Novel Insights on the Biology and Immunological Effects of Histamine: A Road Map for Allergists and Mast Cell Biologists

Histamine (C₅H₉N₃, molecular weight 111.15 g/mol) is a well-studied endogenous biogenic amine composed of an imidazole ring attached to an ethylamine side chain. It has a limited half-life of a few minutes within tissues and in circulation. Several cell types including mast cells (MCs), basophils, platelets, histaminergic neurons, and enterochromaffin cells produce varying amounts of histamine using histidine decarboxylase (HDC). However, only MCs and basophils have complex mechanisms to pack and store histamine in granules along with other mediators using serglycin and its carried glycosaminoglycan (GAG) side chains. Relatively low granule pH (app. 5.5) supports the binding of stored histamine to heparin, whereas exposure to neutral pH following degranulation weakens the binding and histamine becomes liberated. Histamine exerts multifaceted regulatory biofunctions by engaging its four types of heptahelical G protein-coupled receptors (GPCRs) (H1R-H4R), which have different expression profiles and functions. MCs express H1R, H2R, and H4R, which gives them a dual role in histamine biology as producers and responsive target cells. Histamine plays a role in a variety of physiologic and pathologic processes such as cell proliferation, differentiation, hematopoiesis, vascular permeability, embryogenesis, tissue regeneration, and wound healing. The emergence of Histamine Receptor (HR)-deficient mouse models and the development of multiple HR agonists and antagonists have helped to better understand these physiological and pathogenic functions of histamine. Here, we review the biology of histamine with a focus on immunological aspects and the role of histamine in allergy and mast cell biology.