Keystone Epitope Theory: Implications for Hypersensitivity, Autoimmunity and Transplantation
Year: 2025
Type: other
Abstract: HLA class I alleles confer striking risk for T cell–mediated drug hypersensitivity, yet positive predictivevalues are low—typically under 10% and as low as 0.12% for some drug–HLA pairs1,2. We proposethat persistent, human-adapted pathogens—notably herpesviruses—focus postnatal immune memory onconserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). Thephylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted overhundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as eachindividual acquires these infections and builds tissue-specific immune memory. When a drug-altered self-peptide approximates the geometry of such a target and is presented by the same risk HLA in the same nicheat sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching localregulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologousimmunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in thesame tissue where antiviral memory already resides, which helps explain why injury is tissue-restricted; and(iii) public and private TCR solutions that bridge viral and self targets. Beginning with T cell–mediated drughypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis andtransplant rejection, and conclude with proposed experimental validation strategies that may be applicablemore broadly to T cell–mediated hypersensitivity and autoimmunity.
Authors: Mallal, Simon, Phillips, Elizabeth, Asiaee, Amir
Institutions: Murdoch University, Vanderbilt University Medical Center
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7080484353