Further Understanding of Neuro-Immune Interactions in Allergy: Implications in Pathophysiology and Role in Disease Progression

George N Konstantinou,1 Gerasimos N Konstantinou,2,3,* Christopher Koulias,4,* Konstantinos Petalas,5,* Michael Makris4,* 1Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, Thessaloniki, Greece; 2Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 3Centre of Addiction and Mental Health (CAMH), Toronto, ON, Canada; 4Allergy Unit, 2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece; 5Department of Allergy, 251 General Air Force Hospital, Athens, Greece*These authors contributed equally to this workCorrespondence: George N Konstantinou, Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, Eleftheriou Venizelou 11, Kalamaria, Thessaloniki, 55 133, Greece, Tel/Fax +30 231 550 3444, Email gnkonstantinou@gmail.comAbstract: The complicated interaction between the central and the autonomic (sympathetic, parasympathetic, and enteric) nervous systems on the one hand and the immune system and its components, on the other hand, seems to substantially contribute to allergy pathophysiology, uncovering an under-recognized association that could have diagnostic and therapeutic potentials. Neurons connect directly with and regulate the function of many immune cells, including mast cells, the cells that have a leading role in allergic disorders. Proinflammatory mediators such as cytokines, neurotrophins, chemokines, and neuropeptides are released by immune cells, which stimulate sensory neurons. The release of neurotransmitters and neuropeptides caused by the activation of these neurons directly impacts the functional activity of immune cells and vice versa, playing a decisive role in this communication. Successful application of Pavlovian conditioning in allergic disorders supports the existence of a psychoneuroimmunological interplay in classical allergic hypersensitivity reactions. Activation of neuronal homeostatic reflexes, like sneezing in allergic rhinitis, coughing in allergic asthma, and vomiting in food allergy, offers additional evidence of a neuroimmunological interaction that aims to maintain homeostasis. Dysregulation of this interaction may cause overstimulation of the immune system that will produce profound symptoms and exaggerated hemodynamic responses that will lead to severe allergic pathophysiological events, including anaphylaxis. In this article, we have systematically reviewed and discussed the evidence regarding the role of the neuro-immune interactions in common allergic clinical modalities like allergic rhinitis, chronic rhinosinusitis, allergic asthma, food allergy, atopic dermatitis, and urticaria. It is essential to understand unknown – to most of the immunology and allergy experts – neurological networks that not only physiologically cooperate with the immune system to regulate homeostasis but also pathogenetically interact with more or less known immunological pathways, contribute to what is known as neuroimmunological inflammation, and shift homeostasis to instability and disease clinical expression. This understanding will provide recognition of new allergic phenotypes/endotypes and directions to focus on specialized treatments, as the era of personalized patient-centered medicine, is hastening apace.Keywords: immunomodulation, allergic rhinitis, chronic rhinosinusitis, food allergy, allergic asthma, atopic dermatitis, urticaria, neuropeptides, neurotransmitters, neurotrophins, conditioning, behavioral, cognitive, brain