RESUMEN
Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale. We show that SPLASH identifies complex mutation patterns in SARS-CoV-2, discovers regulated RNA isoforms at the single-cell level, detects the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a unifying approach to genomic analysis that enables expansive discovery without metadata or references.
Asunto(s)
Algoritmos , Genómica , Genoma , Análisis de Secuencia de ARN , Humanos , Antígenos HLA/genética , Análisis de la Célula IndividualRESUMEN
T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses.
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Antígenos de Neoplasias/inmunología , Epítopos de Linfocito T/inmunología , Genes MHC Clase I/inmunología , Antígenos HLA/inmunología , Proteínas de Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Presentación de Antígeno/inmunología , Antígenos de Neoplasias/genética , Donantes de Sangre , Linfocitos T CD8-positivos/metabolismo , Femenino , Técnicas de Inactivación de Genes , Genes MHC Clase I/genética , Granzimas/metabolismo , Células HEK293 , Antígenos HLA/genética , Humanos , Proteínas de Neoplasias/genética , Transducción Genética , TransfecciónRESUMEN
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
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Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Antígenos CD8/metabolismo , Análisis por Conglomerados , Femenino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Pérdida de Heterocigocidad , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/inmunología , Polimorfismo de Nucleótido Simple , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.
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Carcinoma de Pulmón de Células no Pequeñas/inmunología , Antígenos HLA/genética , Neoplasias Pulmonares/inmunología , Escape del Tumor , Adulto , Anciano , Anciano de 80 o más Años , Presentación de Antígeno , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estudios de Cohortes , Femenino , Antígenos HLA/inmunología , Humanos , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido SimpleRESUMEN
We evaluated the impact of class I and class II human leukocyte antigen (HLA) genotypes, heterozygosity, and diversity on the efficacy of pembrolizumab. Seventeen pembrolizumab clinical trials across eight tumor types and one basket trial in patients with advanced solid tumors were included (n > 3,500 analyzed). Germline DNA was genotyped using a custom genotyping array. HLA diversity (measured by heterozygosity and evolutionary divergence) across class I loci was not associated with improved response to pembrolizumab, either within each tumor type evaluated or across all patients. Similarly, HLA heterozygosity at each class I and class II gene was not associated with response to pembrolizumab after accounting for the number of tests conducted. No conclusive association between HLA genotype and response to pembrolizumab was identified in this dataset. Germline HLA genotype or diversity alone is not an important independent determinant of response to pembrolizumab and should not be used for clinical decision-making in patients treated with pembrolizumab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Genotipo , Mutación de Línea Germinal/genética , Antígenos HLA/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Factores de Edad , Femenino , Estudios de Asociación Genética , Heterocigoto , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/mortalidad , Polimorfismo Genético , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Factores Sexuales , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.
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Anticuerpos Antivirales/metabolismo , Epítopos/metabolismo , Infecciones por Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Genotipo , Herpesvirus Humano 4/fisiología , Epítopos Inmunodominantes/metabolismo , Proteínas Virales/metabolismo , Adolescente , Adulto , Anciano , Estudios de Cohortes , Mapeo Epitopo , Epítopos/genética , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/genética , Femenino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Inmunidad Humoral , Epítopos Inmunodominantes/genética , Masculino , Persona de Mediana Edad , Péptidos/genética , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo Heredable , Estudios Seroepidemiológicos , Carga Viral , Proteínas Virales/genética , Adulto JovenRESUMEN
Risk factors for most autoimmune diseases are multifactorial genetic variants modified by environmental risk factors. Type 1 diabetes and celiac disease share high-risk HLA haplotypes, and the prevalence of both diseases has increased in many regions during the past half century. Unknown environmental factors are suspected to have increased the disease penetrance. Celiac disease depends on immune responses to dietary gluten, whereas the environmental risk factors for type 1 diabetes are not yet clear. Here, we consider the shared heritable genetic factors and review evidence of the dietary and microbial exposures, particularly in early life, that might influence the pathogenesis of one or both diseases. A deeper mechanistic understanding of the environmental factors responsible for increased risk of these diseases should provide opportunities to manipulate exposure in children carrying defined risk markers and thus prevent and attenuate disease, as well as to identify new therapeutic strategies for patients.
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Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Animales , Autoantígenos/inmunología , Enfermedad Celíaca/microbiología , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/microbiología , Dieta , Microbioma Gastrointestinal , Antígenos HLA/genética , Humanos , Lactante , Infecciones/complicaciones , Factores de RiesgoRESUMEN
Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.
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Linfocitos B/fisiología , Biomarcadores de Tumor/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Linfoma de Células B Grandes Difuso/genética , Carcinogénesis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Linaje de la Célula , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Antígenos HLA/metabolismo , Humanos , Vigilancia Inmunológica , Linfoma de Células B Grandes Difuso/metabolismo , Escape del Tumor/genéticaRESUMEN
Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.
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COVID-19/inmunología , SARS-CoV-2/patogenicidad , Adulto , Enzima Convertidora de Angiotensina 2/metabolismo , Presentación de Antígeno , Biomarcadores/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , COVID-19/patología , Femenino , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Inmunidad Innata , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Células T Asesinas Naturales/inmunología , Neumonía/inmunología , Neumonía/patología , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.
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Cromatina/genética , Cromatina/metabolismo , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , G-Cuádruplex , Síndrome de Inmunodeficiencia con Hiper-IgM/etiología , Síndrome de Inmunodeficiencia con Hiper-IgM/metabolismo , Mutación , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biología Computacional/métodos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Activación Enzimática , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Inmunofenotipificación , Activación de Linfocitos/genética , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones TransgénicosRESUMEN
Increasing evidence indicates CD4+ T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.
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Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/inmunología , Mapeo Epitopo/métodos , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Inmunoterapia/métodos , Espectrometría de Masas/métodos , Neoplasias/terapia , Algoritmos , Alelos , Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Conjuntos de Datos como Asunto , Antígenos HLA/genética , Antígenos HLA-D/metabolismo , Humanos , Neoplasias/inmunología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Programas InformáticosRESUMEN
The outcome after infection with the human immunodeficiency virus type 1 (HIV-1) is a complex phenotype determined by interactions among the pathogen, the human host and the surrounding environment. An impact of host genetic variation on HIV-1 susceptibility was identified early in the pandemic, with a major role attributed to the genes encoding class I human leukocyte antigens (HLA) and the chemokine receptor CCR5. Studies using genome-wide data sets have underscored the strength of these associations relative to variants located throughout the rest of the genome. However, the extent to which additional polymorphisms influence HIV-1 disease progression, and how much of the variability in outcome can be attributed to host genetics, remain largely unclear. Here we discuss findings concerning the functional impact of associated variants, outline methods for quantifying the host genetic component and examine how available genome-wide data sets may be leveraged to discover gene variants that affect the outcome of HIV-1 infection.
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Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos HLA/genética , Interacciones Huésped-Patógeno/genética , Receptores CCR5/genética , Animales , Progresión de la Enfermedad , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Infecciones por VIH/genética , HumanosRESUMEN
The cellular immune response to HIV-1 has now been studied in extraordinary detail. A very large body of data provides the most likely reasons that the HIV-specific cellular immune response succeeds in a small number of people but fails in most. Understanding the success and failure of the HIV-specific cellular immune response has implications that extend not only to immunotherapies and vaccines for HIV-1 but also to the cellular immune response in other disease states. This Review focuses on the mechanisms that are most likely responsible for durable and potent immunologic control of HIV-1. Although we now have a detailed picture of the cellular immune responses to HIV-1, important questions remain regarding the nature of these responses and how they arise.
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Vacunas contra el SIDA/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Inmunidad Celular , Animales , Antígenos Virales/inmunología , Enfermedades Asintomáticas , Citotoxicidad Inmunológica/genética , Progresión de la Enfermedad , Epítopos de Linfocito T/inmunología , Infecciones por VIH/terapia , Sobrevivientes de VIH a Largo Plazo , Antígenos HLA/genética , Humanos , Inmunoterapia , Polimorfismo Genético , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of the pancreatic ß-cells. Genome-wide association (GWAS) and fine mapping studies have been conducted mainly in European ancestry (EUR) populations. We performed a multi-ancestry GWAS to identify SNPs and HLA alleles associated with T1D risk and age at onset. EUR families (N = 3223), and unrelated individuals of African (AFR, N = 891) and admixed (Hispanic/Latino) ancestry (AMR, N = 308) were genotyped using the Illumina HumanCoreExome BeadArray, with imputation to the TOPMed reference panel. The Multi-Ethnic HLA reference panel was utilized to impute HLA alleles and amino acid residues. Logistic mixed models (T1D risk) and frailty models (age at onset) were used for analysis. In GWAS meta-analysis, seven loci were associated with T1D risk at genome-wide significance: PTPN22, HLA-DQA1, IL2RA, RNLS, INS, IKZF4-RPS26-ERBB3, and SH2B3, with four associated with T1D age at onset (PTPN22, HLA-DQB1, INS, and ERBB3). AFR and AMR meta-analysis revealed NRP1 as associated with T1D risk and age at onset, although NRP1 variants were not associated in EUR ancestry. In contrast, the PTPN22 variant was significantly associated with risk only in EUR ancestry. HLA alleles and haplotypes most significantly associated with T1D risk in AFR and AMR ancestry differed from that seen in EUR ancestry; in addition, the HLA-DRB1*08:02-DQA1*04:01-DQB1*04:02 haplotype was 'protective' in AMR while HLA-DRB1*08:01-DQA1*04:01-DQB1*04:02 haplotype was 'risk' in EUR ancestry, differing only at HLA-DRB1*08. These results suggest that much larger sample sizes in non-EUR populations are required to capture novel loci associated with T1D risk.
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Diabetes Mellitus Tipo 1 , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Diabetes Mellitus Tipo 1/genética , Masculino , Femenino , Población Blanca/genética , Edad de Inicio , Alelos , Cadenas alfa de HLA-DQ/genética , Población Negra/genética , Niño , Hispánicos o Latinos/genética , Antígenos HLA/genética , AdolescenteRESUMEN
The major histocompatibility complex (MHC) encodes a range of immune response genes, including the human leukocyte antigens (HLAs) in humans. These molecules bind peptide antigens and present them on the cell surface for T cell recognition. The repertoires of peptides presented by HLA molecules are termed immunopeptidomes. The highly polymorphic nature of the genres that encode the HLA molecules confers allotype-specific differences in the sequences of bound ligands. Allotype-specific ligand preferences are often defined by peptide-binding motifs. Individuals express up to six classical class I HLA allotypes, which likely present peptides displaying different binding motifs. Such complex datasets make the deconvolution of immunopeptidomic data into allotype-specific contributions and further dissection of binding-specificities challenging. Herein, we developed MHCpLogics as an interactive machine learning-based tool for mining peptide-binding sequence motifs and visualization of immunopeptidome data across complex datasets. We showcase the functionalities of MHCpLogics by analyzing both in-house and published mono- and multi-allelic immunopeptidomics data. The visualization modalities of MHCpLogics allow users to inspect clustered sequences down to individual peptide components and to examine broader sequence patterns within multiple immunopeptidome datasets. MHCpLogics can deconvolute large immunopeptidome datasets enabling the interrogation of clusters for the segregation of allotype-specific peptide sequence motifs, identification of sub-peptidome motifs, and the exportation of clustered peptide sequence lists. The tool facilitates rapid inspection of immunopeptidomes as a resource for the immunology and vaccine communities. MHCpLogics is a standalone application available via an executable installation at: https://github.com/PurcellLab/MHCpLogics.
Asunto(s)
Visualización de Datos , Péptidos , Humanos , Péptidos/química , Antígenos HLA/genética , Antígenos de Histocompatibilidad , Aprendizaje Automático , Análisis por ConglomeradosRESUMEN
Recent advances in cancer immunotherapy have highlighted the potential of neoantigen-based vaccines. However, the design of such vaccines is hindered by the possibility of weak binding affinity between the peptides and the patient's specific human leukocyte antigen (HLA) alleles, which may not elicit a robust adaptive immune response. Triggering cross-immunity by utilizing peptide mutations that have enhanced binding affinity to target HLA molecules, while preserving their homology with the original one, can be a promising avenue for neoantigen vaccine design. In this study, we introduced UltraMutate, a novel algorithm that combines Reinforcement Learning and Monte Carlo Tree Search, which identifies peptide mutations that not only exhibit enhanced binding affinities to target HLA molecules but also retains a high degree of homology with the original neoantigen. UltraMutate outperformed existing state-of-the-art methods in identifying affinity-enhancing mutations in an independent test set consisting of 3660 peptide-HLA pairs. UltraMutate further showed its applicability in the design of peptide vaccines for Human Papillomavirus and Human Cytomegalovirus, demonstrating its potential as a promising tool in the advancement of personalized immunotherapy.
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Algoritmos , Vacunas contra el Cáncer , Método de Montecarlo , Humanos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/genética , Antígenos HLA/inmunología , Antígenos HLA/genética , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , MutaciónRESUMEN
A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation. We investigated whether ERAP variants influence HLA-associated HIV-1 adaptation with demonstrable effects on overall HIV-1 disease outcome. Utilizing host and viral data of 249 West Australian individuals with HIV-1 subtype B infection, we identified a novel association between two linked ERAP2 single nucleotide polymorphisms (SNPs; rs2248374 and rs2549782) with plasma HIV RNA concentration (viral load) (P adjusted = 0.0024 for both SNPs). Greater HLA-associated HIV-1 adaptation in the HIV-1 Gag gene correlated significantly with higher viral load, lower CD4+ T cell count and proportion; P = 0.0103, P = 0.0061, P = 0.0061, respectively). When considered together, there was a significant interaction between the two ERAP2 SNPs and HLA-associated HIV-1 adaptation on viral load (P = 0.0111). In a comprehensive multivariate model, addition of ERAP2 haplotypes and HLA associated adaptation as an interaction term to known HLA and CCR5 determinants and demographic factors, increased the explanatory variance of population viral load from 17.67% to 45.1% in this dataset. These effects were not replicated in publicly available datasets with comparably sized cohorts, suggesting that any true global epistasis may be dependent on specific HLA-ERAP allelic combinations. Our data raises the possibility that ERAP2 variants may shape peptide repertoires presented to HLA class I-restricted T cells to modulate the degree of viral adaptation within individuals, in turn contributing to disease variability at the population level. Analyses of other populations and experimental studies, ideally with locally derived ERAP genotyping and HLA-specific viral adaptations are needed to elucidate this further.
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Aminopeptidasas , Epistasis Genética , Infecciones por VIH , VIH-1 , Polimorfismo de Nucleótido Simple , Humanos , Aminopeptidasas/genética , Infecciones por VIH/inmunología , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/genética , Australia , Masculino , Femenino , Antígenos HLA/genética , Carga Viral , Adulto , Persona de Mediana EdadRESUMEN
Research on human leukocyte antigen (HLA) molecules in coronavirus disease 2019 (COVID-19) raised high expectations but has yielded limited results. Augusto et al.'s recent study in Nature unveils a strong association of HLA-B*15:01 with asymptomatic COVID-19, representing an important contribution to genetics in COVID-19.
Asunto(s)
COVID-19 , Humanos , COVID-19/genética , Alelos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA/genética , Antígenos HLA-B/genéticaRESUMEN
Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.
Asunto(s)
Carcinoma de Células Renales , Genotipo , Antígenos HLA , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antígenos HLA/genética , Antígenos HLA/inmunología , Nivolumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano de 80 o más AñosRESUMEN
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.