Associations between HLA-II variation and antibody specificity are predicted by antigen properties
Abstract Background Human leukocyte antigen class II (HLA-II) genes are highly polymorphic affecting the specificity of human antibody responses, as presentation of processed antigen peptides by HLA-II on B cells is essential for T helper cell dependent affinity maturation and class switching. The c...
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BMC
2025-06-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-025-01486-w |
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| author | Gabriel Innocenti Sergio Andreu-Sánchez Nicolai V. Hörstke Hesham Elabd Iros Barozzi Andre Franke Máté Manczinger Thomas Vogl |
| author_facet | Gabriel Innocenti Sergio Andreu-Sánchez Nicolai V. Hörstke Hesham Elabd Iros Barozzi Andre Franke Máté Manczinger Thomas Vogl |
| author_sort | Gabriel Innocenti |
| collection | DOAJ |
| description | Abstract Background Human leukocyte antigen class II (HLA-II) genes are highly polymorphic affecting the specificity of human antibody responses, as presentation of processed antigen peptides by HLA-II on B cells is essential for T helper cell dependent affinity maturation and class switching. The combination of high-throughput immunoassays and genome-wide association studies has recently revealed strong associations between HLA-II variants and antibody responses against specific antigens. However, factors underlying these associations remain incompletely understood. Methods Here, we have leveraged paired data sets of SNP arrays and functional antibody epitope repertoires against 344,000 peptide antigens in 1940 individuals to mine for key determinants linking genetics and antibody specificity. Results We show that secreted proteins and antigens presented in small modules (i.e., viruses) are significantly more frequently associated with HLA-II alleles, than membrane bound or intracellular proteins. This data suggests a model in which antibody responses against separate antigen units composed of single or few proteins dominate HLA-II associations. In contrast, the presence of manifold intracellular or membrane proteins (peptides of which could be bound by different HLA-II alleles) on bacterial cells dilutes potential associations to antibody specificities. Conclusions Hence, genetic associations to antibody specificities are shaped by antigen intrinsic properties. Given the prominent role of HLA-II alleles in infection, autoimmune diseases, allergies, and cancer, our work provides a theoretical framework to study antigen/HLA-II risk factors in these disease settings and will fuel the design of improved immunogenetics screens. |
| format | Article |
| id | doaj-art-9e259ba14523488abf43942fc376044e |
| institution | OA Journals |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj-art-9e259ba14523488abf43942fc376044e2025-08-20T02:05:39ZengBMCGenome Medicine1756-994X2025-06-0117112210.1186/s13073-025-01486-wAssociations between HLA-II variation and antibody specificity are predicted by antigen propertiesGabriel Innocenti0Sergio Andreu-Sánchez1Nicolai V. Hörstke2Hesham Elabd3Iros Barozzi4Andre Franke5Máté Manczinger6Thomas Vogl7Center for Cancer Research, Medical University of ViennaDepartment of Genetics, University of Groningen, University Medical Center GroningenCenter for Cancer Research, Medical University of ViennaInstitute of Clinical Molecular Biology, Kiel University & University Medical Centre Schleswig-HolsteinCenter for Cancer Research, Medical University of ViennaHCEMM-BRC Systems Immunology Research GroupSystemic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research CentreCenter for Cancer Research, Medical University of ViennaAbstract Background Human leukocyte antigen class II (HLA-II) genes are highly polymorphic affecting the specificity of human antibody responses, as presentation of processed antigen peptides by HLA-II on B cells is essential for T helper cell dependent affinity maturation and class switching. The combination of high-throughput immunoassays and genome-wide association studies has recently revealed strong associations between HLA-II variants and antibody responses against specific antigens. However, factors underlying these associations remain incompletely understood. Methods Here, we have leveraged paired data sets of SNP arrays and functional antibody epitope repertoires against 344,000 peptide antigens in 1940 individuals to mine for key determinants linking genetics and antibody specificity. Results We show that secreted proteins and antigens presented in small modules (i.e., viruses) are significantly more frequently associated with HLA-II alleles, than membrane bound or intracellular proteins. This data suggests a model in which antibody responses against separate antigen units composed of single or few proteins dominate HLA-II associations. In contrast, the presence of manifold intracellular or membrane proteins (peptides of which could be bound by different HLA-II alleles) on bacterial cells dilutes potential associations to antibody specificities. Conclusions Hence, genetic associations to antibody specificities are shaped by antigen intrinsic properties. Given the prominent role of HLA-II alleles in infection, autoimmune diseases, allergies, and cancer, our work provides a theoretical framework to study antigen/HLA-II risk factors in these disease settings and will fuel the design of improved immunogenetics screens.https://doi.org/10.1186/s13073-025-01486-wHLA-IIMHC-IIAntibody-repertoiresB-cellsGWASPhIP-Seq |
| spellingShingle | Gabriel Innocenti Sergio Andreu-Sánchez Nicolai V. Hörstke Hesham Elabd Iros Barozzi Andre Franke Máté Manczinger Thomas Vogl Associations between HLA-II variation and antibody specificity are predicted by antigen properties Genome Medicine HLA-II MHC-II Antibody-repertoires B-cells GWAS PhIP-Seq |
| title | Associations between HLA-II variation and antibody specificity are predicted by antigen properties |
| title_full | Associations between HLA-II variation and antibody specificity are predicted by antigen properties |
| title_fullStr | Associations between HLA-II variation and antibody specificity are predicted by antigen properties |
| title_full_unstemmed | Associations between HLA-II variation and antibody specificity are predicted by antigen properties |
| title_short | Associations between HLA-II variation and antibody specificity are predicted by antigen properties |
| title_sort | associations between hla ii variation and antibody specificity are predicted by antigen properties |
| topic | HLA-II MHC-II Antibody-repertoires B-cells GWAS PhIP-Seq |
| url | https://doi.org/10.1186/s13073-025-01486-w |
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