Allergic diseases, in one form or another, affect 1 in 4 subjects in the United States, with the incidence of asthma and food related hypersensitivities increasing especially among children. While malleable genetic and environmental components play an important role, immunological aspects associated with atopy remain major risk factors underlying the pathogenesis of these diseases and allergic inflammation in general. Despite advances in the development of novel biologic modifiers, new therapeutics continue to be sought and seemingly have the best chance of being developed with a greater understanding of the molecular and cellular mechanisms involved. Among the immune cells implicated in allergic disease, few have received in recent years the level of attention given to basophils. In humans, these rare granulocytes release inflammatory mediators (histamine and LTC4) and cytokines (IL-4 and IL-13) central in the pathogenesis of allergic disease. Ancillary studies in mice now indicate that basophils possess professional antigen-presenting cell (APC) capabilities that are most important in initiating the Th2 responses that are hallmark in allergic diseases. Translation of these findings to the human system is now essential in pushing the field forward not to mention towards understanding how basophils might be better targeted for therapeutic intervention.
Four aims are proposed.
Aim 1 expands on our preliminary data by further characterizing basophil-mediated APC activity. Parameters will be defined using blood basophils as well as immature culture-derived basophils (CDBA) from allergic and non-allergic subjects. In particular, they focus on the importance of specific IgE, the requirement of MHC class II, other co-stimulatory molecules, and what subpopulations of T cells are activated (e.g. CD4/CD8, memory, na ve). Studies in Aim 2 address clinically relevant issues of how localize allergen challenge in vivo impacts basophil APC activity that of circulating basophils as well as those migrating to the site of allergen challenge (e.g. lung).
Aim 3 addresses the hypothesis that basophil APC activity is differentially regulated by innate immune stimuli (e.g. TLR) and by specific cytokines (e.g. IL-3/IL-33 vs. IFN-α/β) hypotheses arising from our published observations. Finally, Aim 4 focuses more on basophil/DC interactions and predicts that basophils play a critical role in the maturation of DCs into APCs that promote Th2 development. Our unique ability to investigate human basophils and their interactions with DCs makes this application highly innovative, and increases the probability that novel, significant and clinically relevant findings will be discovered.
Basophils are a type of white blood cell that release substances that cause allergy symptoms. We believe that basophils interact with other white blood cells (T cells and dendritic cells) causing them to worsen allergies. By identifying the parameters and mechanisms underlying these interactions, we might better understand why allergy persists and, more importantly, develop new strategies to treat allergic diseases in general.
| Borriello, Francesco; Longo, Michele; Spinelli, Rosa et al. (2015) IL-3 synergises with basophil-derived IL-4 and IL-13 to promote the alternative activation of human monocytes. Eur J Immunol 45:2042-51 |
| Frischmeyer-Guerrerio, Pamela A; Schroeder, John T (2012) Cellular immune response parameters that influence IgE sensitization. J Immunol Methods 383:21-9 |
