Alloreactivity entails the recognition of cells and tissues from one individual as foreign by T cells and other immune effectors from another individual. Alloreactive immune responses play an important role in various clinical contexts, in particular in transplantation. Major drivers of these responses are the highly immunogenic, non-self HLA molecules. However, the immunogenicity of these allogeneic HLA molecules has been observed to vary according to certain immunobiological and immunogenetic parameters, leading to the concept of differential alloreactivity. Recent progress in unveiling the underpinnings of this phenomenon has been made for the frequently mismatched HLA-DP allotypes, whose singular genomic, structural and population genetics characteristics offer an ideal scenario for these investigations. Studies in the HLA-DP context have highlighted the immunopeptidome overlap between self and non-self HLA allotypes, as well as its editing by non-classical class II chaperones HLA-DM and HLA-DO, as a main determinant of their immunogenicity likely via indirect effects of thymic education. Recent evidence suggests that these observations could also be extended to alloresponses directed against HLA molecules encoded by other loci. How these functional characteristics of HLA molecules shape allorecognition by T-cell subsets, and how they translate into different clinical consequences in the context of transplantation will be the subject of the present review.
{"title":"Differential Alloreactivity: Lessons Learned From a Singular HLA Locus","authors":"Esteban Arrieta-Bolaños","doi":"10.1111/tan.70489","DOIUrl":"10.1111/tan.70489","url":null,"abstract":"<p>Alloreactivity entails the recognition of cells and tissues from one individual as foreign by T cells and other immune effectors from another individual. Alloreactive immune responses play an important role in various clinical contexts, in particular in transplantation. Major drivers of these responses are the highly immunogenic, non-self HLA molecules. However, the immunogenicity of these allogeneic HLA molecules has been observed to vary according to certain immunobiological and immunogenetic parameters, leading to the concept of differential alloreactivity. Recent progress in unveiling the underpinnings of this phenomenon has been made for the frequently mismatched HLA-DP allotypes, whose singular genomic, structural and population genetics characteristics offer an ideal scenario for these investigations. Studies in the HLA-DP context have highlighted the immunopeptidome overlap between self and non-self HLA allotypes, as well as its editing by non-classical class II chaperones HLA-DM and HLA-DO, as a main determinant of their immunogenicity likely via indirect effects of thymic education. Recent evidence suggests that these observations could also be extended to alloresponses directed against HLA molecules encoded by other loci. How these functional characteristics of HLA molecules shape allorecognition by T-cell subsets, and how they translate into different clinical consequences in the context of transplantation will be the subject of the present review.</p>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/tan.70489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of a Novel HLA-F*01:31 Allele by PolyseqOne and Oxford Nanopore Sequencing","authors":"Gang Li, Zhijie Bai, Yuan Yao, Lin Chen, Zhongwei Sun","doi":"10.1111/tan.70493","DOIUrl":"10.1111/tan.70493","url":null,"abstract":"<div>\u0000 \u0000 <p><i>HLA-F*01:31</i> differs from <i>HLA-F*01:04:01</i> by one nonsynonymous nucleotide substitution in codon 183 in exon 3.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterisation of the Novel HLA-DQA1*03:02:05 Allele by Next-Generation Sequencing","authors":"Chen Chen, Qimin Wu, Fang Wang, Wei Zhang, Faming Zhu","doi":"10.1111/tan.70478","DOIUrl":"10.1111/tan.70478","url":null,"abstract":"<div>\u0000 \u0000 <p><i>HLA-DQA1*03:02:05</i> differs from <i>HLA-DQA1*03:02:01:01</i> by one nucleotide substitution at position 639 located in exon 4.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification of the Novel HLA-A*02:540:02N Allele by Next-Generation Sequencing","authors":"Charlène Bouthemy, Jean Milhès, Marylise Fort, Nicolas Congy-Jolivet","doi":"10.1111/tan.70499","DOIUrl":"10.1111/tan.70499","url":null,"abstract":"<div>\u0000 \u0000 <p><i>HLA-A*02:540:02N</i> differs from <i>A*02:01:01:01</i> by one nucleotide substitution in codon 99 in exon 3.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Detection of the HLA-DQB1*03:319 Allele in a Taiwanese Individual","authors":"Kuo-Liang Yang, Py-Yu Lin","doi":"10.1111/tan.70501","DOIUrl":"10.1111/tan.70501","url":null,"abstract":"<div>\u0000 \u0000 <p>One nucleotide substitution in codon 133 of <i>HLA-DQB1*03:03:02:01</i> results in a novel allele <i>HLA-DQB1*03:319</i>.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia K. Holloway, Thomas R. Turner, Sebastian J. F. Hopper, Neema P. Mayor
Single molecule real-time sequencing identifies the novel recombinant allele HLA-DPB1*01:01:01:31.
单分子实时测序鉴定出新的重组等位基因HLA-DPB1*01:01:01:31。
{"title":"Identification of the Novel Recombinant Allele HLA-DPB1*01:01:01:31 in a Haematopoietic Cell Donor","authors":"Mia K. Holloway, Thomas R. Turner, Sebastian J. F. Hopper, Neema P. Mayor","doi":"10.1111/tan.70495","DOIUrl":"10.1111/tan.70495","url":null,"abstract":"<div>\u0000 \u0000 <p>Single molecule real-time sequencing identifies the novel recombinant allele <i>HLA-DPB1*01:01:01:31</i>.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular Definition of the Novel HLA-DQB1*04:107 Allele Identified in Brazil Through Next-Generation Sequencing","authors":"Kayo Thiago Ribeiro Perroni, Fernanda Pelisson Massi, Bruna Karina Banin Hirata, Quirino Alves de Lima Neto, Jeane Eliete Laguila Visentainer","doi":"10.1111/tan.70496","DOIUrl":"10.1111/tan.70496","url":null,"abstract":"<div>\u0000 \u0000 <p>The novel <i>HLA-DQB1*04:107</i> allele differs from <i>DQB1*04:01:01:03</i> by a change of A>G in exon 2.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Aparecida da Silva Pereira, Sâmila Natiane Ferreira, Cássia Cristina Alves Gonçalves, Mirella Carneiro dos Reis, Carolina da Paz Zampier, Isabela de Carvalho Leitão, Monique de Souza Almeida Lopes, Artur Duque Rossi, Sheila Coelho Soares-Lima, Rafael Mello Galliez, Shana Priscila Coutinho Barroso, Orlando da Costa Ferreira Junior, Amilcar Tanuri, Terezinha Marta Pereira Pinto Castiñeiras, Átila Duque Rossi, Cynthia Chester Cardoso
COVID-19 is a respiratory disease caused by SARS-CoV-2, in which severe outcomes are primarily driven by an exacerbated immune response. The HLA region has been extensively investigated in COVID-19 due to its central role in the immune response, although genetic associations vary across populations. Here, the association of HLA genetic variability with COVID-19 severe respiratory outcomes was investigated in an admixed population from Rio de Janeiro, Brazil. Results of a comparative study between mild and severe COVID-19 cases involving 306 individuals have suggested risk associations with severe COVID-19 for the HLA-DPB1*13:01 allele (OR = 3.42, 95% CI = 1.05–11.16, p = 0.041) and the HLA-B*39 allele group (OR = 3.26, 95% CI = 1.16–9.13, p = 0.024), although statistical significance was lost after FDR adjustment for multiple comparisons (adjusted p > 0.05). Amino acid analyses showed that a serine at position 116 of HLA-B conferred protection against severe COVID-19 (OR = 0.4774, 95% CI = 0.28–0.81, p = 0.006, adjusted p = 0.031). In silico analysis using the NetMHCpan tool predicted that this residue, located in the HLA-B peptide-binding groove, has enhanced binding affinity to immunodominant SARS-CoV-2 epitopes, suggesting a functional mechanism underlying the observed protection. The association of single nucleotide variants at the HLA region was also investigated, and no statistically significant association was found. Results obtained in the present study underscore the importance of HLA in COVID-19 severity, likely mediated by its influence on viral peptide presentation, and advance our understanding of the genetic underpinnings of severe disease in admixed populations.
COVID-19是由SARS-CoV-2引起的一种呼吸道疾病，其严重后果主要是由免疫反应加剧引起的。由于HLA区域在免疫反应中的核心作用，在COVID-19中已被广泛研究，尽管遗传关联因人群而异。本研究在巴西里约热内卢的混合人群中研究了HLA遗传变异与COVID-19严重呼吸结局的关系。一项涉及306例轻、重度COVID-19病例的比较研究结果显示，HLA-DPB1*13:01等位基因组（OR = 3.42, 95% CI = 1.05-11.16, p = 0.041）和HLA-B*39等位基因组（OR = 3.26, 95% CI = 1.16-9.13, p = 0.024）与重症COVID-19存在风险关联，但经FDR校正后，多重比较无统计学意义（校正p >； 0.05）。氨基酸分析显示，HLA-B第116位的丝氨酸对严重的COVID-19具有保护作用（OR = 0.4774, 95% CI = 0.28-0.81, p = 0.006，调整后p = 0.031）。使用NetMHCpan工具进行的硅分析预测，该残基位于HLA-B肽结合槽中，与免疫优势的SARS-CoV-2表位的结合亲和力增强，提示观察到的保护作用的功能机制。HLA区域单核苷酸变异的相关性也被调查，没有发现有统计学意义的关联。本研究的结果强调了HLA在COVID-19严重程度中的重要性，可能是通过其对病毒肽呈现的影响来介导的，并促进了我们对混合人群中严重疾病的遗传基础的理解。
{"title":"HLA-B Serine 116 Confers Protection Against Severe COVID-19 in a Cohort From Rio de Janeiro, Brazil","authors":"Maria Aparecida da Silva Pereira, Sâmila Natiane Ferreira, Cássia Cristina Alves Gonçalves, Mirella Carneiro dos Reis, Carolina da Paz Zampier, Isabela de Carvalho Leitão, Monique de Souza Almeida Lopes, Artur Duque Rossi, Sheila Coelho Soares-Lima, Rafael Mello Galliez, Shana Priscila Coutinho Barroso, Orlando da Costa Ferreira Junior, Amilcar Tanuri, Terezinha Marta Pereira Pinto Castiñeiras, Átila Duque Rossi, Cynthia Chester Cardoso","doi":"10.1111/tan.70479","DOIUrl":"https://doi.org/10.1111/tan.70479","url":null,"abstract":"<p>COVID-19 is a respiratory disease caused by SARS-CoV-2, in which severe outcomes are primarily driven by an exacerbated immune response. The HLA region has been extensively investigated in COVID-19 due to its central role in the immune response, although genetic associations vary across populations. Here, the association of HLA genetic variability with COVID-19 severe respiratory outcomes was investigated in an admixed population from Rio de Janeiro, Brazil. Results of a comparative study between mild and severe COVID-19 cases involving 306 individuals have suggested risk associations with severe COVID-19 for the <i>HLA-DPB1*13:01</i> allele (OR = 3.42, 95% CI = 1.05–11.16, <i>p</i> = 0.041) and the <i>HLA-B*39</i> allele group (OR = 3.26, 95% CI = 1.16–9.13, <i>p</i> = 0.024), although statistical significance was lost after FDR adjustment for multiple comparisons (adjusted <i>p</i> > 0.05). Amino acid analyses showed that a serine at position 116 of HLA-B conferred protection against severe COVID-19 (OR = 0.4774, 95% CI = 0.28–0.81, <i>p</i> = 0.006, adjusted <i>p</i> = 0.031). In silico analysis using the NetMHCpan tool predicted that this residue, located in the HLA-B peptide-binding groove, has enhanced binding affinity to immunodominant SARS-CoV-2 epitopes, suggesting a functional mechanism underlying the observed protection. The association of single nucleotide variants at the HLA region was also investigated, and no statistically significant association was found. Results obtained in the present study underscore the importance of HLA in COVID-19 severity, likely mediated by its influence on viral peptide presentation, and advance our understanding of the genetic underpinnings of severe disease in admixed populations.</p>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/tan.70479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterisation of a New HLA-DRB4*01:169 Allele Detected in Two HLA-Identical Siblings","authors":"Juan López-Pérez, Daniel García-Cuesta, Miriam Vilches-Moreno, Guillermo Rodriguez, Antonio Nieto","doi":"10.1111/tan.70488","DOIUrl":"https://doi.org/10.1111/tan.70488","url":null,"abstract":"<div>\u0000 \u0000 <p>The <i>HLA-DRB4*01:169</i> allele differs from <i>DRB4*01:01:01:01</i> by a non-synonymous mutation in codon 111 in exon 3.</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The HLA-C*12:04:04 Allele Identified by Next Generation Sequencing in an Individual From Tamil Nadu, India","authors":"D. Meshach Paul, D. Nithiya Shree, S. N. Abishek, P. Gopinath, Chitra Chandran","doi":"10.1111/tan.70497","DOIUrl":"https://doi.org/10.1111/tan.70497","url":null,"abstract":"<div>\u0000 \u0000 <p>Novel <i>HLA-C*12:04:04</i> differs from <i>HLA-C*12:04:02:02</i> by a single synonymous nucleotide substitution in exon 5 (ATC>ATT).</p>\u0000 </div>","PeriodicalId":13172,"journal":{"name":"HLA","volume":"106 6","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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