RESUMEN
Two different single nucleotide substitutions in intron 2 give rise to novel HLA-DQB1*03:02:01 alleles.
Asunto(s)
Alelos , Cadenas beta de HLA-DQ , Intrones , Humanos , Prueba de Histocompatibilidad , Cadenas beta de HLA-DQ/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Two nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-B*35:01:01:39 and -B*35:03:01:32.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Intrones , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Three nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-DQB1*03:01:01:54, -DQB1*03:01:01:56, -DQB1*03:01:01:58.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Cadenas beta de HLA-DQ/genética , IntronesRESUMEN
HLA-DPA1*02:01:25 differs from DPA1*02:01:01:02 by a synonymous transition in exon 2.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , Exones/genéticaRESUMEN
Seven different single nucleotide substitutions in non-coding regions gave rise to novel HLA-DPA1*01:03:01 variants.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , Prueba de HistocompatibilidadRESUMEN
Characterization by next-generation sequencing of four novel HLA alleles: C*17:03:01:07, C*16:01:01:39, B*15:17:01:07, and B*44:03:01:57.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Nucleótidos , Humanos , Regiones no Traducidas 3' , AlelosRESUMEN
HLA-DQA1*05:71, the first HLA-DQA1 allele with Aspartic Acid at residue 208 in the transmembrane domain.
Asunto(s)
Ácido Aspártico , Humanos , Ácido Aspártico/genética , Alelos , Análisis de Secuencia de ADN , Cadenas alfa de HLA-DQ/genéticaRESUMEN
The novel HLA-DQB1*03:02:01:14 was likely generated by a recombination event between DQB1*03:02:01:01 and DQB1*03:03:02:01.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Recombinación Genética , Humanos , Alelos , Cadenas beta de HLA-DQ/genéticaRESUMEN
Two transitions in intronic regions give rise to the novel alleles: HLA-DQB1*05:02:01:13 and HLA-DQB1*05:02:01:14.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Cadenas beta de HLA-DQ/genética , IntronesRESUMEN
A missense nucleotide substitution in codon -17 in the leader peptide results in the novel HLA-DRB1*04:354 allele.
Asunto(s)
Nucleótidos , Valina , Humanos , Cadenas HLA-DRB1/genética , Alelos , Valina/genética , Exones/genéticaRESUMEN
The failure to identify HLA null alleles in bone marrow transplantation could be life-threatening because this could result in an HLA mismatch with the ability to trigger the graft-vs-host disease (GVHD) and to reduce patient's survival. In this report we describe the identification and characterization of the novel HLA-DPA1*02:66:02N allele with a non-sense codon in exon 2. This new allele was discovered in two unrelated bone marrow donors during routine HLA-typing using next-generation sequencing (NGS). DPA1*02:66:02N is homologous to DPA1*02:01:01:03 with a single nucleotide difference in exon 2, codon 50, where the replacement of C located at genomic position 3825 by T, causes the formation of a premature stop codon (TGA), resulting in a null allele. This description illustrates the benefits of HLA typing by NGS since it permits to reduce ambiguities, identify new alleles, analyze multiple HLA loci and improve transplantation outcome.
Asunto(s)
Codón sin Sentido , Cadenas alfa de HLA-DP , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , Exones/genética , Codón , Prueba de Histocompatibilidad/métodosRESUMEN
A synonymous substitution in exon 2 and intronic insertion results in the novel HLA-DQA1*01:04:07 allele.
Asunto(s)
Antígenos HLA-DQ , Humanos , Antígenos HLA-DQ/genética , Alelos , Cadenas alfa de HLA-DQ/genética , ExonesRESUMEN
A nonsynonymous nucleotide substitution in exon 1 results in the novel HLA-DQB1*03:493 allele.
Asunto(s)
Ácido Glutámico , Señales de Clasificación de Proteína , Humanos , Alelos , Ácido Glutámico/genética , Secuencia de Bases , Cadenas beta de HLA-DQ/genéticaRESUMEN
The novel HLA class I allele, HLA-B*49:78, was detected in a Spanish Caucasian individual.
Asunto(s)
Antígenos HLA-B , Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Genes MHC Clase I , Antígenos HLA-B/genética , HumanosRESUMEN
BACKGROUND AND PURPOSE: Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum. METHODS: We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry. RESULTS: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio = 165, 95% confidence interval = 10.2-239.4, p < 0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women. CONCLUSIONS: Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period.
Asunto(s)
Esclerosis Múltiple , Ácidos Grasos Volátiles , Femenino , Humanos , Oportunidad Relativa , Embarazo , Estudios Prospectivos , RecurrenciaRESUMEN
Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.
Asunto(s)
Inmunosenescencia/inmunología , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Bandas Oligoclonales/inmunología , Activinas/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , Antígeno B7-H1/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Linfocitos T/inmunología , Adulto JovenRESUMEN
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
Asunto(s)
Astrocitos/fisiología , Comunicación Celular , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Microglía/fisiología , Esclerosis Múltiple/fisiopatología , Análisis de la Célula Individual , Animales , Antígenos CD/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Sistema Nervioso Central/fisiopatología , Encefalomielitis Autoinmune Experimental/patología , Efrina-B3/metabolismo , Herpesvirus Suido 1/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Esclerosis Múltiple/patología , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , RNA-Seq , Especies Reactivas de Oxígeno/metabolismo , Receptor EphB3/antagonistas & inhibidores , Receptor EphB3/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Transducción de Señal , Linfocitos T/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Epstein-Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls-P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.
