Contact
allergy to environmental
xenobiotics is a common and important problem, but it is unclear why some chemicals are potent sensitizers and others weak/nonsensitizers. We explored this by investigating why similar chemicals,
2,4-dinitrochlorobenzene (
DNCB) and
2,4-dinitrothiocyanobenzene (
DNTB), differ in their ability to induce
contact hypersensitivity (CHS).
DNCB induced CHS in humans, whereas at similar doses
DNTB did not. However, following
DNCB sensitization,
DNTB elicited CHS in vivo and stimulated
DNCB-responsive T cells in vitro, suggesting that differences in response to these compounds lie in the sensitization phase. In contrast to
DNCB,
DNTB failed to induce emigration of epidermal Langerhans cells in naive individuals. Examination for
protein dinitrophenylation in skin revealed that
DNCB penetrated into the epidermis, whereas
DNTB remained bound to a
thiol-rich band within the stratum corneum.
DNTB reacted rapidly with
reduced glutathione in vitro and was associated with a decrease in the free
thiol layer in the stratum corneum, but not in the nucleated epidermis. By contrast,
DNCB required GST facilitation to react with gluthathione and, following penetration through the stratum corneum, depleted
thiols in the viable epidermis. Chemical depletion of the
thiol-rich band or removing it by tape stripping allowed increased penetration of
DNTB into the epidermis. Our results suggest that the dissimilar sensitizing potencies of
DNCB and
DNTB in humans are determined by a previously undescribed outer epidermal biochemical redox barrier, a chemical component of the innate immune defense mechanisms that defend against sensitization by highly reactive environmental chemicals.