Does irritation potency contribute to the skin sensitization potency of contact allergens?

Chemicals that possess the capacity to cause skin sensitization have long been recognized to be reactive (electrophilic) or at least the precursor of an electrophile. The chemical species (hapten) covalently bound to skin protein then forms the antigen to which the immune system responds, with sufficient exposure ultimately leading to skin sensitization. However, for this process to occur, many have also considered that in addition to haptenation of skin protein, secondary stimuli (danger signals) are also necessary. Such signals might reasonably be expected to derive from keratinocytes and/or Langerhans cells perturbed by the chemical sensitizer. Whether this disturbance comes from the haptenation process itself or from other properties of the chemical is unknown. We hypothesized that chemicals that were stronger sensitizers might appear so, in part, as a consequence not only of greater (pro)electrophilic reactivity, but also if they were more able to produce inflammatory (danger) signals. To assess this, the sensitizing potency of 55 chemicals in the local lymph node assay was compared with their ability to produce pro-inflammatory signal release, measured as a function of their relative skin irritancy in guinea pigs. A limited trend was demonstrated, consistent with the hypothesis, but indicating that either skin irritation is a poor measure of danger signals, or that such signals are perhaps no more than a necessary requirement for the acquisition of skin sensitization rather than a key determinant of the relative potency of a skin sensitizing chemical. In addition, it is possible that irritancy alone does not represent a complete surrogate marker for the ability of a chemical to produce danger signals relevant to the induction of skin sensitization.