The important role of non-covalent drug-protein interactions in drug hypersensitivity reactions

Abstract

Drug hypersensitivity reactions (DHR) are heterogeneous and unusual immune reactions with rather unique clinical presentations. Accumulating evidence indicates that certain non-covalent drug-protein interactions are able to elicit exclusively effector functions of antibody reactions or complete T-cell reactions which contribute substantially to DHR. Here, we discuss three key interactions; (a) mimicry: whereby soluble, non-covalent drug-protein complexes ("fake antigens") mimic covalent drug-protein adducts; (b) increased antibody affinity: for example, in quinine-type immune thrombocytopenia where the drug gets trapped between antibody and membrane-bound glycoprotein; and (c) p-i-stimulation: where naïve and memory T cells are activated by direct binding of drugs to the human leukocyte antigen and/or T-cell receptors. This transient drug-immune receptor interaction initiates a polyclonal T-cell response with mild-to-severe DHR symptoms. Notable complications arising from p-i DHR can include viral reactivations, autoimmunity, and multiple drug hypersensitivity. In conclusion, DHR is characterized by abnormal immune stimulation driven by non-covalent drug-protein interactions. This contrasts DHR from "normal" immunity, which relies on antigen-formation by covalent hapten-protein adducts and predominantly results in asymptomatic immunity.

Keywords: allo-immunity; drug hypersensitivity; fake antigen; heterologous immunity; virus reactivation.

FIGURE 1

(a) Fake antigen model: Drug‐specific IgE responses are induced by covalent drug‐protein adducts; fake antigens are non‐covalent, but still rather affine drug‐protein complexes, which react with preformed drug‐specific IgE on Fc‐IgεRI–expressing cells. This cross‐links the bound IgE and may induce immediate anaphylaxis. (b) Enhanced affinity model (quinine induced DITP): Low affine antibodies (IgG, IgM) directed to membrane components such as GP on thrombocytes, or the Rh system on erythrocytes, may exist in many individuals and remain asymptomatic. Therapy with quinine or other substances can (rarely) induce a blood cell dyscrasia such as immune thrombocytopenia or hemolytic anemia. The drugs bind non‐covalently to the CDR of anti‐GP or anti‐Rh antibodies (labile, can be washed away) and increase the affinity of the antibody for the target structure. The antibody/drug bind to the blood cells, which are removed from the circulation (adapted from ³⁸ )

FIGURE 2

p‐i stimulation results in an acute drug‐dependent disease (acute DHR), often followed by late reactions in the absence of drug: Acute reaction. The drug binds to immune receptors, for example, to a peptide presenting cleft of a HLA molecule (p‐i) and thereby makes the self‐HLA look like an allo‐HLA. This provides a strong, allo‐like, stimulatory signal to a substantial portion of CD4 and CD8 cells, which are poly‐specific (= one TCR/T cell is able to react with different peptides). The reactive T cells expand (over weeks) and cause a cytotoxic reaction with a severe DHR, such as MPE or DRESS. If CD8/NK cell reactions dominate, this can result in SJS/TEN. Late reactions: Further symptoms appear in the absence of drug over the following weeks. The p‐i activation induces a change in the memory and naïve T cells to a more alert state. When the TCR/T cell of p‐i activated cells cross‐reacts with a peptide presented by the unmodified self‐HLA, the T cells exert effector mechanisms (eg, cytotoxicity, cytokine release). (1) As a substantial portion of memory T cells are devoted to the control of herpesviruses (HHV6, CMV, EBV), the p‐i activation includes many T cells directed against herpes virus peptide–expressing cells. This causes their destruction and the release of herpes viruses into the circulation. Virus reactivation occurs in the first 3–6 weeks after the onset of DRESS. (2) The p‐i activation may also include self‐peptide reactive T cells. Their encounter with self‐peptides continues their activation, they expand and attack the self‐peptide presented cells, thus autoimmunity ensues. Self‐peptide–specific T cells have a low precursor frequency, and the symptoms appear after >4–6 weeks. The late complication of viral reactivations and autoimmunity occurs primarily in DRESS but not in SJS/TEN, where exhaustion of the activated CD8+ T cells may block further reactivity

FIGURE 3

Immune reactions to drugs are determined by drug binding to proteins—how and where. The type of binding (covalent or non‐covalent) and whether selected proteins are targeted (immune receptors, antibody binding sites) determine whether the functional consequence is (silent) immunity or drug hypersensitivity. In drug hypersensitivity, the non‐covalent drug‐protein interactions can lead to abnormal immune stimulations based on allo‐immune–like reactions (p‐i), formation of fake antigens or enhancement of antibody affinity. This unusual immune stimulation makes drug hypersensitivity reactions peculiar, which is also mirrored in the clinic, difficulties in drug hypersensitivity analysis and prediction (see text)