Allergic disorders are a rising health problem in Western countries; in particular, the incidence of pediatric food allergy has increased dramatically in the last decade. As part of the evolutionary conserved humoral response, IgE is a potent mediator of innate and adaptive immunity and an abundant immunoglobulin at the surface of the gastrointestinal (GI) tract. IgE is known to exert protective functions in Th2 type responses during helminth infections; however, most life-threatening food allergies are also caused by IgE-mediated immune activation. Thus, the overall research goal of Fiebiger laboratory is centered around developing a better understanding of the mechanisms that set apart protective Th2 immune responses from allergic Th2 immune responses.
Our studies are centered on pathways that regulate allergic sensitization towards food. Commonly, the phenomenon of oral tolerance results in unresponsiveness of the immune system to antigens after oral intake. We hypothesize that unwanted immune responses to food develop when (I) the host fails to mount sufficient oral tolerance after antigen contact, or alternatively, though not mutually exclusive, (II) oral tolerance is broken in the mucosa of the GI tract. In the center of both immune events, mucosal dendritic cells (DCs) guide antigen recognition and presentation, which subsequently regulate the ensuing tolerizing or inflammatory adaptive responses. On the one hand, our strategies aim at understanding how mucosal dendritic cells regulate oral tolerance and its failure. In a complementary approach, we study mast cells and basophil functions because these cell types are the main effector cells of the IgE-mediated allergic cascade. Using humanized mouse models for in vivo experiments in combination with mechanistic cell-based studies, we endeavor to understand and modulate the responsiveness to food antigens during development of, as well as in already-established, food allergies.
Functions of the dendritic-cell-bound IgE pool in allergy
Recent studies of the laboratory on IgE-mediated Th2 responses in food allergy and asthma models showed that allergic responses were significantly less severe in FcεRI-humanized strains than in WT controls. Since these mouse strains reflect the human IgE network better than wild type animals, these results are highly important for our understanding of human allergy. This finding was rather surprising because IgE-mediated activation of the immune system is generally considered strictly pro-inflammatory. The current focus of this research project is to gain a better understanding of the mechanism underlying protective functions of IgE in humans with the goal to use this novel immunological feature of IgE for preventive and therapeutic purposes in allergy.
Using the IgE-receptor humanized murine models, we expanded our research beyond the role of IgE in allergy to study the function of IgE in immune defense mechanisms. We defined IgE-mediated antigen cross-presentation by DCs as a mechanism that contributes to human anti-tumor defense. This unexpected IgE pathway provides a mechanistic explanation for epidemiologic data that have shown an inverse correlation of IgE-mediated allergies and cancer. This novel pathway has therapeutic implications as it can be targeted in cell-based immunotherapy.
Studying the immunological mechanisms underlying inflammatory bowel disease (IBD)
IBD patients reportedly have elevated serum IgE, yet they rarely present with classical signs of allergic reactions. The observation that the serum IgE pool in IBD patients contains IgE with specificity for food and that mast cells, which are innate effector cells of IgE-mediated immune activation, are found in infiltrates of human IBD lesions are two important arguments for the necessity of reevaluating the role of IgE in IBD. The focus of this research program is to gain mechanistic insight into how IgE-mediated immune activation influences the development, severity and chronicity of IBD.
Basic-translational studies towards a better understanding, diagnosis and treatment of eosinophilc esophagitis (EoE)
EoE is considered a chronic allergic disorder of the upper gastrointestinal tract with an alarmingly increasing incidence in recent years. EoE presents itself highly heterogeneous, also with regards to treatment response, with many patients continuing to have frequent relapses. Major advances in the understanding of the pathophysiology have been accomplished, but there has been a significant delay in the development of effective treatments. One of the main limitations has been the difficulty to get the diagnosis and to assess the response to therapy given the necessity to perform gastrointestinal endoscopy and biopsy as the only reliable method for evaluation. The focus of this research project is to develop better insight into pathophysiologic mechanisms of EoE that can improve diagnosis as well as treatment strategies.