Date of Award

December 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Kumi Nagamoto-Combs

Abstract

Food allergen consumption has been suspected to influence mood and behavior in individuals who are sensitized but tolerant to the food. Using a mouse model of subclinical cow’s milk allergy (CMA), we previously showed that C57BL/6J mice sensitized to β-lactoglobulin (BLG, Bos d 5) exhibited elevated BLG-specific IgE levels even without observable allergic reactions, suggest developing immune responses towards the allergen. We also observed elevated cytokine and chemokine levels, astrogliosis and cortical demyelination along with behavioral changes such as anxiety-like and depression-like behavior after consuming a whey-containing diet for two weeks. Furthermore, we demonstrated the possible immune cell infiltration and interaction in central nervous system (CNS) with elevated CD45+ immunoreactive cells in brain parenchyma and degranulated mast cells associated with IgE in the dura of BLG-sensitized mice. Moving forward with these previous observations, next we determined how peripheral inflammatory signal reaches the CNS and promotes neurobehavioral changes. We hypothesized that BLG-induced specific chemokine receptor-expressing immune cell phenotype/s migrate to the CNS via chemotaxis and promote neurobehavioral changes. To test this hypothesis, we conducted three studies using male and female CMA mice. Study one conducted to determine whether specific chemokine receptor-expressing immune cell phenotype/s elevated in CMA mouse brains and demonstrated CXCR5+ immune cells significantly increased only in male CMA mouse brains. Next, we conducted study two to determine whether CMA induced CXCR5+ immune cells migrating from periphery to the brain and promoting neurobehavioral changes, finding fluorescently labeled splenocytes migrate to the dura, increased brain microglia, CXCR5-expression on neurons and elevated brain CXCL13 levels in BLG-sensitized male recipients. Parallel to the study two, study three was performed by blocking CXCR5 chemokine receptor to determine the effect of CXCR5-CXCL13 chemotaxis on CMA-induced neurobehavioral changes, and found CXCR5 chemokine receptor blocking reduced microgliosis, CXCR5 expression on neurons, CXCL13 levels and improved behavior in male CMA mice. Together findings of this dissertation indicate significant therapeutic approach of blocking CXCR5 receptor on food-allergy induced neurobehavioral pathology in sub clinically sensitized individuals with repeated allergen exposure.

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