Keystone Epitope Theory: Implications for Hypersensitivity, Autoimmunity, and Transplantation
Year: 2026
Type: review
Abstract: 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.
Source: Pathogens and Immunity
Authors: SIMON MALLAL, Amir Asiaee, Elizabeth Phillips
Institutions: Murdoch University, Vanderbilt University Medical Center
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Awards: Mechanisms of Immune Activation in Hypertension, Improving Prediction of Drug Action, HIV-1 adaptation to HLA-restricted immune responses, Immunogenetic predictors of active and incipient TB in HIV-negative and -positive close TB contacts, Causal Effect Estimation of Regulatory Molecules, Tennessee Center for AIDS Research (TN-CFAR), The intersection of immunity and cardiovascular diseases, Cancer Center Support Grant, Vanderbilt-coordinated human Virome Collaborative Center (V2C2), Pharmacogenomics of HIV Therapy, NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
OpenAlex ID: W7201960748