Within the recent decade, the central question about SLIT focused on its clinical effectiveness. Ever since the meta-analysis by Wilson et al. (1), this question has been partially answered and so other questions came up such as which immunological mechanisms determine whether SLIT is successful or not. It is very likely that APC such as LCs play a crucial role in inducing desired allergen-specific tolerance and protective shift from a Th2 to a modified Th2 immune response, while MCs account for the observed side-effects, such as oral itching or sublingual edema (3, 4). As the oral cavity harbors distinctive types of mucosal tissue, such as masticatory, lining, and lingual mucosa (19) another fundamental but not less important question is – how are immune cells important for SLIT distributed within the oral mucosal tissue. Further on mucosal sites appear to be most promising for allergen application, in respect of cells relevant for allergen uptake such as FcεRI+ oLCs on the one hand and cells responsible for adverse reactions such as oMCtc on the other hand. In this report, we could demonstrate that (i) oMCtc show similar distribution within the oral mucosal tissue with significantly highest presence within the gingiva; (ii) oLCs are more frequently located within the vestibulum, bucca, palatum, and lingua; and (iii) show the strongest expression of FcεRI in the vestibulum. Furthermore, we could show that oLCs from all investigated regions display comparable stimulatory capacity towards allogeneic T cells. Nevertheless, as oral mucosal cell suspension was used, cells other than oLCs may also in part account for the stimulatory capacity. However, as described previously the oLCs displayed a higher stimulatory capacity than epidermal LCs, which might not only result from their different expression of co-stimulatory molecules and MHC classes I and II expression but also from their higher exposure to antigen as well as allergen. Although SLIT has been shown to be a safe alternative compared to SCIT, various local adverse reactions such as oral itching are often observed and represent one major reason for discontinuation of therapy (4). The herein observed sublingual localization of MCs within the duct and lobe of sublingual glands might explain the caruncle swelling in some SLIT patients so that based on these data, other application sites, such as palatum or vestibulum, which do not contain excessive glands might represent attractive alternative application sites for such patients especially as the quantity of oLCs exceeded that of oMCtc– reflected by a positive oLC/oMCtc ratio within these regions. Nevertheless, high numbers of oMCtc might not only account for the observed side-effects of SLIT but also contribute to allergen presentation as it has been shown that MC activation-induced LCs migration in mice (20). The observed accumulation of oLCs within the rete ridges might point towards a higher migratory activity of oLCs, where they could get in contact with CD3+ T cells located in the lamina propria for efficient antigen/allergen presentation. This speculation is further supported by recent publications, which report about the presence of CD4+ T cells and CD83+ dendritic cells within inflamed lamina propria of gingival tissue suggesting a local antigen presentation site apart from regional lymph nodes, a mechanism which might account for the effectiveness of SLIT (21, 22). In view of the oLCs distribution within different regions of the oral cavity, the fact of postmortem alteration has to be considered. In this context, a previous study could demonstrate that postmortem cell density within the oral mucosa is equivalent to ex vivo density (17). Nevertheless, other APC subsets such as plasmacytoid dendritic cells have been shown to play a crucial role in allergy. However, in a previous study we could show that these cells are virtually absent from the uninflamed oral mucosa (19). It has been shown that the sublingual region has the highest permeability within the oral mucosa (23), which might justify its current preference as allergen-application site. Nevertheless, other oral mucosa sites such as buccal mucosa were found to have a high diffusion rate as well (23, 24), which should be sufficient for allergen uptake as allergens reside up to 20 h within the oral cavity after application (25). At any rate, more studies investigating allergen uptake within the different regions of the oral cavity are necessary to draw a final conclusion on this issue.
In view of our data, different mucosal regions such as the vestibulum or bucca might represent alternative application sites because of high oLCs density and high FcεRI expression on oLC presuming most effective allergen uptake, especially in SLIT patients suffering from sublingual edema and swelling of caruncle for it is anatomically separated from the sublingual region by teeth alignment. Furthermore, our data might serve as a basis for the development of new application forms of SLIT such as tablets or stripes, which assure allergen uptake within a defined and limited oral region to increase the efficacy and safety of SLIT.