Undressing DReSS as p-i mediated disease

抄録

Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) is a severe T cell-mediated hypersensitivity reaction. T cells in DReSS are stimulated via the p-i mechanism (pharmacological interaction with immune receptors), where the drug shows an off-target binding to immune receptors (TCR and/or HLA) leading to an unorthodox activation of T cells. P-i stimulations are particularly strong in DReSS, as the causative drugs are typically administered at high doses for prolonged durations (>7 days) and bind with relatively high affinity to a specific HLA allele and/or TCR. This mechanism results in delayed yet profound immune activation, progressing through four distinct phases.

1. Clinically Silent Phase: During the asymptomatic stage, the immune tolerance is disrupted. The precursor frequency of p-i-reactive T cells is low, requiring time for expansion (typically >2 weeks) before reaching a threshold that is sufficient to cause symptoms.

2. Acute Phase: Characterized by massive immune activation, lymphocytosis, lymphadenopathy, elevated levels of cytokines and cytotoxic molecules, fever, (facial) edema, and eosinophilia. P-i-activated CD4+ and CD8+ T cells are polyclonal, leading to widespread tissue damage via cytotoxicity, which affects the skin (exanthems), liver (hepatitis), and other organs. Despite drug withdrawal, T cells remain highly reactive, resulting in flare-up reactions (subacute phase).

3. Viraemia and autoimmunity phase: After 3-4 weeks, p-i-stimulated T cells may react with cytotoxicity to their original target peptide from viral (e.g., HHV6, CMV, and EBV) or autoantigenic origin, leading to viremia and potential autoimmunity.

4. Chronic Phase: The strong p-i stimulation leaves a long-term imprint on the immune system, resulting in sustained T cell hyperreactivity and a predisposition to multiple drug hypersensitivity (MDH), where exposure to structurally unrelated drugs may trigger new hypersensitivity reactions years after the initial DReSS episode.

The p-i concept provides a unifying explanation for many puzzling aspects of DReSS and has significant implications for diagnosis, management, and prevention. Recognizing drug concentration, therapy duration, and HLA affinity as key determinants of strong p-i-mediated immune activation can improve risk assessment, early diagnosis, and intervention strategies for DReSS.