Innocenti, G. and Andreu-Sánchez, S. and Hörstke, N.V. and Elabd, H. and Barozzi, I. and Franke, A. and Manczinger, Máté and Vogl, T. (2025) Associations between HLA-II variation and antibody specificity are predicted by antigen properties. GENOME MEDICINE, 17 (1). No. 65. ISSN 1756-994X
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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. © The Author(s) 2025.
| Item Type: | Article |
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| Additional Information: | Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, Vienna, 1090, Austria Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands Institute of Clinical Molecular Biology, Kiel University & University Medical Centre Schleswig-Holstein, Kiel, Germany Systemic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary HCEMM-BRC Systems Immunology Research Group, Szeged, Hungary Export Date: 12 June 2025; Cited By: 0; Correspondence Address: T. Vogl; Center for Cancer Research, Medical University of Vienna, Vienna, Borschkegasse 8a, 1090, Austria; email: thomas.vogl@meduniwien.ac.at |
| Uncontrolled Keywords: | INFECTION; ARTICLE; B-CELLS; prediction; ALLELE; human; membrane protein; risk factor; genetic association; gene frequency; controlled study; cohort analysis; PROTEIN SECRETION; nonhuman; Antibody Specificity; Genetic Variation; machine learning; human cell; b lymphocyte; binding affinity; antigen binding; Allergy; autoimmune disease; ANTIBODY RESPONSE; cell protein; Genome-Wide Association Study; gene function; immunological parameters; HLA antigen class 2; bacterial cell; B lymphocyte receptor; GWAS; malignant neoplasm; Single Nucleotide Polymorphism array; MHC-II; internalization (cell); PhIP-Seq; HLA-II; Antibody-repertoires; antigen property; HLA II gene; |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 11 Mar 2026 10:16 |
| Last Modified: | 11 Mar 2026 10:16 |
| URI: | https://real.mtak.hu/id/eprint/235541 |
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