Abstract The Keystone Epitope Theory proposes that a small set of human-adapted, persistent organisms focus postnatal immune hierarchies on shared, functionally linked epitopes. This review examines the clinical implications of this phenomenon, focusing on why modified self-ligands can bypass regulation, why only a minority of HLA risk allele carriers develop disease, and how tissue-restricted presentation and entrenched memory contribute to phenotypes in T cell–mediated drug hypersensitivity, organ-specific autoimmunity, and transplantation. We synthesize three strands of evidence: (i) heterologous immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) niche-matched antigen display that makes keratinocyte‑ or organ-restricted injury intelligible; and (iii) public and private TCR solutions that bridge viral and self targets. Companion pieces provide context (foundational trait matrix 1; interoperable T–NK wiring 2; ecological analysis of RNA viruses and tumor 3); we briefly cross-reference them where needed and keep this paper focused on clinical misdirection and mitigation. Framed: What is the problem? Some modified self-ligands can recruit entrenched antiviral memory; why does this happen? Reflects postnatal keystone focusing that prioritizes constrained, tissue-matched targets, and how we can leverage or avoid this? Requires reading T–NK interoperability on shared peptide–HLA in the right niche. We end with practical rules for risk prediction, monitoring, and mitigation in hypersensitivity, autoimmunity, and transplantation.
Mallal et al. (2026) studied this question.