RESUMEN
How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.
Asunto(s)
Cadenas HLA-DRB1 , Femenino , Humanos , Lactante , Masculino , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Población Negra/genética , Vacunas contra Hepatitis B/inmunología , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/genética , Sitios de Carácter Cuantitativo , Uganda , Vacunación , Tos Ferina/prevención & control , Tos Ferina/inmunología , Tos Ferina/genética , Burkina Faso , Sudáfrica , Pueblo Africano , Pueblo EuropeoRESUMEN
BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.
Asunto(s)
Tortícolis , Humanos , Tortícolis/inmunología , Tortícolis/genética , Masculino , Femenino , Persona de Mediana Edad , Proteómica , Adulto , Anciano , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Autoanticuerpos/sangreRESUMEN
The HLA-B*53:69 allele differs from HLA-B*53:01:01:01 by two nucleotide changes in exon 3.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Exones/genética , Análisis de Secuencia de ADN , Prueba de HistocompatibilidadRESUMEN
A nucleotide mutation in codon 75 of HLA-C*04:01:01:01 results in a novel allele HLA-C*04:279N.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Codón , Mutación , Análisis de Secuencia de ADN , Prueba de HistocompatibilidadRESUMEN
Between January 2018 and June 2021, the Ezer Mizion recruited 223,960 donors. All donors were typed for their HLA class I and II alleles at high resolution by Next Generation Sequencing techniques. Comparison between the sequences obtained from these donors and those in the IPD-IMGT/HLA Database, revealed 122 Novel HLA alleles that were found in 133 donors. Most of the alleles, 94 (77%) were identified in the HLA class I genes (30, 35, and 29 in HLA-A, -B, and -C, respectively), and 28 (23%) were detected in the HLA class II genes (9 in HLA-DRB1 and -DQB1 and 10 in -DPB1). Most of these novel alleles, 106 (86.9%) comprised single nucleotide variation (SNV), 9 (7.4%) present multiple amino acids variation, 4 and 3 were generated because of deletions and insertions, respectively. Ten of these novel alleles were seen to be null alleles.
Asunto(s)
Trasplante de Médula Ósea , Médula Ósea , Humanos , Haplotipos , Alelos , Sistema de RegistrosRESUMEN
The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.
Asunto(s)
Trasplante de Riñón , Rechazo de Injerto/genética , Supervivencia de Injerto/genética , Antígenos de Histocompatibilidad Clase I/genética , HumanosRESUMEN
One nucleotide substitution in Codon 58 of HLA-C*06:02:01:01 results in a novel allele, HLA-C*06:195.
Asunto(s)
Antígenos HLA-C , Trasplante de Células Madre Hematopoyéticas , Alelos , Secuencia de Bases , Exones/genética , Antígenos HLA-C/genética , Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , TaiwánRESUMEN
One nucleotide substitution in codon 73 of HLA-A*01:01:01:01 results in a novel allele, HLA-A*01:211.
Asunto(s)
Médula Ósea , Donantes de Tejidos , Alelos , Sustitución de Aminoácidos , Secuencia de Bases , Exones/genética , Antígenos HLA-A/genética , Prueba de Histocompatibilidad , Humanos , Malasia , Análisis de Secuencia de ADNRESUMEN
One nucleotide substitution in codon 89 of HLA-B*38:02:01:01 results in a novel allele, HLA-B*38:64.
Asunto(s)
Antígenos HLA-B , Trasplante de Células Madre Hematopoyéticas , Alelos , Secuencia de Bases , Exones/genética , Antígenos HLA-B/genética , Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Malasia , Alineación de Secuencia , Análisis de Secuencia de ADN , TaiwánRESUMEN
One nucleotide substitution in codon 38 of HLA-DQB1*06:01:01:01 results in a novel allele, HLA-DQB1*06:132.
Asunto(s)
Médula Ósea , Alelos , Exones/genética , Cadenas beta de HLA-DQ/genética , Prueba de Histocompatibilidad , Humanos , Malasia , Análisis de Secuencia de ADNRESUMEN
Nucleotide substitutions in codon 38 of HLA-DQB1*05:03:01:01 result in a novel allele, HLA-DQB1*05:66:01.
Asunto(s)
Médula Ósea , Alelos , Secuencia de Bases , Exones/genética , Cadenas beta de HLA-DQ/genética , Humanos , MalasiaRESUMEN
One nucleotide substitution in codon 87 of HLA-DQB1*05:02:01:01 results in a novel allele, HLA-DQB1*05:116.
Asunto(s)
Alelos , China , Exones/genética , Cadenas beta de HLA-DQ/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-DPB1*10:01:05 differs from HLA-DPB1*10:01:01:01 by a single synonymous nucleotide substitution in exon 2, 38 G>A.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Secuencia de Bases , Cadenas beta de HLA-DP , Humanos , Arabia SauditaRESUMEN
One nucleotide substitution in codon 85 of HLA-DPB1*04:01:01:01 results in a novel allele, HLA-DPB1*454:01.
Asunto(s)
Alelos , Secuencia de Bases , Cadenas beta de HLA-DP/genética , Humanos , MalasiaRESUMEN
One nucleotide substitution in codon 84 of HLA-DPB1*02:01:02:01 results in a novel allele, HLA-DPB1*526:01.
Asunto(s)
Alelos , Secuencia de Bases , Codón , Cadenas beta de HLA-DP/genética , HumanosRESUMEN
One nucleotide substitution in codon 112 of HLA-B*15:349:01 results in a novel allele, HLA-B*15:349:02.
Asunto(s)
Médula Ósea , Antígenos HLA-B , Alelos , Sustitución de Aminoácidos , Secuencia de Bases , Exones/genética , Antígenos HLA-B/genética , Prueba de Histocompatibilidad , Humanos , Malasia , Análisis de Secuencia de ADN , Donantes de TejidosRESUMEN
HLA-A*68:227 differs from HLA-A*68:84 by two single nucleotide substitutions in codon 10 and 90.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Antígenos HLA-A , Prueba de Histocompatibilidad , Humanos , Arabia SauditaRESUMEN
DNA substitutions from codons 69 to 71 of HLA-B*35:05:01:01 result in a novel allele, HLA-B*35:368.
Asunto(s)
Antígenos HLA-B , Trasplante de Células Madre Hematopoyéticas , Alelos , Secuencia de Bases , Exones/genética , Antígenos HLA-B/genética , Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Malasia , Análisis de Secuencia de ADN , TaiwánRESUMEN
A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.
Asunto(s)
Alelos , Genética de Población , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Frecuencia de los Genes , Haplotipos , HumanosRESUMEN
Novel allele HLA-DPB1*906:01 is possibly a recombinant between DPB1*04:02:01:01 and DPB1*06:01:01:01.