Drug-protein complexes based on non-covalent bindings can cause degranulation of sensitized MC.
The necessity of covalent bonds between drug and protein is a prerequisite for initiating an immune response to the drug/hapten, both in animal models as well as in humans. It is also observed for eliciting an MC degranulation in previously sensitized animals using in vitro prepared hapten-protein adducts. However, it has not been established, whether a non-covalent bound complex is sufficient for interaction and cross-linking specific IgE in already sensitized animals or not. One reason might be, that the experiments with relatively labile drug-protein complexes did not deliver consistent, reproducible results. It is an exception that some of the non-covalent bindings between drug and protein reach an affinity which makes cross-linking of IgE/FcεRI possible. Thus, symptomatic IgE mediated drug allergy is rare.
The main arguments for the role of non-covalent drug-protein complexes in drug re-exposure reactions are summarized in table 3. Immediate skin test reactivity to drugs like beta-lactams (<15 min) occurs before covalent binding between beta-lactam and protein takes place (17-19). The necessity of covalent bonds cannot explain the immediate reactivity seen in BAT (<5 min) and the clinical setting (anaphylaxis <5 min).
For some drugs, metabolism is required to form the reactive metabolite: E.g., sulfamethoxazole (SMX) is metabolized in the liver to sulfamethoxazole hydroxylamine (SMX-NHOH), which is further oxidated in the tissue to the reactive hapten SMX-NO, able to undergo covalent bonds (13). This metabolism lasts >6-10 hrs (13). But skin test reactivity and in-vitro BAT can be observed within 15min with SMX itself, which does not have hapten characteristics. The IgE detected is cross-reactive with covalently bound SMX-NO and non-covalently bound SMX. Such a cross-reactivity of the immune system has already been observed in T-cell reactions to SMX and SMX-NO (28).