Drug-protein adducts based on covalent bonds are necessary to
stimulate the immune system.
To initiate an IgE-immune response to a small drug-like a beta-lactam, a
complex interplay of antigen-presenting cells (APC), T cells and B cells
takes place (1,7). Neither the drug itself (too small) or the protein
(often a self protein, to which tolerance exists) elicit a reaction. It
is the novel hapten-protein adduct, which represents the antigen, which
stimulates B- and T cells. For T-cell stimulation, the hapten-protein
adduct is processed inside APC into smaller peptides and then presented
on HLA. These immunogenic peptides keep the drug bound to the amino-acid
only if the bonds between peptide and drug are covalent and stable.
For instance, amoxicilloyl- albumin is taken up by dendritic
cells (DC) and/or B-cells acting as APCs. This hapten-protein adduct is
processed inside the APC to peptides. Due to the covalent link between
the hapten and protein/peptide, the peptides resulting from processing
and presented to T cells still carry the amoxicilloyl group. A
non-covalent bond between drug and protein would be disrupted by
intracellular processing. This presentation of new (drug- modified)
peptides stimulates T-cells, which secrete IL-4/IL-13 to provide help
for B-cell maturation into IgE-producing plasma cells. The secreted
specific IgE binds immediately to the high affinity Fc-receptor for IgE
(FcεRI) on mast cells (MC) and basophils the individual is sensitized
(figure 3). But even if therapy is continued, no symptoms appear.