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1.
Immunobiology ; 225(3): 151955, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32517882

RESUMO

SARS Coronavirus-2 (SARS-CoV-2) pandemic has become a global issue which has raised the concern of scientific community to design and discover a counter-measure against this deadly virus. So far, the pandemic has caused the death of hundreds of thousands of people upon infection and spreading. To date, no effective vaccine is available which can combat the infection caused by this virus. Therefore, this study was conducted to design possible epitope-based subunit vaccines against the SARS-CoV-2 virus using the approaches of reverse vaccinology and immunoinformatics. Upon continual computational experimentation, three possible vaccine constructs were designed and one vaccine construct was selected as the best vaccine based on molecular docking study which is supposed to effectively act against the SARS-CoV-2. Thereafter, the molecular dynamics simulation and in silico codon adaptation experiments were carried out in order to check biological stability and find effective mass production strategy of the selected vaccine. This study should contribute to uphold the present efforts of the researches to secure a definitive preventative measure against this lethal disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/química , Vacinas Virais/biossíntese , Sequência de Aminoácidos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Biologia Computacional/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Progressão da Doença , Epitopos/química , Epitopos/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Plasmídeos/química , Plasmídeos/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Conformação Proteica , Genética Reversa/métodos , Alinhamento de Sequência , Vacinas de Subunidades , Proteínas Virais/genética , Proteínas Virais/imunologia
2.
Exp Clin Transplant ; 18(3): 275-283, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32519618

RESUMO

OBJECTIVES: COVID-19 is a great threat to the modern world and significant threat to immunocompromised patients, including patients with chronic renal failure. We evaluated COVID-19 incidence among our hemodialysis patients and investigated the most probable immune mechanisms against COVID-19. MATERIALS AND METHODS: Baskent University has 21 dialysis centers across Turkey, with 2420 patients on hemodialysis and 30 on peritoneal dialysis. Among these, we retrospectively evaluated 602 patients (257 female/345 male) with chronic renal failure receiving hemodialysis as renal replacement therapy; 7 patients (1.1%) were infected with SARS-CoV-2. We retrospectively collected patient demographic characteristics, clinical data, and immunological factors affecting the clinical course of the disease. We divided patients into groups and included 2 control groups (individuals with normal renal functions): group I included COVID-19-positive patients with normal renal function, group II included COVID-19-positive hemodialysis patients, group III included COVID-19-negative hemodialysis patients, and group IV included COVID-19-negative patients with normal renal function. Lymphocyte subsets in peripheral blood and typing of human leukocyte antigens were analyzed in all groups, with killer cell immunoglobulin like receptor genes analyzed only in COVID-19-positive patients and healthy controls. RESULTS: No deaths occurred among the 7 COVID-19-positive hemodialysis patients. Group I patients were significantly older than patients in groups II and III (P = .039, P = .030, respectively) but not significantly different from group IV (P = .060). Absolute counts of natural killer cells in healthy controls were higherthan in other groups (but not significantly). ActivatedT cells were significantly increased in both COVID-19-positive groups versus COVID-19-negative groups. Groups showed significant differences in C and DQ loci with respect to distribution of alleles in both HLA classes. CONCLUSIONS: Although immunocompromised patients are at greater risk for COVID-19, we found lower COVID-19 incidence in our hemodialysis patients, which should be further investigated in in vitro and molecular studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Hospedeiro Imunocomprometido , Falência Renal Crônica/terapia , Infecções Oportunistas/epidemiologia , Pneumonia Viral/epidemiologia , Diálise Renal/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno , Humanos , Incidência , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Linfócitos T/imunologia , Resultado do Tratamento , Turquia/epidemiologia , Adulto Jovem
4.
Eur Rev Med Pharmacol Sci ; 24(8): 4607-4615, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32374001

RESUMO

COVID-19 pandemic can cause irreparable damage to the involved society. This study aimed to provide a summary of the up-to-dated clinical display, diagnostics, molecular and genetic implications for COVID-19 infected patients. In this review, 73 research articles published before 25 March 2020 were analyzed to better understand the clinical characteristics of patients and to introduce the available serological, hematology and molecular diagnostic methods. Apart from articles extracted from PubMed and Google Scholar, WHO (https://www.who.int/), NHC (National Health Commission of the People's Republic of China (http://www.nhc.gov.cn/), NICE (National Institute for Health and Clinical Excellence, https://www.nice.org.uk/), CDC (Centers for Disease Control and Prevention, https://www.cdc.gov/), and National Administration of Traditional Chinese Medicine (http://www.satcm.gov.cn/) were also accessed to search for eligible studies. Papers published between January 1, 2020, and 25 March 2020 were searched in English and the terms "2019-nCoV, Covid-19, Clinical Characteristics OR manifestation, method of detection, COVID-19 Genome and molecular test" were used. As the pandemic continues to evolve, there have been reports about the possibility of asymptomatic transmission of this newly emerged pneumonia virus. We highlighted the role of HLA haplotype in virus infection as HLA typing will provide susceptibility information for personalized prevention, diagnosis, and treatment in future studies. All the data in this article will assist researchers and clinicians to develop their clinical views regarding infected patients and to emphasize the origin of SARS-CoV-2 for diagnostics.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Antígenos HLA/genética , Pneumonia Viral/diagnóstico , Autopsia , Doenças Cardiovasculares/etiologia , Infecções por Coronavirus/complicações , Genoma Viral , Haplótipos , Humanos , Nefropatias/etiologia , Hepatopatias/etiologia , Pandemias , Pneumonia Viral/complicações , RNA Viral/isolamento & purificação , Manejo de Espécimes
5.
Biomed Res Int ; 2020: 2683286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32461973

RESUMO

Background: A new endemic disease has spread across Wuhan City, China, in December 2019. Within few weeks, the World Health Organization (WHO) announced a novel coronavirus designated as coronavirus disease 2019 (COVID-19). In late January 2020, WHO declared the outbreak of a "public-health emergency of international concern" due to the rapid and increasing spread of the disease worldwide. Currently, there is no vaccine or approved treatment for this emerging infection; thus, the objective of this study is to design a multiepitope peptide vaccine against COVID-19 using an immunoinformatics approach. Method: Several techniques facilitating the combination of the immunoinformatics approach and comparative genomic approach were used in order to determine the potential peptides for designing the T-cell epitope-based peptide vaccine using the envelope protein of 2019-nCoV as a target. Results: Extensive mutations, insertion, and deletion were discovered with comparative sequencing in the COVID-19 strain. Additionally, ten peptides binding to MHC class I and MHC class II were found to be promising candidates for vaccine design with adequate world population coverage of 88.5% and 99.99%, respectively. Conclusion: The T-cell epitope-based peptide vaccine was designed for COVID-19 using the envelope protein as an immunogenic target. Nevertheless, the proposed vaccine rapidly needs to be validated clinically in order to ensure its safety and immunogenic profile to help stop this epidemic before it leads to devastating global outbreaks.


Assuntos
Betacoronavirus/imunologia , Biologia Computacional/métodos , Infecções por Coronavirus/imunologia , Epitopos/imunologia , Pneumonia Viral/imunologia , Vacinas de Subunidades/imunologia , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Sequência de Aminoácidos , Infecções por Coronavirus/prevenção & controle , Epitopos/química , Epitopos de Linfócito T/imunologia , Evolução Molecular , Antígenos HLA/imunologia , Humanos , Modelos Moleculares , Pandemias , Software , Proteínas Virais/química
6.
J Korean Med Sci ; 35(12): e78, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32233158

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) typing is important for transplant patients to prevent a severe mismatch reaction, and the result can also support the diagnosis of various disease or prediction of drug side effects. However, such secondary applications of HLA typing results are limited because they are typically provided in free-text format or PDFs on electronic medical records. We here propose a method to convert HLA genotype information stored in an unstructured format into a reusable structured format by extracting serotype/allele information. METHODS: We queried HLA typing reports from the clinical data warehouse of Seoul National University Hospital (SUPPREME) from 2000 to 2018 as a rule-development data set (64,024 reports) and from the most recent year (6,181 reports) as a test set. We used a rule-based natural language approach using a Python regex function to extract the 1) number of patients in the report, 2) clinical characteristics such as indication of the HLA testing, and 3) precise HLA genotypes. The performance of the rules and codes was evaluated by comparison between the extracted results from the test set and a validation set generated by manual curation. RESULTS: Among 11,287 reports for development set and 1,107 for the test set describing HLA typing for a single patient, iterative rule generation developed 124 extracting rules and 8 cleaning rules for HLA genotypes. Application of these rules extracted HLA genotypes with 0.892-0.999 precision and 0.795-0.998 recall for the five HLA genes. The precision and recall of the extracting rules for the number of patients in a report were 0.997 and 0.994 and those for the clinical variable extraction were 0.997 and 0.992, respectively. All extracted HLA alleles and serotypes were transformed according to formal HLA nomenclature by the cleaning rules. CONCLUSION: The rule-based HLA genotype extraction method shows reliable accuracy. We believe that there are significant number of patients who takes profit when this under-used genetic information will be return to them.


Assuntos
Antígenos HLA/genética , Teste de Histocompatibilidade , Armazenamento e Recuperação da Informação , Processamento de Linguagem Natural , Algoritmos , Data Warehousing , Registros Eletrônicos de Saúde , Genótipo , Humanos , Seul
7.
Anticancer Res ; 40(4): 2043-2051, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234895

RESUMO

BACKGROUND/AIM: While there has been a rapid development in genomic data mining approaches for T-cell receptor recombinations (TcR), less emphasis has been placed on B-cell receptor (BcR) recombinations. MATERIALS AND METHODS: We obtained lung cancer exome files from the cancer genome atlas (TCGA) and mined the files for TcR and BcR recombination reads. RESULTS: There was a robust detection of BcR light chain recombination reads in lung adenocarcinoma (TCGA-LUAD) samples, and there was a correlation between the detection of light chain recombination reads and a more favorable outcome. This result was supported by analyses of the expression of B-cell markers as indicated by LUAD RNASeq files. CONCLUSION: BcR and TcR recombination reads recovered from LUAD WXS files, either alone or in combination with the human leukocyte antigen (HLA) type, are likely to have prognostic value.


Assuntos
Adenocarcinoma de Pulmão/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Intervalo Livre de Doença , Exoma/genética , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Interferência de RNA , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Recombinação Genética/imunologia
8.
Zhonghua Xue Ye Xue Za Zhi ; 41(3): 204-209, 2020 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-32311889

RESUMO

Objective: To explore the impact of the natural killer cell immunoglobulin-like receptor/human leukocyte antigen (KIR/HLA) receptor-ligand model in single unrelated cord blood transplantation (sUCBT) . Methods: Between July 2012 and June 2018, 270 patients with malignant hematologic diseases receiving single-unit UCBT were divided into two groups. Group 1 (n=174) patients lacked a C-ligand for inhibitory KIR on UCB NK cells (patients homozygous C1/C1 or C2/C2) . Group 2 (n=96) patients expressed both C ligands for inhibitory KIR in the receptor (patients heterozygous C1/C2) . Results: A total of 270 patients (146 males, 124 females) with a median age of 13 years (1-62) were included in this retrospective study. All patients received a myeloablative conditioning regimen (without ATG) . The ratio of neutrophil engraftment for group 1 and 2 were both 98.9%, the median time of neutrophil engraftment for group 1 and 2 was 16 (10-41) days vs 17 (11-33) days (P=0.705) . The ratio of platelet engraftment was 88.5% for group 1 and 87.5% for group 2, the median time of platelet engraftment was 35 (11-113) days vs 38.5 (13-96) days (P=0.317) . The cumulative incidence of Ⅱ-Ⅳ acute GVHD in 100 days was 38.7% (95%CI 31.4%-45.9%) for group 1 and 50.0% (95%CI 39.6%-59.6%) for group 2 (P=0.075) , but multivariate analysis showed that HLA-C ligand absence was an independent protective factor for Ⅱ-Ⅳ acute GVHD after transplantation (P=0.036) . Patients in absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower relapse rate than patients with both C-ligands (group 2) : 17.7% (95%CI 11.7%-24.9%) vs 22.7% (95%CI 4.4%-32.2%) after 3 years (P=0.288) . The median follow-up time was 742 (335-2 512) days. The 3-year OS was 72.1% for group 1 and 60.5% for group 2 (P=0.079) . There was no statistically significant difference between the two groups in 3-year disease-free survival [64.9% (95%CI 56.2%-72.3%) vs 55.4% (95%CI 44.4%-65.0%) (χ(2)=3.027, P=0.082) ]. Non-relapse mortality for group 1 was 12.1% (95%CI 7.7%-17.4%) and for group 2 was 16.7% (95%CI 10.0%-24.8%) (P=0.328) . Conclusion: Patients lacking a KIR-ligand of HLA group C1 or C2 had a lower incidence of grades Ⅱ-Ⅳ acute GVHD after sUCBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Antígenos HLA , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptores KIR , Estudos Retrospectivos , Adulto Jovem
9.
Immunohematology ; 36(1): 1-3, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32324037

RESUMO

CONCLUSIONS: The presence of HLA antibodies in patient serum or plasma may make antibody identification difficult. These HLA antibodies may mask the presence of clinically significant red blood cell (RBC) alloantibodies. Because platelets strongly express HLA antigens, it is possible to remove HLA antibodies by adsorbing the patient's serum or plasma using a platelet pool. Large numbers of random platelets are pooled to ensure a wide variety of HLA types are present. Elimination of the reactivity after adsorption suggests the presence of HLA antibodies in the patient's serum or plasma. The adsorbed patient sample may then be used to evaluate RBC alloantibodies without HLA antibody interference.


Assuntos
Plaquetas , Adsorção , Eritrócitos , Antígenos HLA , Humanos , Isoanticorpos
10.
Mol Immunol ; 120: 146-163, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32126449

RESUMO

Buruli ulcer is an emerging tissue-necrosis infectious disease, caused by the pathogen Mycobacterium ulcerans, leading to permanent deformity if untreated. Despite this debilitating condition, no specific disease-modifying therapeutics or vaccination is available to date. Therefore, we aimed to design an effective multi-epitope vaccine against M. ulcerans using vaccinomics approach. Briefly, the highest antigenic PE-PGRS protein was selected from which the promiscuous T- and B-cell epitopes were predicted. After rigorous assessment, 15 promising T- and B-cell epitopes were selected. The identified T-cell epitopes showed marked interactions towards their HLA-binding alleles and provided 99.8 % world population coverage. Consequently, a vaccine chimera was designed by connecting these epitopes with suitable linkers and LprG adjuvant. The vaccine construct was highly antigenic, immunogenic and non-allergenic; hence, subjected to homology modelling. The molecular docking and dynamics simulation revealed a strong and stable interaction between vaccine and toll-like receptor 2. The binding energy and dissociation constant were -15.3 kcal/mol and 5.9 × 10-12 M, respectively. The computer-simulated immune responses showed abundance of immunoglobulins, increased interferon-γ production, and macrophages activation which are crucial for immune response against M. ulcerans. Furthermore, disulfide bridging and in silico cloning were also performed. These results suggest that the vaccine, if validated experimentally, will be a promising candidate against M. ulcerans and prevent Buruli ulcer disease.


Assuntos
Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/química , Vacinas Bacterianas/imunologia , Proteínas de Membrana/química , Proteínas de Membrana/imunologia , Mycobacterium ulcerans/imunologia , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Vacinas Bacterianas/genética , Úlcera de Buruli/imunologia , Úlcera de Buruli/prevenção & controle , Simulação por Computador , Desenho de Fármacos , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/química , Antígenos HLA/imunologia , Humanos , Proteínas de Membrana/genética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium ulcerans/química , Mycobacterium ulcerans/genética , Engenharia de Proteínas , Vacinas de Subunidades/química , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
12.
Ann Hematol ; 99(5): 1099-1110, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32206853

RESUMO

For patients without an HLA-matched donor, an HLA-mismatched unrelated donor (MMUD) has been considered as an alternative donor in allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a nationwide retrospective study to compare the transplant outcomes among 1-, 2-, and 3-locus (allele/antigen) mismatched unrelated donors (1MMUD n = 2044, 2MMUD n = 492, and 3MMUD n = 73) in allo-HCT and to assess the impact of antithymocyte globulin (ATG) in allo-HCT from 1-3MMUD. 2MMUD and 3MMUD were independent significant adverse factors for grade III-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR] 1.72, p < 0.001 and HR 2.48, p < 0.001), non-relapse mortality (NRM) (HR 1.47, p < 0.001 and HR 2.00, p < 0.001), and overall survival (OS) (HR 1.21, p = 0.0066 and HR 1.60, p = 0.0015). Conversely, the use of ATG was an independent favorable factor for grade III-IV acute GVHD (HR 0.43, p < 0.001), NRM (HR 0.51, p < 0.001), and OS (HR 0.74, p = 0.0012). On the other hand, HLA compatibility and the use of ATG were not associated with a risk of relapse. An interaction test between the number of HLA mismatches and the use of ATG revealed that the effect of ATG on NRM and OS in the 2MMUD group was significantly less than that in the 1MMUD group (HR 1.53, p = 0.036 and HR 2.34, p = 0.0046). This study indicated that the number of HLA mismatches and the use of ATG were significantly associated with not only GVHD, but also NRM and OS. Whereas the use of ATG could improve transplant outcomes in allo-HCT from 1MMUD, its effectiveness with 2MMUD and 3MMUD was limited.


Assuntos
Soro Antilinfocitário/administração & dosagem , Transplante de Medula Óssea , Loci Gênicos , Antígenos HLA , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade
13.
Am J Hematol ; 95(6): 630-636, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157700

RESUMO

Micro-transplantation (MST) by chemotherapy, combined with granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (GPBSC) infusion, from an HLA partial matched related donor has shown some encouraging effective therapy for acute myeloid leukemia (AML). However, the outcome of human leukocyte antigen (HLA) fully mismatched unrelated donor-derived MST in such patients is still unknown. In the present study, we compared the efficacy of HLA fully mismatched unrelated donor-derived MST, and partly matched related donor-derived MST, in AML of 126 patients from two centers in China, These patients, aged 16 to 65 years, were given three or four courses of MST, which consisted of a high dosage cytarabine followed by GPBSC from unrelated donor or related donor. There was a statistically significant difference in 3-year leukemia-free survival (LFS) and 3-year overall survival (OS) between the unrelated and the related group. The non-treatment-related mortality (NRM) rates of patients, and other adverse complications, were no different in the two groups. In conclusion, unrelated donor-derived MST is believed to be a safe treatment, with efficacy similar to or higher than related donor-derived MST. This result provides support for the potential of MST for expanding the donor selection. However, the specific mechanism of action needs further study.


Assuntos
Leucemia Mieloide Aguda , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Antígenos HLA , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
14.
Gene ; 735: 144399, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32001374

RESUMO

The origin of Arab-speaking population is classified according to their geographical location, ethnic background, and historical influx of nearby and distant populations. Data on HLA class I and class II loci in (Arabian Peninsula) Bahraini population are lacking. We analyzed HLA genetic profile of Bahrainis with neighboring communities, and with Levantines, North Africans, Sub-Saharans, Europeans, and Asians, using genetic distances, neighbor-joining dendrograms, correspondence and haplotype analysis. HLA class I and class II genotyping were done by high resolution PCR-SSP in 175 Bahraini subjects. In total, 19 HLA-A, 33 HLA-B, 15 HLA-C, 14 DRB1 and 7 DQB1 alleles were identified. The most common class I alleles were A*02:01:01 (18.3%), A*01:01:01(15.4%), B*35:01:02 (12.9%), C*12:01:01 (15.1%), and C*04:01:01 (14.9%), while DRB1*03:01:01 (18.0%), DQB1*02:01:01 (29.1%), and DQB1*05:01:01 (24.9%) were the most frequent class II alleles. Significant linkage disequilibrium was seen between all HLA loci pairs. DRB1*03:01:01-DQB1*02:01:01 (15.18%) was the most frequent two-locus haplotype. Significant negative Fnd values were observed, indicating balancing selection at studied loci. Bahrainis appear to be related to Western Mediterranean (North Africans, Iberians and French), but relatively distinct from Levantines (Palestinians, Lebanese, and Jordanians) and Sub-Saharans. This indicates limited genetic contribution of Levantine Arabs and Sub-Saharans to the Bahraini gene pool.


Assuntos
Frequência do Gene , Antígenos HLA/genética , Haplótipos , População/genética , Barein , Feminino , Antígenos HLA/classificação , Migração Humana , Humanos , Desequilíbrio de Ligação , Masculino , Filogenia
16.
Hum Genet ; 139(6-7): 813-819, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32055998

RESUMO

Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (Pcombined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P < 5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.


Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Genética Humana , Leishmania/imunologia , Leishmaniose/genética , Leishmaniose/imunologia , Polimorfismo de Nucleotídeo Único , Regulação da Expressão Gênica , Antígenos HLA/imunologia , Humanos , Leishmania/genética , Leishmaniose/parasitologia
17.
Muscle Nerve ; 61(5): 570-574, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035011

RESUMO

Herein we report a case of sporadic inclusion-body myositis (sIBM) occurring at an unusually young age in a patient with primary Sjögren syndrome, and use the case to explore possible shared mechanisms for disease susceptibility. Possible factors may include the association of both conditions with the 8.1 ancestral haplotype; the presence of anti-cN1A antibodies, which, although considered specific for sIBM, are also seen in pSS; and the shared association with T-cell large granular lymphocyte leukemia (T-LGLL). Further evaluation of this patient did in fact reveal underlying T-LGLL and mechanisms by which T cells in sIBM may escape immune regulation and contribute to disease phenotype are explored. Despite myofiber infiltration with CD8-positive T cells in sIBM, and, although sIBM is traditionally considered treatment-refractory, we report a significant response to the anti-CD20 monoclonal antibody, rituximab, and discuss possible mechanisms by which this response may be mediated.


Assuntos
5'-Nucleotidase/imunologia , Autoanticorpos/imunologia , Leucemia Linfocítica Granular Grande/imunologia , Miosite de Corpos de Inclusão/imunologia , Síndrome de Sjogren/imunologia , Adulto , Azatioprina/uso terapêutico , Linfócitos T CD8-Positivos/patologia , Feminino , Antígenos HLA/genética , Haplótipos , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Leucemia Linfocítica Granular Grande/complicações , Imagem por Ressonância Magnética , Metotrexato/uso terapêutico , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/terapia , Prednisolona/uso terapêutico , Rituximab/uso terapêutico , Síndrome de Sjogren/complicações , Síndrome de Sjogren/terapia
18.
Nat Genet ; 52(3): 247-253, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066938

RESUMO

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1-3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.


Assuntos
Autoimunidade/genética , Variação Genética , Antígenos HLA/genética , Cadeias beta de HLA-DQ/genética , Ativação Linfocitária/genética , Regiões Promotoras Genéticas/genética , Alelos , Linfócitos T CD4-Positivos , Sistemas CRISPR-Cas , Linhagem Celular , Regulação da Expressão Gênica , Loci Gênicos , Técnicas de Genotipagem , Antígenos HLA/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Humanos , Imunidade Celular , Linfócitos T Reguladores
19.
Int J Immunogenet ; 47(1): 13-23, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31903698

RESUMO

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade/métodos , Sistema de Registros , Doadores não Relacionados , Chile , Genética Populacional , Alemanha , Antígenos HLA/genética , Antígenos HLA/imunologia , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunogenética , Índia , Polônia , Reino Unido , Estados Unidos
20.
Am J Kidney Dis ; 75(1): 114-123, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255336

RESUMO

With implementation of the Kidney Allocation System, the growth of kidney paired donation programs, and advances in desensitization and immunosuppression, the outlook for "untransplantable" kidney transplantation candidates has never been more promising. The Kidney Allocation System prioritized compatible matches for candidates with calculated panel-reactive antibody levels of 98%, 99%, or 100% and broadened allocation of non-A1 and non-A1-B subgroup kidneys to blood group type B candidates. Concurrently, the growth of kidney paired donation programs and use of incompatible transplantation as part of kidney paired donation to achieve "more compatible" kidney transplantation has improved options for candidates with an incompatible living donor. Finally, advances in desensitization and immunosuppression have strengthened the ability to manage donor-specific antibodies and antibody-mediated rejection. Although no patient should be labeled "untransplantable" due to blood group type or donor-specific antibody, all candidates should be provided with individualized and realistic counseling regarding their anticipated wait times for deceased donor or kidney paired donation matching, with early referral to expert centers when needed. In this Perspective, we consider blood group type ABO incompatibility, HLA antigen incompatibility, antibody-mediated rejection, kidney paired donation, and recent developments in incompatible transplantation in more depth and recommend an approach to the sensitized candidate.


Assuntos
Incompatibilidade de Grupos Sanguíneos/imunologia , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Transplante de Rim/métodos , Sistema ABO de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/métodos , Doação Dirigida de Tecido , Seleção do Doador , Humanos , Doadores Vivos , Obtenção de Tecidos e Órgãos
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