Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Medzhitov, Ruslan

Abstract

Organisms are challenged on a day-to-day basis with the decision of what, when and how much of a given food source to eat. These fundamental decisions require sensory mechanisms that evaluate the relative quantities of desired nutrients and harmful toxins present in each food source and integration of these factors with the current organismal state. In mammals, this sensing is accomplished by a diverse array of cells types, including epithelial cells, neurons, and immune cells which communicate the value of ingested food with the brain. Moreover, the immune system can store memory of past harm a given food source was associated with, leading to extraordinarily long-lasting behavioral adaptations. Mast cells, best known for their importance in mediating symptoms of allergies, are myeloid cells that reside at mucosal surfaces and expand rapidly in response to inflammatory cues. These cells not only display the capacity to innately recognize and respond to select noxious environmental substances and molecules released by damaged cells, but also can respond to food antigens directly through IgE-FceR1 immune complexes. Upon activation, mast cells produce potent mediators capable of eliciting neuronal excitation and physiological changes in rapid time scales. Thus, mast cells are excellent candidates to evaluate the quality of ingested food items and drive adaptive physiological and behavioral reflexes. This thesis explores how organisms evaluate and ultimately initiate defensive behavioral and physiological reflexes towards noxious substances found in food. Chapter 1 provides an overview of the mechanisms by which organisms sense and seek out food sources in their environments and the challenges they encounter in this endeavor. Chapter 2 introduces defensive mechanisms utilized to minimize harm secondary to ingestion, and how exaggeration of these defenses leads to clinically evident adverse food reactions. Chapter 3 explores the ability and mechanism by which mast cells sense food-components in the allergic host and lead to food avoidance behaviors. The potential contributions of mast cells to nausea-like responses to innately noxious environmental substances are also discussed, as are findings related to fundamental differences in allergen avoidance between mouse background strains. Chapter 4 examines how microenvironmental cues in the intestine alter mast cell functionality and links this to divergent requirements for anaphylaxis initiated by different routes of exposure. Finally, in Chapter 5, I propose that oral anaphylactic responses represent exaggeration of a fundamental behavioral response to noxious food items.

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