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PURPOSE: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. METHODS: Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. RESULTS: Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs. CONCLUSIONS: The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome.
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Factores de Transcripción Forkhead , Enfermedades Genéticas Ligadas al Cromosoma X , Linfocitos T Reguladores , Humanos , Turquía , Masculino , Preescolar , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Linfocitos T Reguladores/inmunología , Lactante , Femenino , Niño , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congénito , Enfermedades del Sistema Inmune/diagnóstico , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/terapia , Enfermedades del Sistema Inmune/congénito , Autoinmunidad , Adolescente , DiarreaRESUMEN
N6-methyladenosine (m6A) represents the most prevalent and significant internal modification in mRNA, with its critical role in gene expression regulation and cell fate determination increasingly recognized in recent research. The immune system, essential for defense against infections and maintaining internal stability through interactions with other bodily systems, is significantly influenced by m6A modification. This modification acts as a key post-transcriptional regulator of immune responses, though its effects on different immune cells vary across diseases. This review delineates the impact of m6A modification across major system-related cancers-including those of the respiratory, digestive, endocrine, nervous, urinary reproductive, musculoskeletal system malignancies, as well as acute myeloid leukemia and autoimmune diseases. We explore the pathogenic roles of m6A RNA modifications within the tumor immune microenvironment and the broader immune system, highlighting how RNA modification regulators interact with immune pathways during disease progression. Furthermore, we discuss how the expression patterns of these regulators can influence disease susceptibility to immunotherapy, facilitating the development of diagnostic and prognostic models and pioneering new therapeutic approaches. Overall, this review emphasizes the challenges and prospective directions of m6A-related immune regulation in various systemic diseases throughout the body.
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Adenosina , Neoplasias , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/metabolismo , Metilación , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/metabolismoRESUMEN
Inborn errors of immunity (IEI) are a diverse group of disorders caused by defects in immune system structure or function, involving both innate and adaptive immunity. The 2022 update of the IEI classification includes 485 distinct disorders, categorized into ten major disease groups. With the rapid development of molecular biology, the specific pathogenesis of many IEI has been revealed, making gene therapy possible in preclinical and clinical research of this type of disease. This article reviews the advancements in gene therapy for IEI, aiming to increase awareness and understanding of these disorders.
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Terapia Genética , Humanos , Enfermedades del Sistema Inmune/terapia , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , AnimalesRESUMEN
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
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Factores de Transcripción Forkhead , Enfermedades Genéticas Ligadas al Cromosoma X , Terapia Genética , Mutación de Línea Germinal , Interleucina-10 , Linfocitos T Reguladores , Animales , Factores de Transcripción Forkhead/genética , Ratones , Interleucina-10/genética , Interleucina-10/inmunología , Terapia Genética/métodos , Linfocitos T Reguladores/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Interleucinas/inmunología , Interleucinas/genética , Diarrea/genética , Diarrea/terapia , Diarrea/inmunología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/genética , Enfermedades Intestinales/terapia , Dependovirus/genética , Ratones Endogámicos C57BL , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/terapia , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/congénito , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congénito , Ratones Noqueados , Activación de Linfocitos/inmunología , Humanos , Interleucina-27/genéticaRESUMEN
More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, 47.9% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried "Slavic" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enrich genetic databases.
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Pruebas Genéticas , Humanos , Femenino , Masculino , Niño , Preescolar , Lactante , Estudios de Cohortes , Federación de Rusia/epidemiología , Adolescente , Mutación/genética , Recién Nacido , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Congénitas/epidemiología , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/diagnóstico , Predisposición Genética a la EnfermedadRESUMEN
Both non-malignant and malignant lymphoproliferative disorders (LPD) are commonly seen in patients with inborn errors of immunity (IEI), which may be the presenting manifestations or may develop during the IEI disease course. Here we review the clinical, histopathological, and molecular features of benign and malignant LPD associated with IEI and recognize the diagnostic challenges.
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Enfermedades del Sistema Inmune , Trastornos Linfoproliferativos , Niño , Humanos , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/genética , Enfermedades del Sistema Inmune/complicaciones , Enfermedades del Sistema Inmune/genéticaRESUMEN
Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.
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Biomarcadores , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Anciano , Adulto Joven , Envejecimiento/inmunología , Envejecimiento/genética , Aprendizaje Automático , Adolescente , Estudios de Casos y Controles , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/genética , TranscriptomaRESUMEN
The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.
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Secuenciación del Exoma , Proteínas Filagrina , Humanos , Masculino , Femenino , Adulto , Predisposición Genética a la Enfermedad/genética , Persona de Mediana Edad , Enfermedades del Sistema Inmune/genética , Análisis de la Aleatorización Mendeliana , Mutación , Proteómica , Variación Genética , Asma/genética , Asma/inmunología , Anciano , Dermatitis Atópica/genética , Dermatitis Atópica/inmunologíaRESUMEN
In 2005, Altuvia and colleagues were the first to identify the gene that encodes miR-451 in the human pituitary gland, located in chromosome region 17q11.2. Subsequent studies have confirmed that miR-451 regulates various immune cells, including T cells, B cells, microglia, macrophages, and neutrophils, thereby influencing disease progression. The range of immune-related diseases affected encompasses various cancers, lymphoblastic leukemia, and injuries to the lungs and spinal cord, among others. Moreover, miR-451 is produced by immune cells and can regulate both their own functions and those of other immune cells, thus creating a regulatory feedback loop. This article aims to comprehensively review the interactions between miR-451 and immune cells, clarify the regulatory roles of miR-451 within the immune system, and assess its potential as both a therapeutic target and a biomarker for immune-related diseases.
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Biomarcadores , Enfermedades del Sistema Inmune , MicroARNs , Humanos , MicroARNs/genética , Animales , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Regulación de la Expresión GénicaRESUMEN
PIWI-interacting RNA (piRNA) is the most abundant small non-coding RNA in animal cells, typically 26-31 nucleotides in length and it binds with PIWI proteins, a subfamily of Argonaute proteins. Initially discovered in germ cells, piRNA is well known for its role in silencing transposons and maintaining genome integrity. However, piRNA is also present in somatic cells as well as in extracellular vesicles and exosomes. While piRNA has been extensively studied in various diseases, particular cancer, its function in immune diseases remains unclear. In this review, we summarize current research on piRNA in immune diseases. We first introduce the basic characteristics, biogenesis and functions of piRNA. Then, we review the association of piRNA with different types of immune diseases, including autoimmune diseases, immunodeficiency diseases, infectious diseases, and other immune-related diseases. piRNA is considered a promising biomarker for diseases, highlighting the need for further research into its potential mechanisms in disease pathogenesis.
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Enfermedades del Sistema Inmune , ARN Interferente Pequeño , Humanos , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Animales , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/metabolismo , ARN de Interacción con PiwiRESUMEN
Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).
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Alemtuzumab , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Alemtuzumab/uso terapéutico , Pueblo Asiatico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Japón , Enfermedades del Sistema Inmune/genéticaRESUMEN
This Viewpoint reviews the history and current state of gene therapy for inborn errors of immunity.
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Terapia Genética , Enfermedades del Sistema Inmune , Humanos , Terapia Genética/métodos , Enfermedades del Sistema Inmune/genéticaRESUMEN
BACKGROUND: ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity (IEIs), specifically categorized as a "disease of immune dysregulation." Cases of this condition, reported by our team and others, are very limited worldwide. As such, our current knowledge of this new disease remains preliminary. This review aims to provide a brief overview of the clinical manifestations, pathogenesis, and treatment strategies for this novel IEI. DATA SOURCES: A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 deficiency. Our search strategy was "ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor" as of the time of manuscript submission. RESULTS: The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer, abdominal pain, and diarrhea in pediatric males. In some cases, immunodeficiency and autoimmunity can also be prominent. Targeted Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 gene. Western blotting for ELF4 expression of the patient's cells can confirm the pathogenic effect of the variant. To fully confirm the pathogenicity of the variant, further functional test is strongly advised. Glucocorticoid and biologics are the mainstream management of ELF4 deficiency disorder. CONCLUSIONS: Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of DEX. When atypical presentations are prominent, variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 function. Experience of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.
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Proteínas de Unión al ADN , Factores de Transcripción , Humanos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Enfermedades del Sistema Inmune/genéticaRESUMEN
Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.
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Osteogénesis Imperfecta , Humanos , Osteogénesis Imperfecta/genética , Proteínas del Choque Térmico HSP47/genética , Proteínas del Choque Térmico HSP47/metabolismo , Animales , Enfermedades del Sistema Inmune/genética , Osteoclastos/metabolismoRESUMEN
The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades del Sistema Inmune , Herencia Multifactorial , Trastornos del Neurodesarrollo , Polimorfismo de Nucleótido Simple , Humanos , Trastornos del Neurodesarrollo/genética , Enfermedades del Sistema Inmune/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Herencia Multifactorial/genéticaRESUMEN
Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes. Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations. Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases. Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.
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Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Trastornos Migrañosos , Polimorfismo de Nucleótido Simple , Humanos , Trastornos Migrañosos/genética , Trastornos Migrañosos/epidemiología , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/epidemiología , Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Factores de RiesgoRESUMEN
The pathophysiology of several illnesses, including cancer and autoimmune diseasesdepends on human regulatory T cells (Tregs), and abnormalities in these cells may function as triggers for these conditions. Cancer and autoimmune, and gynecological diseases are associated with the differentiation of the proinflammatory T cell subset TH17 and its balance with the production of Treg. Recently, long non-coding RNAs (lncRNAs) have become important regulatory molecules in a wide range of illnesses. During epigenetic regulation, they can control the expression of important genes at several levels by affecting transcription, post-transcriptional actions, translation, and protein modification. They might connect with different molecules, such as proteins, DNA and RNA, and their structural composition is intricate. Because lncRNAs regulatebiological processes, including cell division, death, and growth, they are linked to severaldiseases. A notable instance of this is the lncRNA NEAT1, which has been the subject of several investigations to ascertain its function in immune cell development. In the context of immune cell development, several additional lncRNAs have been connected to Treg cell differentiation. In this work, we summarize current findings about the diverse functions of lncRNAs in Treg cell differentiation and control of the Th17/Treg homeostasis in autoimmune disorders, cancers, as well as several gynecological diseases where Tregs are key players.
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Enfermedades Autoinmunes , Diferenciación Celular , ARN Largo no Codificante , Linfocitos T Reguladores , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/inmunología , Linfocitos T Reguladores/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Diferenciación Celular/inmunología , Diferenciación Celular/genética , Animales , Células Th17/inmunología , Neoplasias/inmunología , Neoplasias/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/genéticaRESUMEN
BACKGROUND: Drug targets with genetic evidence are expected to increase clinical success by at least twofold. Yet, translating disease-associated genetic variants into functional knowledge remains a fundamental challenge of drug discovery. A key issue is that the vast majority of complex disease associations cannot be cleanly mapped to a gene. Immune disease-associated variants are enriched within regulatory elements found in T-cell-specific open chromatin regions. RESULTS: To identify genes and molecular programs modulated by these regulatory elements, we develop a CRISPRi-based single-cell functional screening approach in primary human T cells. Our pipeline enables the interrogation of transcriptomic changes induced by the perturbation of regulatory elements at scale. We first optimize an efficient CRISPRi protocol in primary CD4+ T cells via CROPseq vectors. Subsequently, we perform a screen targeting 45 non-coding regulatory elements and 35 transcription start sites and profile approximately 250,000 T -cell single-cell transcriptomes. We develop a bespoke analytical pipeline for element-to-gene (E2G) mapping and demonstrate that our method can identify both previously annotated and novel E2G links. Lastly, we integrate genetic association data for immune-related traits and demonstrate how our platform can aid in the identification of effector genes for GWAS loci. CONCLUSIONS: We describe "primary T cell crisprQTL" - a scalable, single-cell functional genomics approach for mapping regulatory elements to genes in primary human T cells. We show how this framework can facilitate the interrogation of immune disease GWAS hits and propose that the combination of experimental and QTL-based techniques is likely to address the variant-to-function problem.