Hapten reactions:
Hapten stimulations of T cells occur due to the formation of a new antigen, which is based on stable bonds between drugs and proteins. The new antigen is processed and presented as a haptenized peptide to T cells. Such antigen stimulations are common in contact dermatitis. Importantly, co-stimulation (e.g., engagement of adhesion molecules between APCs and T cells) is required to initiate an immune response. Contact dermatitis however is an incomplete model for systemic DHR, as orally or parentally administered drugs are unable to provide a co-stimulatory signal [10]. Thus, even if the drug can act as hapten and hapten-protein complexes are formed, the missing co-stimulation may prevent an immune reaction and DHR [7].
The most frequent elicitors of DHR are β-lactams, which are also often involved in virus-exacerbated DHR. Treatment with β-lactams (e.g., amoxicillin) results in ubiquitous haptenization of both soluble and cell-bound proteins [7]. Thus, one condition for a conventional immune response – formation of an antigen – is already fulfilled upon simple administration. This formation of new antigens, however, is clearly insufficient for developing a clinically apparent immune response/DHR, as only <8% of β-lactam-treated patients develop symptoms of DH [31]. If β-lactams are administered during a viral infection, the ongoing systemic inflammation with high expression of adhesion molecules and presence of cytokines (IFN-γ, TNF, IL-1, IL-6, etcsignificantly increases hapten-specific immunity. [32] (Fig 1).
p-i reactions: When drugs elicit systemic T cell responses, this reaction relies predominantly on the non-covalent binding of drugs to certain parts of TCR or HLA molecules (p-i stimulations) [10]. This binding to immune receptors is unique, as it can induce unorthodox T cell activation in the absence of co-stimulation. This type of T cell activation has been shown to share some features of an allo-reaction [9] and drug binding to the HLA-peptide-TCR complex makes it look like an allo-HLA-peptide-TCR complex [33]. As such, allo-reactions are characterized by high levels of cytotoxicity, a feature also observed in T cell-mediated DHR [17, 18, 20].
P-i stimulations may happen with all drugs, including drugs that have hapten-like characteristics, as covalent bonds are always preceded by non-covalent drug binding to a suitable site in the protein [10, 34]. Even when the drug binds directly to immune receptors, no functional consequence may be observed, as the interaction is of low affinity and is only transient. Such low affinity binding remains unnoticed and does not stimulate immune activation and clinical symptoms.
Under certain circumstances, this low affinity binding may become relevant (Fig 2). Viral infections can induce systemic immune reactions [32]. This may increase the expression of HLA and adhesion molecules on APC and tissue-resident cells, while the broad T cell activation results in increased expression of TCR and of other adhesion molecules. This increase in immune receptor expression enhances the probability of low affine p-i interactions, and the overall avidity (i.e., the sum of low affine drug/immune receptor interactions) increases. The interaction of altered HLA-drug-TCR may also become sufficiently stable and result in T cell activation and clinical symptoms (Fig 2). Whether the increased expression of costimulatory molecules (T-cells, APC) does also contribute to the stability of the labile TCR-drug-HLA complex and thus symptomatic DH is unknown, but possible (see Sars-Cov2 infection and DH ).
Examples of viral infections, which prime for DHR: