profiles and counts of specific immune subsets. Furthermore, genetic regulators of immune function may only demonstrate activity in specific disease-linked contexts. Here we explore steps taken to dissect the genetic determinants of variation in immune response across cell counts and function, and the insights these have provided into human immunity.
Asunto(s)
Sistema Inmunológico/inmunología , Inmunidad/inmunología , Variación Genética/genética , Variación Genética/inmunología , Humanos , Inmunidad/genéticaRESUMEN
Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.
Asunto(s)
Linfocitos T CD8-positivos/citología , Antígeno CTLA-4/inmunología , Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/terapia , Adulto , Anticuerpos/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/genética , Proliferación Celular , Quimiocina CCL4/genética , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Sistema Inmunológico , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Análisis de la Célula Individual , Adulto JovenRESUMEN
We tackle modelling and inference for variable selection in regression problems with many predictors and many responses. We focus on detecting hotspots, that is, predictors associated with several responses. Such a task is critical in statistical genetics, as hotspot genetic variants shape the architecture of the genome by controlling the expression of many genes and may initiate decisive functional mechanisms underlying disease endpoints. Existing hierarchical regression approaches designed to model hotspots suffer from two limitations: their discrimination of hotspots is sensitive to the choice of top-level scale parameters for the propensity of predictors to be hotspots, and they do not scale to large predictor and response vectors, for example, of dimensions 103-105 in genetic applications. We address these shortcomings by introducing a flexible hierarchical regression framework that is tailored to the detection of hotspots and scalable to the above dimensions. Our proposal implements a fully Bayesian model for hotspots based on the horseshoe shrinkage prior. Its global-local formulation shrinks noise globally and, hence, accommodates the highly sparse nature of genetic analyses while being robust to individual signals, thus leaving the effects of hotspots unshrunk. Inference is carried out using a fast variational algorithm coupled with a novel simulated annealing procedure that allows efficient exploration of multimodal distributions.
RESUMEN
IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.
Asunto(s)
Autoinmunidad/genética , Subunidad alfa del Receptor de Interleucina-7/genética , Interleucina-7/inmunología , Monocitos/inmunología , Espondilitis Anquilosante/genética , Alelos , ARN Helicasas DEAD-box/inmunología , ARN Helicasas DEAD-box/metabolismo , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Voluntarios Sanos , Humanos , Interleucina-7/metabolismo , Subunidad alfa del Receptor de Interleucina-7/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Lipopolisacáridos/inmunología , Monocitos/metabolismo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/patología , Líquido Sinovial/citología , Líquido Sinovial/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4-6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.
Asunto(s)
Artritis Reumatoide/genética , Descubrimiento de Drogas , Redes Reguladoras de Genes , Genoma Humano , Inmunidad Innata/genética , Sitios de Carácter Cuantitativo , Selección Genética , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.