Project Grant R21AI178523

REGULATION OF IGE PRODUCTION DURING AEROALLERGEN SENSITIZATION - PROJECT SUMMARY/ABSTRACT ASTHMA IS A DEBILITATING LUNG DISEASE MARKED BY REVERSIBLE AIRWAY OBSTRUCTION THAT AFFECTS OVER 5% OF THE US POPULATION AND IS GROWING IN PREVALENCE. IN THE MAJORITY OF CASES OF ASTHMA, ALLERGIC INFLAMMATION AROUND THE BRONCHIAL AIRWAYS CONTRIBUTES TO DISEASE PATHOGENESIS. A KEY PATHWAY IN THE INITIATION OF ALLERGIC IMMUNE RESPONSES IS ELICITED BY ANTIBODIES OF THE IGE ISOTYPE. IN ALLERGIC INDIVIDUALS, IGE ANTIBODIES ARE PRODUCED WITH SPECIFICITY FOR COMPONENTS OF HARMLESS ENVIRONMENTAL SUBSTANCES, TERMED ALLERGENS. HOWEVER, THE MECHANISMS RESPONSIBLE FOR THE PRODUCTION OF IGE SPECIFIC FOR ALLERGENS INHALED INTO THE RESPIRATORY TRACT (AEROALLERGENS) REMAIN POORLY CHARACTERIZED. ONE OF THE MAJOR LIMITATIONS IN UNDERSTANDING THE PROCESS OF ALLERGIC SENSITIZATION THROUGH THE RESPIRATORY TRACT HAS BEEN TECHNICAL DIFFICULTY IN DIRECT STUDIES OF IGE PRODUCING PLASMA CELLS AND THEIR B CELL PRECURSORS. MY LABORATORY HAS DEVELOPED METHODOLOGY ENABLING THE SENSITIVE IDENTIFICATION OF THESE RARE IGE- EXPRESSING CELLS BY FLOW CYTOMETRY AND MICROSCOPY. THE FOCUS OF THIS PROJECT IS TO APPLY THIS ROBUST METHODOLOGY TO STUDY THE GENERATION OF IGE-EXPRESSING CELLS FOLLOWING AEROALLERGEN EXPOSURE THROUGH THE RESPIRATORY TRACT. IN ORDER TO DO A DETAILED ANALYSIS OF TISSUES INVOLVED IN RESPIRATORY TRACT IMMUNITY, WE WILL STUDY MOUSE MODELS OF ALLERGIC AIRWAY DISEASE. THE OVERALL OBJECTIVE OF THIS PROJECT IS TO STUDY THE CELLULAR RESPONSE LEADING TO THE PRODUCTION OF IGE IN ALLERGIC SENSITIZATION THROUGH THE RESPIRATORY TRACT. THE SPECIFIC AIMS OF THIS STUDY ARE TO: 1) CHARACTERIZE THE GENERATION AND FATE OF IGE B CELLS AND PLASMA CELLS AND THEIR TISSUE LOCALIZATION IN DIFFERENT MODELS OF AEROALLERGEN SENSITIZATION AND 2) DETERMINE THE RELATIVE ABUNDANCE OF ALLERGEN-SPECIFIC IGE B CELLS AND PLASMA CELLS COMPARED WITH OTHER ISOTYPES (IGM, IGG, AND IGA) AND ESTABLISH THEIR CLONAL RELATIONSHIPS. THE RESULTS FROM THESE STUDIES WILL PROVIDE IMPORTANT INSIGHTS INTO IGE PRODUCTION AFTER ALLERGEN EXPOSURE VIA THE RESPIRATORY TRACT. MORE BROADLY, THIS STUDY WILL INCREASE OUR UNDERSTANDING OF THE WAYS IN WHICH WE MAY DEVELOP SENSITIZATION VERSUS TOLERANCE TO AEROALLERGENS.