From HLA Association to Tissue Injury: Lessons from Drug Hypersensitivity and Multiple Sclerosis

Abstract

HLA associations are among the strongest genetic signals in immune-mediated disease, yet they rarely explain incomplete penetrance, tissue localization, or opposing effects of different alleles. We use T cell-mediated drug hypersensitivity and multiple sclerosis as complementary mechanistic anchors. Drug hypersensitivity shows that a defined exposure can create or alter a peptide-HLA surface and recruit pre-existing class I-restricted memory. Patch-confirmed abacavir reactions beginning within 36 hours, together with abacavir-responsive cells in drug-unexposed carriers, make de novo naive priming and a concurrent CD4 or B-cell arm non-obligatory at tissue injury. Multiple sclerosis adds a lifelong antigen source and separates HLA-DRB1*15:01-associated class II specificity from class I-dependent control of Epstein-Barr virus antigen pressure and candidate tissue execution. Together, these systems resolve three HLA functions: specificity and focusing, antigen-source control, and tissue execution; and three temporal stages: imprinting and licensing, tissue recall, and local amplification. Injury requires compatible receptor-HLA context, a relevant ligand at sufficient density, natural presentation in the appropriate tissue niche, and permissive local regulation. We separate target selection from innate and cytokine amplification, distinguish antibody-executed disease from cellular architectures, and propose a lesion-anchored receptor-first workflow that converts HLA associations into experimentally adjudicable mechanistic endotypes.