RESUMO
In the past, identification of HLA alleles was limited to sequencing the region of the gene coding for the peptide binding groove, resulting in a lack of sequence information in the HLA database, challenging HLA allele assignment software programs. We investigated full-length sequences of 19 HLA class I and 7 HLA class II alleles, and we extended another 47 HLA class I alleles with sequences of 5' and 3' UTR regions that were all not yet available in the IPD-IMGT/HLA database. We resolved 8638 unknown nucleotides in the coding sequence of HLA class I and 2139 of HLA class II. Furthermore, with full-length sequencing of the 26 alleles, more than 90 kb of sequence information was added to the non-coding sequences, whereas extension of the 47 alleles resulted in the addition of 5.5 kb unknown nucleotides to the 5' UTR and > 31.7 kb to the 3' UTR region. With this information, some interesting features were observed, like possible recombination events and lineage evolutionary origins. The continuing increase in the availability of full-length sequences in the HLA database will enable the identification of the evolutionary origin and will help the community to improve the alignment and assignment accuracy of HLA alleles.
Assuntos
Evolução Biológica , Nucleotídeos , Alelos , Regiões 3' não Traduzidas/genética , Membrana Celular , Nucleotídeos/genéticaRESUMO
High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9-10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with 'high' or 'low' HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Neoplasias , Humanos , Criança , Adulto Jovem , Doadores não Relacionados , Estudos Retrospectivos , Teste de Histocompatibilidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/etiologiaRESUMO
OBJECTIVES: To evaluate the concordance between Google Maps® application (GM®) and clinical practice measurements of ambulatory function (e.g., Ambulation Score (AS) and respective Expanded Disability Status Scale (EDSS)) in people with multiple sclerosis (pwMS). MATERIALS AND METHODS: This is a cross-sectional multicenter study. AS and EDSS were calculated using GM® and routine clinical methods; the correspondence between the two methods was assessed. A multinomial logistic model is investigated which demographic (age, sex) and clinical features (e.g., disease subtype, fatigue, depression) might have influenced discrepancies between the two methods. RESULTS: Two hundred forty-three pwMS were included; discrepancies in AS and in EDDS assessments between GM® and routine clinical methods were found in 81/243 (33.3%) and 74/243 (30.4%) pwMS, respectively. Progressive phenotype (odds ratio [OR] = 2.8; 95% confidence interval [CI] 1.1-7.11, p = 0.03), worse fatigue (OR = 1.03; 95% CI 1.01-1.06, p = 0.01), and more severe depression (OR = 1.1; 95% CI 1.04-1.17, p = 0.002) were associated with discrepancies between GM® and routine clinical scoring. CONCLUSION: GM® could easily be used in a real-life clinical setting to calculate the AS and the related EDSS scores. GM® should be considered for validation in further clinical studies.
Assuntos
Esclerose Múltipla , Ferramenta de Busca , Estudos Transversais , Avaliação da Deficiência , Fadiga/diagnóstico , Fadiga/epidemiologia , Humanos , Esclerose Múltipla/diagnósticoRESUMO
Interferon beta (IFNß) was the first specific disease-modifying treatment licensed for relapsing-remitting multiple sclerosis, and is still one of the most commonly prescribed treatments. A strong body of evidence supports the effectiveness of IFNß preparations in reducing the annual relapse rate, magnetic resonance (MRI) disease activity and disease progression. However, the development of binding/neutralizing antibodies (BAbs/NAbs) during treatment negatively affects clinical and MRI outcomes. Therefore, guidelines for the clinical use for the detection of NAbs in MS may result in better treatment of these patients. In October 2012, a panel of Italian neurologists from 17 MS clinics convened in Milan to review and discuss data on NAbs and their clinical relevance in the treatment of MS. In this paper, we report the panel's recommendations for the use of IFNß Nabs detection in the early identification of IFNß non-responsiveness and the management of patients on IFNß treatment in Italy, according to a model of therapeutically appropriate care.
Assuntos
Anticorpos Neutralizantes/sangue , Fatores Imunológicos/uso terapêutico , Interferon beta/imunologia , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Diagnóstico Precoce , Humanos , Fatores Imunológicos/imunologia , Itália , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/economia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/economia , Esclerose Múltipla Recidivante-Remitente/imunologia , Proteínas de Resistência a Myxovirus/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
HLA-DQB1*06:02:61 differs from HLA-DQB1*06:02:01:01 by one nucleotide substitution in exon 4-5512 G>A.
Assuntos
Alelos , Éxons , Cadeias beta de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Cadeias beta de HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Sequência de Bases , Análise de Sequência de DNA/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
HLA-DQA1*01:03:11 differs from HLA-DQA1*01:03:01:02 by one nucleotide substitution in codon 59 in exon 2.
Assuntos
Nucleotídeos , Humanos , Alelos , Cadeias alfa de HLA-DQ/genética , Éxons/genéticaRESUMO
HLA-DQA1*02:01:14 differs from HLA-DQA1*02:01:01:02 by one nucleotide substitution in codon 105 in exon 3.
Assuntos
Alelos , Humanos , Cadeias alfa de HLA-DQ/genética , Análise de Sequência de DNA , CódonRESUMO
Human leukocyte antigen (HLA) typing was done in 426 Lebanese subjects of 88 families, in which 347 haplotypes were identified. The A, B, C, DRB1, DRB3/4/5, DQB1 and DPB1 loci were typed at high resolution. This study shows that information theory, as originally developed by Claude Shannon in 1948, provides a promising theoretical foundation to study the population genetics of a genetic system like HLA. Although Lebanese carry HLA alleles found in other populations, the association of these alleles into haplotypes is quite unique. Comparisons are made with the main ethnic groups. Two haplotypes well represented in the Lebanese population are not identified in any global population: L1 = {A*26:01:01 - B*35:01:01:01- C*04:01:01:01- DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01} and L2 = {A*02:02 - B*41:01- C*17:01:01:01 -DRB1*11:04:01 - DRB3*02:02:01:01- DQB1*03:01:01:01}. By studying linkage disequilibrium in two blocks at a time, with the division of the blocks at different levels in consecutive cycles, conserved haplotypes in full linkage disequilibrium come to light, such as {A*26:01:01- B*35:01:01:01 - C*04:01:01:01 - DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01- DPB1*03:01:01} and {A*33:01:01 - B*14:02:01 - C*08:02:01 - DRB1*01:02:01- DQB1*05:01:01:01 - DPB1*04:01:01:01}.
Assuntos
Alelos , Etnicidade/genética , Variação Genética/imunologia , Antígenos HLA/genética , Feminino , Frequência do Gene , Genética Populacional , Antígenos HLA/classificação , Antígenos HLA/imunologia , Haplótipos , Teste de Histocompatibilidade , Humanos , Teoria da Informação , Líbano , Desequilíbrio de Ligação , Masculino , Tipagem MolecularRESUMO
HLA testing is an essential part of the process to identify a donor who may be a good match for the patients who need haematopoietic stem cells from bone marrow, peripheral blood or cord blood and the DNA typing in high resolution is now recommended as the Scientific Societies also describe in their standards. Recently the new PCR-Luminex HLA typing method, based on the reverse sequence specific oligonucleotide probes coupled with a microsphere beads in an array platform, has been well established. We report the data from 146 samples previously typed to a four digits level and used to evaluate the accuracy, sensitivity and performance of the new high definition DRB1 by PCR-Luminex kit. One hundred and forty-six samples from unrelated healthy donors, haematological patients or external proficiency tests were used in this study. The Luminex high definition DRB1 typing represents a versatile method and may be easily introduced in the routine, particularly when the technical team has already acquired experience on the technique. Only few HLA allelic combinations need an additional typing by PCR-SSP or SBT to solve the ambiguous results thus reducing the time necessary to produce a final report.
Assuntos
Cadeias HLA-DRB1/análise , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Humanos , Análise em Microsséries/métodos , Microesferas , Sondas de Oligonucleotídeos/genética , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
HLA-DRB4*01:151 differs from DRB4*01:01:01:01 by one nucleotide substitution in codon 178 in exon 3.
Assuntos
Cadeias HLA-DRB4 , Alelos , Códon , Éxons/genética , Cadeias HLA-DRB4/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-DQA1*05:53 differs from HLA-DQA1*05:05:01:01 by one nucleotide substitution in codon 221 in exon 4.
Assuntos
Alelos , Éxons/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-DRB1*11:04:21 differs from HLA-DRB1*11:04:01 by one nucleotide substitution in codon 69 in exon 2.
Assuntos
Cadeias HLA-DRB1 , Alelos , Sequência de Bases , Éxons/genética , Cadeias HLA-DRB1/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-A*30:181 differs from HLA-A*30:01:01 by one nucleotide substitution in Exon 4832 G to A.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação de Sentido Incorreto , Alelos , Éxons/genética , Antígenos HLA-A/genética , HumanosRESUMO
BACKGROUND: Persistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit - erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow. DESIGN AND METHODS: The donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit - erythroid colonies singly picked out after 14 days of incubation. RESULTS: The proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit - erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. Conclusions Our results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.
Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Núcleo Celular/patologia , Quimerismo , Eritrócitos/patologia , Hemoglobinopatias/etiologia , Talassemia beta/terapia , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Doadores de Tecidos , Adulto Jovem , Talassemia beta/complicaçõesRESUMO
HLA-DPA1*01:60 differs from HLA-DPA1*01:03:01:04 by one nucleotide substitution in codon 224 in exon 4.
Assuntos
Cadeias alfa de HLA-DP , Alelos , Éxons/genética , Cadeias alfa de HLA-DP/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-B*44:02:68 differs from B*44:02:01:01 by one synonmous nucleotide substitution in codon-10 GGG- > GGA.
Assuntos
Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Códon , Antígenos HLA-B/genética , HumanosRESUMO
HLA-DRB3*03:49 differs from DRB3*03:01:01:01 by one nucleotide substitution in codon 191 in exon 4.
Assuntos
Cadeias HLA-DRB3 , Alelos , Códon , Éxons/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB3/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNARESUMO
The new allele HLA-DPB1*1149:01 differs from HLA-DPB1*09:01:01 by one nucleotide substitution in Exon 4.
Assuntos
Alelos , Sequência de Bases , Éxons/genética , Cadeias beta de HLA-DP/genética , HumanosRESUMO
The novel HLA-DRB1*03:01:32 allele differs from HLA-DRB1*03:01:01:01 by one nucleotide substitution in exon 4.