Original article Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy? Within recent years, sublingual immunotherapy (SLIT) has been proven to represent a safe and effective alternative to subcutaneous immunotherapy (SCIT) in the treatment of allergic rhinitis (1). While severe systemic adverse reactions such as anaphylaxis have not been observed so far, the most frequently reported side-effects consist of local reactions within the oral mucosa espe- cially in the sublingual region and gastrointestinal tract (2). So far the underlying immunological mechanisms of SLIT are not quite clear. However, while antigen- presenting cells (APC) such as oral Langerhans cells (oLC) are thought to play a major role in the effectiveness of SLIT (3), oral mast cells (oMC) most likely account for adverse reactions such as oral itching and sublingual edema caused by histamine release (4). Langerhans cells (LCs) are outposts of the immune system and are located within the epithelium suprabasal layer of all body surface organs, where they capture and process antigens (5). As part of adaptive immunity, LCs are capable of stimulat- ing immune responses by activating antigen-specific T cells after migration to the regional lymph node (6, 7). However, LCs are not only prone to initiate antigen-specific T-cell immune responses but are also capable of stimulating protective immune reactions, which are characterized by tolerance induction towards allergens (5). We could show recently, that oLCs Background: Sublingual immunotherapy (SLIT) represents an alternative to subcutaneous immunotherapy. While antigen-presenting cells such as Langer- hans cells (LCs) are thought to contribute to the effectiveness of SLIT, mast cells (MCs) most likely account for adverse reactions such as sublingual edema. As little is known about LCs and MCs within the oral cavity, we investigated their distribution in search for mucosal sites with highest LCs and lowest MCs density. Methods: Biopsies were taken simultaneously from human vestibulum, bucca, palatum, lingua, sublingua, gingiva, and skin. Immunohistochemistry and flow cytometry were used to detect MCs, LCs and high affinity receptor for IgE (FceRI) expression of LCs. Mixed lymphocyte reactions were performed to assess their stimulatory capacity. Results: Highest density of MCs was detected within the gingiva, while the lowest density of MCs was found within the palatum and lingua. However, sublingual MCs were located within glands, which might explain swelling of sublingual caruncle in some SLIT patients. Highest density of LCs was detected within the vestibular region with lowest density in sublingual region. Highest expression of FceRI was detected on LCs within the vestibulum. Furthermore LCs from different regions displayed similar stimulatory capacity towards allogeneic T cells. Conclusions: In view of our data, different mucosal regions such as the vestib- ulum might represent alternative SLIT application sites with potent allergen uptake. Our data might serve as a basis for new application strategies for SLIT to enhance efficiency and reduce local adverse reactions. J.-P. Allam 1 , G. Stojanovski 1 , N. Friedrichs 2 , W. Peng 1 , T. Bieber 1 , J. Wenzel 1 , N. Novak 1 Departments of 1 Dermatology and Allergy, and 2 Pathology, University of Bonn, Bonn, Germany Key words: IgE receptor; Langerhans cells; mast cells; oral mucosa; sublingual allergen specific immunotherapy. Natalija Novak, MD Department of Dermatology and Allergy University Bonn Sigmund-Freud-Str. 25 53105 Bonn Germany Accepted for publication 6 November 2007 Abbreviations: 7AAD, 7-amino-actinomycin-D; APC, antigen- presenting cells; cpm, counts per minute; FceRI, high affinity receptor for IgE; FITC, fluorescein-isothiocyanate; HPF, high- power field; LC, Langerhans cells; mAb, monoclonal antibody; MC, mast cell; MHC, major histocompatibility complex; oLC, oral Langerhans cells; oMC, oral mast cells; oMC t, tryptase-positive/ chymase-negative oMC; oMC tc, tryptase-positive/chymase-positive oMC; PE, phycoerythrin; rFI, relative fluorescence index; SCIT, subcutaneous allergen-specific immunotherapy; SLIT, sublingual allergen-specific immunotherapy. Allergy 2008: 63: 720–727 Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard DOI: 10.1111/j.1398-9995.2007.01611.x 720