Beyond histocompatibility: human leukocyte antigen as a cross-disciplinary platform for immune recognition and clinical decision-making.

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.