{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:08:18Z","timestamp":1788869298532,"version":"build-2803163510"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Human leukocyte antigen (HLA) molecules mediate peptide presentation and shape immune recognition, with clinical relevance well beyond donor-recipient matching. This review describes how HLA variation and anti-HLA immunity affect transfusion medicine, autoimmune and infectious diseases, pharmacogenomics, cancer, pregnancy, solid organ transplantation and haematopoietic stem cell transplantation (HSCT). It outlines HLA nomenclature and testing, including sequence-based typing, single-antigen bead assays, virtual crossmatching and molecular mismatch analysis, and considers how population-specific allele and haplotype frequencies affect interpretation. An HLA result must be interpreted in clinical context, including exposure history, donor specificity, antibody strength, assay characteristics, organ type, molecular mismatch, HLA evolutionary divergence, immunosuppression and ancestry. In transfusion medicine, recipient alloimmunisation can cause platelet refractoriness and complicate future transplantation, whereas donor antibodies contribute to transfusion-related acute lung injury. Transfusion-associated graft-versus-host disease is a different cellular complication. In autoimmunity, type 1 diabetes and systemic lupus erythematosus show how HLA class II variation can influence peptide selection, immune tolerance and autoantibody profiles, although most associations are not diagnostic alone. Pharmacogenomic testing has clearer clinical value for selected drugs, including abacavir, carbamazepine and allopurinol. In cancer, loss of classical HLA expression and non-classical HLA-E and HLA-G pathways contribute to immune escape and are being explored as therapeutic targets. In transplantation, HLA assessment increasingly combines donor-specific antibodies, crossmatch results, molecular mismatch and organ-specific risk. Eplet, amino-acid and predicted indirect T-cell epitope mismatch can support risk assessment at population level, but no single score should determine organ allocation or immunosuppression. HSCT differs because the graft transfers a donor immune system, creating competing risks of graft failure, graft-versus-host disease and relapse. Clinical implementation requires reliable assays, validated clinical associations, evidence of patient benefit, multi-ancestry validation, consistent reporting and equitable access. We distinguish established clinical practice from developing risk-stratification methods and early mechanistic findings.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1931212","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:23:20Z","timestamp":1788866600000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond histocompatibility: human leukocyte antigen as a cross-disciplinary platform for immune recognition and clinical decision-making"],"prefix":"10.3389","volume":"17","author":[{"given":"Saikat","family":"Mandal","sequence":"first","affiliation":[{"name":"Translational Medical Sciences, School of Medicine, University of Nottingham","place":["Nottingham, United Kingdom"]},{"name":"NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyisa","family":"Deb","sequence":"additional","affiliation":[{"name":"Transfusion Medicine & Blood Centre, Apollo Excelcare Hospital","place":["Guwahati, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aswin K.","family":"Mohan","sequence":"additional","affiliation":[{"name":"Transfusion Medicine, All India Institute of Medical Sciences","place":["Bibinagar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhasini","family":"Sil","sequence":"additional","affiliation":[{"name":"Transfusion Medicine, Rajiv Gandhi Super Speciality Hospital","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manideepa","family":"Maji","sequence":"additional","affiliation":[{"name":"Hull York Medical School, University of Hull","place":["Hull, United Kingdom"]},{"name":"Haematology, Hull University Teaching Hospitals NHS Trust","place":["Hull, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirin","family":"Hasan","sequence":"additional","affiliation":[{"name":"Queen\u2019s Centre for Oncology, Hull University Teaching Hospitals NHS Trust","place":["Hull, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad Hassan","family":"Ashraf","sequence":"additional","affiliation":[{"name":"HPB Medicine and Gastroenterology, Nottingham University Hospitals NHS Trust","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadeep","family":"Dhali","sequence":"additional","affiliation":[{"name":"Division of Cancer, Imperial College London","place":["London, United Kingdom"]},{"name":"Academic Gastroenterology, Sheffield Teaching Hospitals NHS Trust","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200009073431006","article-title":"The HLA system. 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