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Keystone Epitope Theory: Implications for Hypersensitivity, Autoimmunity, and Transplantation
Journal article   Open access   Peer reviewed

Keystone Epitope Theory: Implications for Hypersensitivity, Autoimmunity, and Transplantation

Simon Mallal, Amir Asiaee and Elizabeth Phillips
Pathogens & immunity, Vol.11(2), pp.16-38
2026
DOI: https://doi.org/10.20411/pai.v11i2.1016
PMID: 42598022
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Published (Version of Record) Open Access CC BY V4.0

Abstract

Drug Hypersensitivity HLA Peptide–HLA TCR Tissue-resident Memory Heterologous Immunity Modified Self Keystone Epitope Theory Herpesvirus
HLA class I alleles confer a striking risk for T cell–mediated drug hypersensitivity, yet positive predictive values are low—typically under 10% and as low as 0.12% for some drug–HLA pairs. We propose that persistent, human-adapted pathogens—notably herpesviruses—focus postnatal immune memory on conserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). The phylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted over hundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as each individual 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 niche at sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching local regulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologous immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in the same 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 drug hypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis and transplant rejection and conclude with proposed experimental validation strategies that may be applicable more broadly to T cell–mediated hypersensitivity and autoimmunity. From keystone protection to clinical misdirection. Postnatal immune focusing concentrates durable tissue-resident memory on conserved peptide–HLA targets in specific niches. Modified self-peptides (drug-altered or post-translationally modified) that approximate this geometry, presented by the same risk HLA in the same tissue, can recruit entrenched antiviral programs and, when mimicking ligand burden is sufficient, exceed local inhibitory set-points. The clinical result is high NPV but low PPV for HLA risk alleles. Abbreviations: TRM, tissue-resident memory T cell; PTM, post-translational modification.

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