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Atopy Research Center
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Project
Clarification of roles of mast cells in the innate immune responses
SupervisorF Hiroko Ushio 
Mast cells are recognized as key effector cells in IgE-associated allergic diseases, and recent accumulating evidence suggests that these cells are also among the central players in the innate immune response. In this project, we will analyze the mechanisms of mast cell activation by various pathogens via the recognition by pattern recognition receptors (PRRs), such as Toll-like receptors and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). Since both allergens and microbial antigens can trigger mast cell activation, and allergic or autoimmune diseases are often exacerbated by pathogen, our knowledge could potentially be exploited therapeutically to modulate host immune responses by targeting these pathways in mast cells.
Mechanisms of allergic sensitization
SupervisorF Toshiro Takai 
Epidermis and epithelia of skin, airways, conjunctivas and intestines have important roles in sensitization and exacerbation of allergic diseases. Environmental and genetic factors, which cause dysfunction of physical barrier and dysregulation of innate/acquired immunity at the barrier surfaces, contribute to the pathogenesis of allergic diseases. Enzymatic activities (such as proteolytic activity) or other biological substances associated with allergens or allergen sources show adjuvant activity, which promotes Th2-dominant immune response and induction of allergen-specific IgE. Epicutaneous route for sensitization to environmental allergens is considered to be important not only in atopic dermatitis but also atopic march, which causes other allergic diseases such as asthma in patients with a previous history of atopic dermatitis. Our approaches to clarify the roles and mechanisms of allergic sensitization is the use of murine models of sensitization (epicutaneous, intranasal, etc.) with protease allergens, pollen, or other biological substances in wild-type and genetically engineered miceCin vitro cellular assays, and analysis of biological activities of allergens combined to the animal experiments.
Functions of antimicrobial (host defense) peptides in the skin immunity
SupervisorF Francois Niyonsaba 
Hundreds of antimicrobial (host defense) peptides (AMPs/HDPs) have been identified in human skin, where they are expressed constitutively or are induced in dangerous situations such as skin injury or infection. Among the skin-derived AMPs/HDPs, human β-defensins, cathelicidin LL-37 and psoriasin (S100A7) etc. have been shown to play key roles in the cutaneous defense. These peptides are implicated in the pathologies of various skin diseases, including psoriasis and atopic dermatitis (AD), which are characterized by abnormal barrier function and differentiation. Our research group has demonstrated that, in addition to the broad-spectrum microbicidal activities, AMPs/HDPs exhibit various immunomodulatory functions in the skin, including the regulation of the keratinocyte migration, proliferation, differentiation, wound healing, control of allergic/inflammatory reactions.
We also demonstrated that AMPs/HDPs regulate the skinfs barrier function. Since the skin barrier is impaired in AD, where AMPs/HDPs are downregulated, we believe that increasing the amounts of AMPs/HDPs in vivo might improve the impaired skin barrier in AD, in addition to killing microbes. Thus, AMPs/HDPs are considered potential therapeutic candidate for AD and other cutaneous infections. More studies are needed to prove it really works.
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