Intracranial Mast Cell Activation And Central Histaminergic Dysregulation In Food Allergy-Associated Neuropathology And Behavioral Changes

Food allergy occurs when the immune system reacts inappropriately to an otherwise harmless food. The hypersensitivity response is known to cause physical symptoms ranging from mild gastrointestinal discomfort to life-threatening anaphylaxis. Curiously, there is growing evidence that some food-allergic individuals experience changes in mood and behavior after consuming an offending food despite not experiencing severe physical symptoms. However, the mechanism(s) through which food allergy may affect the brain and behavior has yet to be elucidated. Previously, we found that inducing non-anaphylactic cow’s milk allergy (CMA) in mice resulted in abnormal behavior, neuroinflammation, and an increased the number of brain mast cells (MCs). The MC is the primary effector cell of the allergic response and releases many pro-inflammatory substances including histamine (HA). HA not only causes the immediate physical symptoms of allergy but also functions as an important neuromodulatory neurotransmitter and regulator of the blood-brain barrier. With these findings, we formed our central hypothesis that food allergy could activate brain MCs in some individuals, disrupting the brain’s central histaminergic system and inducing detrimental neuropathology that negatively affects brain function and behavior. To test this hypothesis, we performed four studies using our non-anaphylactic mouse model of CMA. Study 1 investigated the effects of CMA sensitization on the central histaminergic system, finding greater expression of the HA 3 receptor (H3R) in the brains of sensitized mice. Study 2 further characterized the capabilities of intracranial MCs to degranulate during CMA and demonstrated increased levels of HA in several brain regions of sensitized mice and cortical demyelination. Study 3 used an H3R antagonist to attempt to improve CMA-associated behavioral changes and neuropathology. Finally, Study 4 used transgenic mice expressing specific alleles of human leukocyte antigen (HLA)-II to understand how genetic factors could predispose specific individuals to non-anaphylactic food allergy and food allergy-associated behavioral changes. Together, our findings strongly support the notion that intracranial MCs can be activated during food allergy and disrupt HA signaling, ultimately altering mood and behavior. Furthermore, our studies suggest that therapeutics targeting MCs or HA signaling may be a strategy to treat food allergy-associated behavioral changes in certain susceptible individuals.