RESUMEN
Genomic sequence of HLA-DPA1*01:03:01:73, -DPA1*01:03:01:80, DPA1*01:03:01:82, -DPA1*01:155:01:02, -DPA1*02:02:02:16 alleles in Spanish individuals.
Asunto(s)
Alelos , Cadenas alfa de HLA-DP , Humanos , Cadenas alfa de HLA-DP/genética , Exones , España , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Secuencia de Bases , Alineación de SecuenciaRESUMEN
To analyse the effect of HLA-DPA1 and HLA-DPB1 allelic mismatches on the outcomes of unrelated donor haematopoietic stem cell transplantation (URD-HSCT), we collected 258 recipients with haematological disease who underwent HLA-10/10 matched URD-HSCT. HLA-A, -B, -C, -DRB1, -DQB1, -DRB3/4/5, -DQA1, -DPA1 and -DPB1 typing was performed for the donors and recipients using next-generation sequencing (NGS) technology. After excluding 8 cases with DQA1 or DRB3/4/5 mismatches, we included 250 cases with HLA-14/14 matching for further analysis. Our results showed that the proportion of matched DPA1 and DPB1 alleles was only 10.4% (26/250). The remaining 89.6% of donors and recipients demonstrated DPA1 or DPB1 mismatch. In the DPA1 matched and DPB1 mismatched group, accounting for 18.8% (47/250) of the cohort, DPB1*02:01/DPB1*03:01 allelic mismatches were associated with decreased 2-year OS and increased NRM. DPB1*02:02/DPB1*05:01 and DPB1*02:01/DPB1*05:01 mismatches showed no impact on outcomes. Moreover, the specific allelic mismatches observed were consistent with the DPB1 T-cell epitope (TCE) classification as permissive and non-permissive. We innovatively established an analysis method for DPA1 ~ DPB1 linkage mismatch for cases with both DPA1 and DPB1 mismatched, accounting for 70% (175/250) of the total. DPA1*02:02 ~ DPB1*05:01/DPA1*02:01 ~ DPB1*17:01 linkage mismatches were associated with lower 2-year OS, especially among AML/MDS recipients. DPA1*02:02 ~ DPB1*05:01/DPA1*01:03 ~ DPB1*02:01 linkage mismatches showed no impact on outcomes. In conclusion, applying the DPA1 ~ DPB1 linkage mismatch analysis approach can identify different types of mismatches affecting transplant outcomes and provide valuable insight for selecting optimal donors for AML/MDS and ALL recipients.
Asunto(s)
Alelos , Cadenas alfa de HLA-DP , Cadenas beta de HLA-DP , Trasplante de Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Donante no Emparentado , Humanos , Cadenas beta de HLA-DP/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Cadenas alfa de HLA-DP/genética , Masculino , Prueba de Histocompatibilidad/métodos , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Niño , Preescolar , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunologíaRESUMEN
The novel HLA-DPA1*01:195 allele differs from HLA-DPA1*01:03:01:01 by one nucleotide substitution in exon 4.
Asunto(s)
Alelos , Exones , Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Cadenas alfa de HLA-DP/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Prueba de Histocompatibilidad/métodos , Secuencia de Bases , Análisis de Secuencia de ADN/métodos , Polimorfismo de Nucleótido Simple , Alineación de SecuenciaRESUMEN
The novel HLA-DPA1*02:07:04 allele was detected during the HLA typing for kidney transplantation.
Asunto(s)
Alelos , Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Trasplante de Riñón , Humanos , Cadenas alfa de HLA-DP/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Prueba de Histocompatibilidad/métodos , ExonesRESUMEN
The new HLA-DPA1*01:182 allele differs from HLA-DPA1*01:03:01:04 by a single mismatch in exon 4.
Asunto(s)
Médula Ósea , Cadenas alfa de HLA-DP , Humanos , Alelos , Brasil , Prueba de HistocompatibilidadRESUMEN
HLA-DPA1*02:86 differs from HLA-DPA1*02:01:01 by a single nucleotide substitution at position 680 C > A in exon 4.
Asunto(s)
Alelos , Exones , Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Cadenas alfa de HLA-DP/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Prueba de Histocompatibilidad/métodos , Polimorfismo de Nucleótido Simple , Secuencia de Bases , Análisis de Secuencia de ADN/métodosRESUMEN
HLA-DPA1*02:117 differs from HLA-DPA1*02:02:02:01 by one nucleotide in exon 2.
Asunto(s)
Cadenas alfa de HLA-DP , Nucleótidos , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , China , Análisis de Secuencia de ADNRESUMEN
The novel HLA-DPA1*02:02:15 allele differs from HLA-DPA1*02:02:02:01 by one nucleotide substitution in exon 1.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genéticaRESUMEN
HLA-DPA1*02:124 differs from HLA-DRB1*02:02:02:01 by one nucleotide substitution in codon 5 in exon 2.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , República de CoreaRESUMEN
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
HLA-DPA1*02:122 differs from HLA-DPA1*02:01:01:02 by one nucleotide substitution in codon 78 in exon 2.
Asunto(s)
Cadenas alfa de HLA-DP , Humanos , Alelos , Alineación de Secuencia , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genética , Análisis de Secuencia de ADNRESUMEN
HLA-DPA1*01:03:51 differs from HLA-DPA1*01:03:01:01 by one nucleotide substitution in codon 146 in exon 3.
Asunto(s)
Cadenas alfa de HLA-DP , Humanos , Alelos , Alineación de Secuencia , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genéticaRESUMEN
OBJECTIVE: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. DESIGN: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. RESULTS: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.
Asunto(s)
Colangitis Esclerosante , Humanos , Haplotipos , Colangitis Esclerosante/genética , Cadenas alfa de HLA-DP/genética , Células Asesinas NaturalesRESUMEN
The novel HLA-DPA1*01:130 allele differs from HLA-DPA1*01:03:01:03 by one nucleotide substitution in Exon 3.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genéticaRESUMEN
The novel HLA-DPA1*01:149 allele differs from HLA-DPA1*01:03:01:05 by one nucleotide substitution in exon 2.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genéticaRESUMEN
The novel HLA-DPA1*02:110:02 allele differs from HLA-DPA1*02:01:01:06 by one nucleotide substitution in exon 4.
Asunto(s)
Cadenas alfa de HLA-DP , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Alelos , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genéticaRESUMEN
HLA-DPA1*01:159 differs from HLA-DPA1*01:03:01:03 by one nucleotide substitution in codon 120 in exon 3.
Asunto(s)
Cadenas alfa de HLA-DP , Humanos , Alelos , Alineación de Secuencia , Prueba de Histocompatibilidad , Cadenas alfa de HLA-DP/genética , Análisis de Secuencia de ADNRESUMEN
Four novel HLA Class II alleles, HLA-DPA1*01:03:01:68, -DPA1*01:03:01:71, -DQA1*02:01:01:06, and -DQB1*06:03:01:19, characterized in Spanish individuals.
Asunto(s)
Cadenas alfa de HLA-DP , Humanos , Alelos , Cadenas alfa de HLA-DP/genética , Cadenas beta de HLA-DQ/genética , Haplotipos , Cadenas alfa de HLA-DQ/genética , Frecuencia de los GenesRESUMEN
HLA-DPA1*02:115 differs from HLA-DPA1*02:01:01:06 by one nucleotide substitution in codon 224 in exon 4.
