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.
We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.
Background: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, while infections from non-tuberculous mycobacteria (NTM) represent a growing public health threat. In its 20th year of activity, the Tuberculosis Network European Trials group (TBnet; www.tbnet.eu) is one of the leading research networks in Europe. In this review, we summarize the main advances in TB and NTM that occurred in 2025. Methods: We conducted a non-systematic review of articles published in 2025, with a strong emphasis on research with current or potential impact on clinical practice. We also selected the most impactful papers regarding the management of adult TB, pediatric TB, and NTM infections. Results: Members of the TBnet Steering Committee summarize the main advances in their areas of interest, including epidemiology, pathogenesis, prevention, diagnosis, treatment, pediatric TB, and NTM infections. We also include a summary of future research priorities. Conclusions: The year 2025 presented many exciting advancements in almost all fields of mycobacterial science. This article provides an expert-based, clinically orientated summary of the main new findings in the TB and NTM fields and aims to provide an updated overview of the state of the art in those areas.
Background: To evaluate the impact of sex on acute SARS-CoV-2 infection, 668 participants from the ACTIV-2/A5401 study were followed over a 28-day period. Methods: A primary analysis was performed on 469 participants with quantifiable viral loads at baseline. Results: Male and female participants had comparable nasal SARS-CoV-2 RNA levels at study entry and throughout follow-up. However, sex-specific differences in viral shedding emerged when stratified by symptom duration. In the first 3 days after symptom onset, female participants exhibited higher nasal SARS-CoV-2 RNA levels than males, but lower viral RNA levels thereafter. The higher viral RNA levels in females during the earliest phase of acute COVID-19 were observed even after adjusting for age, race, and region of enrollment. Female participants also tended to have higher symptom scores across days since symptom onset, but no significant correlation was observed between nasal SARS-CoV-2 RNA levels and symptom score regardless of sex. Conclusion: These findings highlight the impact of sex on both viral shedding and symptom dynamics and underscore the importance of considering time since symptom onset when evaluating antiviral therapies for respiratory viruses in clinical trials.
Background: Antibodies play a critical role in the control of pathogens and tumors through their ability to recognize non-self and then direct immune-mediated destruction. Antibodies are generated by plasma cells or plasmablasts, located throughout the tissues, and are transported between blood, lymph, mucosal secretions, and tissues to survey all sites for pathogens or malignant cells. However, mounting evidence suggests antibodies that transit across compartments (from the blood to the brain, mucosal tissues, or placenta) differ from those in systemic circulation. Whether antibodies also differ as they transit from the blood into non-privileged tissues remains unclear. Thus, here we aimed to define the landscape of antibodies that exist within the blood and tissues and begin to define the properties that lead to antibody transfer across compartments. Methods: To analyze tissue antibodies, we performed antibody profiling in chyle, a fluid component of lymph collected via the thoracic duct, contrasting these profiles to matched plasma samples. Results: Equivalent levels of pathogen-specific IgG antibodies and functions were observed across the plasma and lymph in people without HIV. However, this balance in IgG transfer was disrupted in people living with HIV, with significantly lower transfer ratios across several pathogen-specific IgG subpopulations in chyle. Conclusion: Differential transfer of IgG was Fc-receptor dependent, pointing to a mechanism of transfer into tissues during inflammatory disease that may have a critical role in selecting the antibodies able to access the peripheral and lymphoid tissues.
