Proteolytic activity accelerates the T(H)17/T(H)22 recall response to an epicutaneous protein allergen-induced T(H)2 response

Epicutaneous exposure to protein allergens, such as papain, house dust mite (HDM), and ovalbumin (OVA), represents an important mode of sensitization for skin diseases including protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. These diseases are inducible by re-exposure to an allergen at both original skin sensitization and distant skin sites. In this study, we examined the serum IgE/IgG(1) response, differentiation of T-helper (T-H) cells, and epicutaneous T-H recall response in mice pre-sensitized with protein allergens through the back skin and subsequently challenged on the ear skin. Repeated epicutaneous sensitization with allergenic proteins including papain, HDM, OVA, and protease inhibitor-treated papain, but not bovine serum albumin, induced serum allergen-specific antibody production, passive cutaneous anaphylaxis responses, and T(H)2 differentiation in the skin draining lymph node (DLN) cells. Sensitization with papain or HDM, which have protease activity, resulted in the differentiation of T(H)17 as well as T(H)2. In papain- or HDM-sensitized mice, a subsequent single challenge on the ear skin induced the expression of T(H)2 and T(H)17/T(H)22 cytokines. These results suggest that allergenic proteins induce the differentiation of T(H)2 in skin DLN cells and an antibody response. These findings may be useful for identifying proteins of high and low allergenic potential. Moreover, allergenic proteins containing protease activity may also differentiate T(H)17 and induce T(H)2 and T(H)17/T(H)22 recall responses at epicutaneous challenge sites. This suggests that allergen protease activity accelerates the onset of skin diseases caused by protein allergens.