RESUMEN
Immunity to infection has been extensively studied in humans and mice bearing naturally occurring or experimentally introduced germline mutations. Mouse studies are sometimes neglected by human immunologists, on the basis that mice are not humans and the infections studied are experimental and not natural. Conversely, human studies are sometimes neglected by mouse immunologists, on the basis of the uncontrolled conditions of study and small numbers of patients. However, both sides would agree that the infectious phenotypes of patients with inborn errors of immunity often differ from those of the corresponding mutant mice. Why is that? We argue that this important question is best addressed by revisiting and reinterpreting the findings of both mouse and human studies from a genetic perspective. Greater caution is required for reverse-genetics studies than for forward-genetics studies, but genetic analysis is sufficiently strong to define the studies likely to stand the test of time. Genetically robust mouse and human studies can provide invaluable complementary insights into the mechanisms of immunity to infection common and specific to these two species.
Asunto(s)
Enfermedades del Sistema Inmune , Inmunidad , Fenotipo , Animales , Humanos , Ratones , Inmunidad/genética , Enfermedades del Sistema Inmune/genéticaRESUMEN
Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon-mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self-nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid-driven inflammation.
Asunto(s)
Antígenos Virales/inmunología , Autoantígenos/inmunología , Enfermedades del Sistema Inmune/inmunología , Ácidos Nucleicos/inmunología , Virosis/inmunología , Animales , Humanos , Enfermedades del Sistema Inmune/genética , Tolerancia Inmunológica , Inmunidad Innata , Interferón Tipo I/metabolismo , Virosis/genéticaRESUMEN
The discovery of long noncoding RNAs (lncRNA) has provided a new perspective on gene regulation in diverse biological contexts. lncRNAs are remarkably versatile molecules that interact with RNA, DNA, or proteins to promote or restrain the expression of protein-coding genes. Activation of immune cells is associated with dynamic changes in expression of genes, the products of which combat infectious microorganisms, initiate repair, and resolve inflammatory responses in cells and tissues. Recent evidence indicates that lncRNAs play important roles in directing the development of diverse immune cells and controlling the dynamic transcriptional programs that are a hallmark of immune cell activation. The importance of these molecules is underscored by their newly recognized roles in inflammatory diseases. In this review, we discuss the contribution of lncRNAs in the development and activation of immune cells and their roles in immune-related diseases. We also discuss challenges faced in identifying biological functions for this large and complex class of genes.
Asunto(s)
Enfermedades del Sistema Inmune/genética , Inmunidad/genética , ARN Largo no Codificante/inmunología , Animales , Regulación de la Expresión Génica , HumanosRESUMEN
Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics.
Asunto(s)
Antígeno CTLA-4/genética , Proteínas de Transporte de Catión/genética , Genómica , Enfermedades del Sistema Inmune/genética , Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Animales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Enfermedades del Sistema Inmune/terapia , Masculino , Terapia Molecular Dirigida , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapiaRESUMEN
CRISPR-Cas9-based base editing allows precise base editing to achieve conversion of adenosine to guanine or cytosine to thymidine. In this issue of Cell, McAuley et al. use adenine base editing to correct a single base-pair mutation causing human CD3δ deficiency, demonstrating superior efficiency of genetic correction with reduced undesired genetic alterations compared with standard CRISPR-Cas9 editing.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Enfermedades del Sistema Inmune , Humanos , Adenina , Sistemas CRISPR-Cas/genética , Terapia Genética , Mutación , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/terapiaRESUMEN
Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.
Asunto(s)
Regulación de la Expresión Génica/genética , Expresión Génica/inmunología , Enfermedades del Sistema Inmune/genética , Adulto , Femenino , Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/metabolismo , Enfermedades del Sistema Inmune/metabolismo , Enfermedades del Sistema Inmune/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Sitios de Carácter Cuantitativo/inmunología , Transcriptoma/genética , Secuenciación Completa del Genoma/métodosRESUMEN
FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.
Asunto(s)
Diabetes Mellitus Tipo 1/congénito , Diarrea/genética , Factores de Transcripción Forkhead/deficiencia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades del Sistema Inmune/congénito , Linfocitos T Reguladores/inmunología , Adolescente , Animales , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Conjuntos de Datos como Asunto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diarrea/sangre , Diarrea/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Enfermedades del Sistema Inmune/sangre , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Lactante , Masculino , Ratones , Ratones Transgénicos , Mutación , RNA-Seq , Análisis de la Célula Individual , Linfocitos T Reguladores/metabolismo , Adulto JovenRESUMEN
Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
Asunto(s)
Regulación de la Expresión Génica , Enfermedades del Sistema Inmune/patología , Neoplasias/patología , Trastornos del Neurodesarrollo/patología , ARN Largo no Codificante/genética , Animales , Humanos , Enfermedades del Sistema Inmune/genética , Neoplasias/genética , Trastornos del Neurodesarrollo/genética , Transducción de SeñalRESUMEN
Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
Asunto(s)
Variación Genética , Estudio de Asociación del Genoma Completo , Células Madre Hematopoyéticas/metabolismo , Enfermedades del Sistema Inmune/genética , Alelos , Diferenciación Celular , Predisposición Genética a la Enfermedad , Células Madre Hematopoyéticas/patología , Humanos , Enfermedades del Sistema Inmune/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Población Blanca/genéticaRESUMEN
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
Asunto(s)
Epigenómica , Enfermedades del Sistema Inmune/genética , Monocitos/metabolismo , Neutrófilos/metabolismo , Linfocitos T/metabolismo , Transcripción Genética , Adulto , Anciano , Empalme Alternativo , Femenino , Predisposición Genética a la Enfermedad , Células Madre Hematopoyéticas/metabolismo , Código de Histonas , Humanos , Masculino , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Adulto JovenRESUMEN
Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades del Sistema Inmune/genética , Inmunofenotipificación , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Leucocitos/citología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de IgG/genética , Linfocitos T Reguladores/citologíaRESUMEN
The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing â¼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.
Asunto(s)
Citometría de Flujo/métodos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades del Sistema Inmune/genética , Polimorfismo de Nucleótido Simple , Humanos , FenotipoRESUMEN
A major challenge in human genetics is to identify the molecular mechanisms of trait-associated and disease-associated variants. To achieve this, quantitative trait locus (QTL) mapping of genetic variants with intermediate molecular phenotypes such as gene expression and splicing have been widely adopted1,2. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear3,4. Here we show that ADAR-mediated adenosine-to-inosine RNA editing, a post-transcriptional event vital for suppressing cellular double-stranded RNA (dsRNA)-mediated innate immune interferon responses5-11, is an important potential mechanism underlying genetic variants associated with common inflammatory diseases. We identified and characterized 30,319 cis-RNA editing QTLs (edQTLs) across 49 human tissues. These edQTLs were significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements as well as unexpected, highly over-represented cis-natural antisense transcripts. Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases. This unique directional effect agrees with the established mechanism that lack of RNA editing by ADAR1 leads to the specific activation of the dsRNA sensor MDA5 and subsequent interferon responses and inflammation7-9. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.
Asunto(s)
Adenosina Desaminasa , Predisposición Genética a la Enfermedad , Enfermedades del Sistema Inmune , Inflamación , Edición de ARN , ARN Bicatenario , Adenosina/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Elementos Alu/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Inmunidad Innata , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inosina/metabolismo , Helicasa Inducida por Interferón IFIH1/metabolismo , Interferones/genética , Interferones/inmunología , Sitios de Carácter Cuantitativo/genética , Edición de ARN/genética , ARN Bicatenario/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.
Asunto(s)
Adenosina Desaminasa , Enfermedades del Sistema Inmune , Inflamación , Mutación , Proteínas de Unión al ARN , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Animales , Caspasa 8/genética , Caspasa 8/metabolismo , Muerte Celular , Eliminación de Gen , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/metabolismo , Enfermedades del Sistema Inmune/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Mamíferos/genética , Proteínas Quinasas/deficiencia , Proteínas Quinasas/genética , ARN Bicatenario/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de SeñalRESUMEN
FOXP3 gene is a key transcription factor driving immune tolerance and its deficiency causes immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX), a prototypic primary immune regulatory disorder (PIRD) with defective regulatory T (Treg) cells. Although life-threatening, the increased awareness and early diagnosis have contributed to improved control of the disease. IPEX currently comprises a broad spectrum of clinical autoimmune manifestations from severe early onset organ involvement to moderate, recurrent manifestations. This review focuses on the mechanistic advancements that, since the IPEX discovery in early 2000, have informed the role of the human FOXP3+ Treg cells in controlling peripheral tolerance and shaping the overall immune landscape of IPEX patients and carrier mothers, contributing to defining new treatments.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X , Enfermedades del Sistema Inmune , Enfermedades Intestinales , Poliendocrinopatías Autoinmunes , Humanos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Linfocitos T Reguladores , Enfermedades Intestinales/genética , Síndrome , Factores de Transcripción Forkhead/genética , Mutación , Poliendocrinopatías Autoinmunes/genética , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/terapiaAsunto(s)
Diferenciación Celular/genética , Diabetes Mellitus Tipo 1/congénito , Diarrea/genética , Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades del Sistema Inmune/congénito , Linfocitos T Reguladores/inmunología , Alergia e Inmunología/historia , Animales , Diferenciación Celular/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diarrea/inmunología , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Masculino , Ratones Transgénicos , Mutación , Factores SexualesRESUMEN
Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.
Asunto(s)
Consanguinidad , Enfermedades del Sistema Inmune , Pueblos de Medio Oriente , Pueblo Norteafricano , Humanos , África del Norte/epidemiología , Pueblo Norteafricano/genética , Pueblos de Medio Oriente/genética , Enfermedades del Sistema Inmune/genéticaRESUMEN
The signaling networks that control the immune system are coordinated by a myriad of interconnecting phosphorylation and ubiquitylation events. This review provides an overview of mutations in human genes encoding these proteins that give rise to immune diseases. Analysis of the biological effects of these mutations has revealed the true physiological roles of particular signaling networks and promises to revolutionize the treatment of these diseases.
Asunto(s)
Enfermedades del Sistema Inmune/genética , Proteínas Quinasas/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Ubiquitina-Proteína Ligasas/genética , Humanos , Mutación , Fosforilación/genética , Ubiquitinación/genéticaRESUMEN
Foxp3 controls the development and function of regulatory T (Treg) cells, but it remains elusive how Foxp3 functions in vivo. Here, we established mouse models harboring three unique missense Foxp3 mutations that were identified in patients with the autoimmune disease IPEX. The I363V and R397W mutations were loss-of-function mutations, causing multi-organ inflammation by globally compromising Treg cell physiology. By contrast, the A384T mutation induced a distinctive tissue-restricted inflammation by specifically impairing the ability of Treg cells to compete with pathogenic T cells in certain non-lymphoid tissues. Mechanistically, repressed BATF expression contributed to these A384T effects. At the molecular level, the A384T mutation altered Foxp3 interactions with its specific target genes including Batf by broadening its DNA-binding specificity. Our findings identify BATF as a critical regulator of tissue Treg cells and suggest that sequence-specific perturbations of Foxp3-DNA interactions can influence specific facets of Treg cell physiology and the immunopathologies they regulate.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diabetes Mellitus Tipo 1/congénito , Diarrea/genética , Factores de Transcripción Forkhead/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades del Sistema Inmune/congénito , Inflamación/genética , Linfocitos T Reguladores/fisiología , Alelos , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Análisis Mutacional de ADN , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diarrea/inmunología , Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Inflamación/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación Missense/genética , Especificidad de Órganos/genéticaRESUMEN
Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.