Mast Cells Are Key Promoters of Contact Allergy that Mediate the Adjuvant Effects of Haptens

Abstract

A prominent feature of sensitizing environmental compounds that cause allergic contact dermatitis is the rapid induction of an innate inflammatory response that seems to provide danger signals for efficient T cell priming. We generated mouse models of mast cell deficiency, mast cell-specific gene inactivation, and mast cell reporter mice for intravital imaging and showed that these adjuvant effects of contact allergens are mediated by mast cells and histamine. Mast cell deficiency resulted in impaired emigration of skin DCs to the lymph node and contact hypersensitivity was dramatically reduced in the absence of mast cells. In addition, mast cell-specific inactivation of the Il10 gene did not reveal any role for mast cell-derived IL-10 in the regulation of contact allergy. Collectively, we demonstrate that mast cells are essential promoters of contact hypersensitivity, thereby highlighting their potential to promote immune responses to antigens entering via the skin.

Imaging protective mast cells in living mice during severe contact hypersensitivity

“…6) and the results reported by (7) by providing additional evidence that MCs can either amplify or limit the features of CHS reactions, depending on the severity of the model of CHS tested. Notably, Dudeck et al (7) reported that, in models of CHS whose severity based on ear swelling measurements were intermediate between the severe and mild models of acute CHS used in the present study, MCs were important promoters of CHS. The responses to the haptens were weaker in MC-deficient Mcpt5-Cre + ; DTA mice than in the corresponding MC-sufficient control mice, while the opposite result was obtained in MCdeficient Kit W-sh/W-sh mice.…”

“…While this method is useful for identifying exteriorized MC granule structures, it requires (a) that MCs are activated to degranulate, and (b) using specific MC reporter mice (e.g., Mcpt5-EYFP mice; see refs. 7,19) to identify nondegranulated MCs in the dermis prior to their activation (therefore limiting the use of other reporter animal models encoding fluorescent tracers of comparable excitation/emission spectra).…”

“…We proposed, based on experiments performed in mice with a profound MC deficiency related to abnormalities in Kit structure or expression (referred to herein as "Kit-mutant MC-deficient mice"), that MCs and MC production of IL-10 can limit skin pathology during severe contact hypersensitivity (CHS) reactions (6). As noted in that study, it has been appreciated for some time that Kit-mutant mice have several phenotypic abnormalities in addition to their MC deficiency, and subsequently we and others generated Kit-independent MC-deficient mouse strains that are deficient in MC populations due to genetic manipulations independent of alterations in Kit (7)(8)(9)(10)(11)(12).…”

“…Using one Kit-independent MC-deficient strain, Dudeck et al reported evidence that MCs amplify rather than limit CHS responses, and concluded that the exaggerated CHS reactions observed in Kit-mutant animals are not caused by the absence of MCs but instead reflect other effects of the KIT deficiency (7,13). By contrast, based on findings in both Kit-mutant and Kit-independent MC-deficient mice, Gimenez-Rivera et al recently reported that MCs can suppress skin inflammation in a new mouse model of chronic CHS (14).…”

Staphylococcal enterotoxin B-derived haptens promote sensitization

“…8 Some small molecules can covalently attach to protein molecules with large molecular weight; these small molecules are designated haptens; the large protein molecules are named carriers. 9,10 Such a process may result in upregulation of the antigenicity of the carriers, or both of the carriers and haptens. A number of haptens have been recognized relating the pathogenesis of allergic diseases including some plant derivatives (such as urushiol 11 ), some drugs (such as penicillin 12 ) and chemicals (such as trinitrobenzene sulfonic acid 13 ).…”