The Hapten Concept

Low-molecular-weight chemicals (commonly with a molecular mass of less than 1000 Da) are not recognizable by T cells. However, if they are reactive and capable of binding to proteins they may become part of presented peptides (Figure 3) as so-called haptens. In particular electrophilic properties of a chemical will enable it to react with nucleophilic groups of proteins such as the thiol group in cysteins (-SH), amino group of lysine (-NH2) or the hydroxy (-OH) group of tyrosine.22 Known reactive chemicals are isocyanates, quinones, aldehydes, epoxides, beta lactams, and certain nitroaromatics. If a chemical is very reactive, the immune reactions will take place at the site of first contact, e.g., the skin or the lung. Formation of novel antigens recognizable by T cells ('neoantigens') has been shown using the classical hapten trinitrophenol,23 the sensitizing compound of poison ivy, 3-pentadecyl-catechol (urushiol),24 or penicillin.25 Penicillin-induced allergies have been intensively studied. There are immediate type and delayed type forms of penicillin allergy, clinically evident by, e.g., exanthema, urticaria, or specific immunoglobulin E (IgE) formation.26 The contact sites of T cells with the protein penicilloyl adduct have been mapped. Table 3 lists examples of known chemicals that form protein adducts (hapten-carrier conjugates in immunological terms) and can lead to adverse immune reactions. Frequently, protein reactive haptens lead to sensitization after dermal contact or inhalation.

C3 T cell ( \ Antigen presenting cell wY"ell)


MHC + self peptide

MHC + self peptide

Normal state Chemical-induced state

MHC + haptenated self peptide

MHC + haptenated self peptide


MHC + normally not presented self peptides

Allergy, autoimmunity

Figure 3 Possible outcomes of the formation of protein adducts with low-molecular-weight compounds. T cells recognize peptides lying in a groove of the cell surface molecule MHC. T cells with receptors that would recognize self peptides are eliminated in the thymus. (a) Those which escape the thymus elimination processes are kept in an inactive state in the healthy situation. (b) Low-molecular-weight chemicals which can bind to presented peptides, covalently or not, change the form of the peptide, which no longer 'looks' like a self antigen. Tcells can react. Binding to the peptide can occur inside or outside of the cells, depending on the chemical. (c) Low-molecular-weight chemicals can change either the protein degradation or the loading of peptides in the cell and lead to a changed pattern of presentation and presentation of normally not presented peptides. Thus, even if presented peptides are 'self,' Tcells will exist with receptors specific for them, as the selection processes in the thymus will have used the normal set of self peptides, not the cryptic ones. Note that binding of the Tcell receptor to the peptide inside the MHC groove is necessary but not sufficient for Tcell activation. A second signal, i.e., yet another contact of surface molecules by Tcells and antigen-presenting cell, must be provided. This is discussed in the context of the danger hypothesis in the text.

Metals and their salts can also interact with proteins, either by their oxidizing properties, or as haptens, as they can form highly stable coordination bonds with certain amino acids in peptides.27'28 Nickel salts are a well-known example of this type.

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