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1.
Trends Genet ; 38(2): 120-123, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34561103

RESUMEN

The aging process is associated with the accumulation of epigenetic alterations in immune cells, although the origin of these changes is not clear. Understanding this epigenetic drift in the immune system can provide essential information about the progression of the aging process and the immune history of each individual.


Asunto(s)
Inmunosenescencia , Epigénesis Genética , Epigenómica , Inmunosenescencia/genética , Linfocitos T
2.
Am J Transplant ; 24(7): 1161-1171, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38692412

RESUMEN

In this proof-of-concept study, spatial transcriptomics combined with public single-cell ribonucleic acid-sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathologic states by examining biopsies classified across nonrejection, T cell-mediated acute rejection, interstitial fibrosis, and tubular atrophy. Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.


Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Prueba de Estudio Conceptual , Transcriptoma , Rechazo de Injerto/patología , Rechazo de Injerto/genética , Rechazo de Injerto/etiología , Trasplante de Riñón/efectos adversos , Humanos , Perfilación de la Expresión Génica , Pronóstico , Supervivencia de Injerto/inmunología , Biomarcadores/metabolismo , Aloinjertos
3.
Artículo en Inglés | MEDLINE | ID: mdl-38794880

RESUMEN

BACKGROUND: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. METHODS: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. RESULTS: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. CONCLUSIONS: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

4.
Genes Immun ; 23(6): 205-208, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36088493

RESUMEN

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.


Asunto(s)
COVID-19 , Aminoácidos , COVID-19/genética , Exones , Humanos , Inmunoglobulina G/genética , SARS-CoV-2
5.
Int J Mol Sci ; 24(1)2022 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-36613933

RESUMEN

Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-ß1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis.


Asunto(s)
Glomerulonefritis , Enfermedades Renales , Animales , Ratones , Proteínas de Ciclo Celular/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Regulación de la Expresión Génica , Proteínas Nucleares/genética , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Factores de Transcripción/metabolismo
6.
Int J Mol Sci ; 23(23)2022 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-36499730

RESUMEN

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30-7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.


Asunto(s)
Aneurisma de la Aorta Torácica , Enfermedad de la Válvula Aórtica Bicúspide , Animales , Humanos , Ratones , Angiotensina II , Aneurisma de la Aorta Torácica/patología , Estudios Retrospectivos , Factores de Riesgo
7.
Cytokine ; 137: 155354, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33113474

RESUMEN

BACKGROUND AND AIMS: The interferon-induced transmembrane proteins play an important antiviral role by preventing viruses from traversing the cellular lipid bilayer. IFITM3 gene variants have been associated with the clinical response to influenza and other viruses. Our aim was to determine whether the IFITM3 rs12252 polymorphism was associated with the risk of developing severe symptoms of COVID-19 in our population. METHODS: A total of 288 COVID-19 patients who required hospitalization (81 in the intensive care unit) and 440 age matched controls were genotyped with a Taqman assay. Linear regression models were used to compare allele and genotype frequencies between the groups, correcting for age and sex. RESULTS: Carriers of the minor allele frequency (rs12252 C) were significantly more frequent in the patients compared to controls after correcting by age and sex (p = 0.01, OR = 2.02, 95%CI = 1.19-3.42). This genotype was non-significantly more common among patients who required ICU. CONCLUSIONS: The IFITM3 rs12252 C allele was a risk factor for COVID-19 hospitalization in our Caucasian population. The extent of the association was lower than the reported among Chinese, a population with a much higher frequency of the risk allele.


Asunto(s)
Pueblo Asiatico/genética , COVID-19/genética , Proteínas de la Membrana/genética , Proteínas de Unión al ARN/genética , Población Blanca/genética , Anciano , COVID-19/sangre , COVID-19/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Lineales , Masculino , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Polimorfismo Genético , Proteínas de Unión al ARN/sangre , Factores de Riesgo
8.
Mol Cell Proteomics ; 18(6): 1255-1268, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31154438

RESUMEN

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Further, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.


Asunto(s)
Antígenos de Neoplasias/sangre , Neoplasias Encefálicas/sangre , Glioblastoma/sangre , Antígenos de Histocompatibilidad Clase I/sangre , Péptidos/sangre , Proteoma/metabolismo , Alelos , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , Humanos
9.
Nucleic Acids Res ; 47(10): 5016-5037, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-30923829

RESUMEN

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.


Asunto(s)
Apoptosis , Diferenciación Celular , Cromatina/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Células Mieloides/metabolismo , Acetilación , Animales , Células Cultivadas , Cromatina/genética , Epigénesis Genética , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/citología , Procesamiento Proteico-Postraduccional , Transcripción Genética
10.
Int J Mol Sci ; 23(1)2021 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-35008801

RESUMEN

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor ß (TGF-ß). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-ß together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet. Considering the main role of TGF-ß receptors (TßR) in the TGF-ß pathway activation, our aim was to investigate the effects of CCN2 in the regulation of TßRI and TßRII levels in vascular smooth muscle cells (VSMCs). While no differences were observed in TßRI levels, an increase in TßRII expression at both gene and protein level were found 48 h after stimulation with the C-terminal fragment of CCN2 (CCN2(IV)). Cell pretreatment with a TßRI inhibitor did not modify TßRII increment induced by CCN2(VI), demonstrating a TGF-ß-independent response. Secondly, CCN2(IV) rapidly activated the SMAD pathway in VSMCs, this being crucial in the upregulation of TßRII since the preincubation with an SMAD3 inhibitor prevented it. Similarly, pretreatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib abolished TßRII upregulation, indicating the participation of this receptor in the observed responses. Our findings suggest a direct role of CCN2 maintaining the TGF-ß pathway activation by increasing TßRII expression in an EGFR-SMAD dependent manner activation.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Aorta/citología , Receptores ErbB/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Smad/metabolismo
11.
Mol Cell Proteomics ; 17(11): 2132-2145, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30072578

RESUMEN

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Furthermore, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.


Asunto(s)
Antígenos de Neoplasias/sangre , Glioblastoma/sangre , Antígenos HLA/metabolismo , Péptidos/metabolismo , Proteoma/metabolismo , Alelos , Secuencia de Aminoácidos , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/sangre , Membrana Celular/metabolismo , Glioblastoma/cirugía , Humanos , Péptidos/sangre , Péptidos/química , Solubilidad
12.
J Immunol ; 198(2): 937-949, 2017 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-27974453

RESUMEN

Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Epigénesis Genética , Regulación de la Expresión Génica/inmunología , Memoria Inmunológica/genética , Western Blotting , Separación Celular , Inmunoprecipitación de Cromatina , Metilación de ADN , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Memoria Inmunológica/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética , Transcriptoma
13.
J Am Soc Nephrol ; 28(2): 504-519, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27436852

RESUMEN

Renal inflammation has a key role in the onset and progression of immune- and nonimmune-mediated renal diseases. Therefore, the search for novel anti-inflammatory pharmacologic targets is of great interest in renal pathology. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) proteins, was previously found to preserve renal function in experimental polycystic kidney disease. We report here that JQ1-induced BET inhibition modulated the in vitro expression of genes involved in several biologic processes, including inflammation and immune responses. Gene silencing of BRD4, an important BET protein, and chromatin immunoprecipitation assays showed that JQ1 alters the direct association of BRD4 with acetylated histone-packaged promoters and reduces the transcription of proinflammatory genes (IL-6, CCL-2, and CCL-5). In vivo, JQ1 abrogated experimental renal inflammation in murine models of unilateral ureteral obstruction, antimembrane basal GN, and infusion of Angiotensin II. Notably, JQ1 downregulated the expression of several genes controlled by the NF-κB pathway, a key inflammatory signaling pathway. The RelA NF-κB subunit is activated by acetylation of lysine 310. In damaged kidneys and cytokine-stimulated renal cells, JQ1 reduced the nuclear levels of RelA NF-κB. Additionally, JQ1 dampened the activation of the Th17 immune response in experimental renal damage. Our results show that inhibition of BET proteins reduces renal inflammation by several mechanisms: chromatin remodeling in promoter regions of specific genes, blockade of NF-κB pathway activation, and modulation of the Th17 immune response. These results suggest that inhibitors of BET proteins could have important therapeutic applications in inflammatory renal diseases.


Asunto(s)
Azepinas/farmacología , Azepinas/uso terapéutico , Proteínas Cromosómicas no Histona/antagonistas & inhibidores , Enfermedades Renales/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Triazoles/farmacología , Triazoles/uso terapéutico , Animales , Proteínas Cromosómicas no Histona/fisiología , Modelos Animales de Enfermedad , Enfermedades Renales/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/fisiología , Factores de Transcripción/fisiología
14.
Nucleic Acids Res ; 43(2): 760-74, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25539926

RESUMEN

Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis.


Asunto(s)
Metilación de ADN , Regulación de la Expresión Génica , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Linfocitos T/inmunología , Transcripción Genética , Diferenciación Celular/genética , Expresión Génica , Humanos , Linfocitos T/citología , Linfocitos T/metabolismo , Timocitos/citología , Timo/citología , Timo/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
16.
Trends Genet ; 28(10): 506-14, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22824525

RESUMEN

During hematopoiesis, a unique hematopoietic stem cell (HSC) from the bone marrow gives rise to a subset of mature blood cells that directs all the immune responses. Recent studies have shown that this well-defined, hierarchical process is regulated in part by epigenetic mechanisms. Changes in the DNA methylation profile have a critical role in the division of these stem cells into the myeloid and lymphoid lineages and in the establishment of a specific phenotype and functionality in each terminally differentiated cell type. In this review, we describe how the DNA methylation patterns are modified during hematopoietic differentiation and what their role is in cell plasticity and immune function. An in-depth knowledge of these epigenetic mechanisms will help clarify how cell type-specific gene programs are established, and how they can be leveraged in the development of novel strategies for treating immune system-related pathologies.


Asunto(s)
Metilación de ADN , Enfermedades del Sistema Inmune/metabolismo , Animales , Diferenciación Celular , Metilasas de Modificación del ADN/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Humanos , Enfermedades del Sistema Inmune/genética
17.
J Hum Genet ; 60(5): 273-6, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25673014

RESUMEN

The ABCB1 gene encodes the P-glycoprotein (P-gp) that drives the transmembrane efflux of many drugs. The donor ABCB1 polymorphisms have been related with chronic histological damage and long-term renal function among kidney transplanted patients who received cyclosporine A and tacrolimus (Tac). The aim of our study was to determine whether the donor ABCB1 3435 C/T genotype was related with renal function among Tac-treated renal transplanted patients. Kidney donors (n=65) and recipients (n=90) were genotyped for the ABCB1 rs1045642 (c.3435 C/T) and CYP3A5 rs776746 single-nucleotide polymorphisms. The estimated glomerular filtration rate (eGFR) was calculated with the modification of diet in renal disease formulae at five post-transplant times (2 weeks and 1, 3, 6 and 12 months). The recipient ABCB1 and CYP3A5 genotypes had no significant effect on the eGFR at all the post-transplant times. We found significantly lower eGFR values among patients who received a kidney from ABCB1 3435 T carriers (P<0.01). In conclusion, our study confirmed the potential impact of the donor ABCB1 3435 genotype on the post-transplant renal function among patients treated with Tac.


Asunto(s)
Inmunosupresores/uso terapéutico , Riñón/fisiopatología , Tacrolimus/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Femenino , Estudios de Asociación Genética , Tasa de Filtración Glomerular , Humanos , Inmunosupresores/farmacocinética , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Tacrolimus/farmacocinética , Resultado del Tratamiento , Adulto Joven
18.
Clin Chem Lab Med ; 53(10): 1515-9, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25781547

RESUMEN

BACKGROUND: A CYP3A5 gene polymorphism is the main determinant of Tacrolimus (Tac) dose requirements among renal transplanted patients. In spite of the utility of CYP3A5 genotyping to predict the Tac-dose, many patients exhibit an out of range blood Tac level and it is thus likely that other genes/polymorphisms contribute to define Tac bioavailability. To address this issue we searched for coding sequence variants in the ABCB1/MDR1 gene in renal transplanted patients treated with Tac and who had out of the range blood levels. METHODS: We studied 100 renal transplanted patients treated with Tac, 60 of whom had Tac blood levels below (n=39) and above (n=21) the target range (10-15 ng/mL) at 1 week post-transplant. The DNA was subjected to multiplex amplification followed by massive parallel semiconductor sequencing in the Ion Torrent personal genome machine. RESULTS: We found four missense changes, all reported and present in cases above and below the blood Tac target. In addition, we did not find differences in the allele and genotype frequencies for the common rs1045642 polymorphism (p.I1145I) between the groups. CONCLUSIONS: Our results suggested that the ABCB1 variants had no effect on the risk of showing out of range Tac blood levels among renal transplanted patients.


Asunto(s)
Inmunosupresores/administración & dosificación , Trasplante de Riñón/métodos , Tacrolimus/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Alelos , Biomarcadores Farmacológicos/sangre , Citocromo P-450 CYP3A/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Mutación Missense , Farmacogenética , Polimorfismo de Nucleótido Simple , Tacrolimus/sangre , Tacrolimus/farmacocinética
19.
BMC Med ; 12: 34, 2014 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-24565339

RESUMEN

BACKGROUND: Overexpression of autologous proteins can lead to the formation of autoantibodies and autoimmune diseases. MHC class I polypeptide-related sequence A (MICA) is highly expressed in the enterocytes of patients with celiac disease, which arises in response to gluten. The aim of this study was to investigate anti-MICA antibody formation in patients with celiac disease and its association with other autoimmune processes. METHODS: We tested serum samples from 383 patients with celiac disease, obtained before they took up a gluten-free diet, 428 patients with diverse autoimmune diseases, and 200 controls for anti-MICA antibodies. All samples were also tested for anti-endomysium and anti-transglutaminase antibodies. RESULTS: Antibodies against MICA were detected in samples from 41.7% of patients with celiac disease but in only 3.5% of those from controls (P <0.0001) and 8.2% from patients with autoimmune disease (P <0.0001). These antibodies disappeared after the instauration of a gluten-free diet. Anti-MICA antibodies were significantly prevalent in younger patients (P <0.01). Fifty-eight patients with celiac disease (15.1%) presented a concomitant autoimmune disease. Anti-MICA-positive patients had a higher risk of autoimmune disease than MICA antibody-negative patients (P <0.0001; odds ratio = 6.11). The risk was even higher when we also controlled for age (odds ratio = 11.69). Finally, we found that the associated risk of developing additional autoimmune diseases was 16 and 10 times as high in pediatric patients and adults with anti-MICA, respectively, as in those without. CONCLUSIONS: The development of anti-MICA antibodies could be related to a gluten-containing diet, and seems to be involved in the development of autoimmune diseases in patients with celiac disease, especially younger ones.


Asunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Enfermedad Celíaca/sangre , Enfermedad Celíaca/diagnóstico , Antígenos de Histocompatibilidad Clase I/sangre , Adolescente , Adulto , Enfermedades Autoinmunes/dietoterapia , Enfermedad Celíaca/dietoterapia , Niño , Preescolar , Comorbilidad , Dieta Sin Gluten/métodos , Femenino , Glútenes/administración & dosificación , Glútenes/efectos adversos , Humanos , Masculino , Factores de Riesgo , Adulto Joven
20.
BMC Neurosci ; 15: 110, 2014 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-25242463

RESUMEN

BACKGROUND: Cell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS). Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function. RESULTS: Platelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry. The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing. Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function. CONCLUSIONS: Plasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration.


Asunto(s)
Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Enfermedades Desmielinizantes/fisiopatología , Endotelio Vascular/metabolismo , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Adolescente , Adulto , Anciano , Permeabilidad Capilar , Niño , Impedancia Eléctrica , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Trombina/metabolismo , Adulto Joven
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