Haptens are chemicals that are chemically reactive and have
Haptens are chemicals that are chemically reactive and have a tendency to build covalent bonds to some AAs within a protein. For example, at least 13 lysine groups within the albumin molecule have been shown to bind piperacillin and were processed to different modified epitopes within the same protein. For the immune system, accessible modifications may elicit antibody responses to these hapten-modified epitopes. If the 5ht receptors react with the hapten bound to different sites on the same protein, cross-linking of the bound antibodies can occur. This requires a certain sterical distance between these hapten-modified epitopes, otherwise the rather large antibody molecule (their Fab part) would interfere with binding. If the antibody response is predominantly directed to the hapten and distant enough to allow two antibody bindings, cross-linking of the hapten-specific antibodies (including antibodies with the same specificity!) can occur by a single protein. This may enhance and explain why hapten-specific IgE reactions are often fulminant and occasionally even fatal.
Later, the work of Landsteiner et al showed that the delayed reaction to haptens (later shown to be T-cell mediated) is also very specific. Proteins are processed and presented as small 8–20-AA long peptides by MHC-encoded molecules, which as proteins (HLA) appear on the cell surface. Thereby the 14–18 HLA molecules expressed per individual present different peptides (mostly 8–10 AA for HLA class I, ∼14–16 AA for HLA class II), which fit into the peptide binding groove of HLA-molecules. Further work by Weltzien et al demonstrated that the location of the hapten modification (in the middle or at the end of the 9-mer peptide) may influence the functional consequence of the evolving immune response, in particular cross-reactivity and autoimmunity.
It is important to realize that hapten-specific immune responses are complete immune responses, involving stimulation of antibodies and T-cells. Actually, if a drug is able to elicit both B- and T-cell immune responses, it is most likely to have hapten-like characteristics. Haptens are immunogenic and antigenic: their immunogenicity is linked to the ability to activate the innate immune system, mostly by binding to molecules that cause cell activation or damage. For quite a number of molecules it has been shown that haptenization leads to the activation of dendritic cells (DCs) in vitro, and this capacity of haptens is used to identify contact allergens by in vitro tools. The immunogenicity is supplemented by antigenicity, which is the provision of antigenic determinants for the specific immune receptors (B- and T-cell receptors).
The prohapten concept Many drugs are not chemically reactive but are still able to elicit immune-mediated side effects. The prohapten hypothesis reconciles this phenomenon with the hapten hypothesis by stating that a chemically inert drug may become reactive upon metabolism. Sulfamethoxazole (SMX) is a prototype of such a prohapten. It is not chemically reactive itself but gains reactivity and thus antigenicity by a cytochrome p450 dependent metabolism (CYP2C9) in the liver, where SMX-hydroxylamine is formed. This is also found extrahepatically, where it is easily converted to SMX-nitroso (SMX-NO) by oxidation. The latter is chemically highly reactive and binds stably to intracellular proteins (cysteins) creating neoantigenic determinants: this binding to certain intracellular proteins may also result in cell damage, if SMX is given in high doses. Thus, SMX (actually SMX-NO) seems to have both antigenic and immunogenic features. Since many different proteins might be modified, the resulting clinical picture might be as variable as with haptens and SMX is indeed known to cause many different types of diseases affecting many organs [exanthems, anaphylaxis, Stevens–Johnson syndrome (SJS), hepatitis, blood cell dyscrasia, etc.]. These side effects are mediated by antibodies and/or T-cells. In contrast, the conversion of a prohapten to the reactive hapten may occur exclusively in the liver or kidney and may thus cause an isolated hepatitis or interstitial nephritis. Importantly, the metabolite may or may not be a hapten. If it not transformed to a hapten, it may stimulate the immune system like the parent compound (see allopurinol/oxypurinol).