Reviews and Feature Articles: RostrumHistamine in the immune regulation of allergic inflammation☆,☆☆
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Synthesis and metabolism of histamine
Histamine is synthesized by decarboxylation of histidine by L -histidine decarboxylase (HDC), which is dependent on the cofactor pyridoxal-5′-phosphate.2 Mast cells and basophils are the major source of granule-stored histamine, where it is closely associated with the anionic proteoglycans and chondroitin-4-sulfate. Histamine is released when these cells degranulate in response to various immunologic and nonimmunologic stimuli. In addition, several myeloid and lymphoid cell types (dendritic
Histamine receptors, agonists, and antagonists
Histamine exerts its effects by activating histamine receptors (HRs), of which 4 subtypes (HR1, HR2, HR3, and HR4) are recognized (Table I).
Histamine receptors Expression Activated intracellular signals G proteins HR1 Nerve cells, airway and vascular smooth muscles, hepatocytes, chondrocytes, endothelial cells, neutrophils, eosinophils, monocytes, DCs, T cells, B cells Ca2+, cGMP, phospholipase D, phospholipase A2, NF-κB Gq/11 HR2 Nerve cells, airway and vascular smooth muscles,
Immune regulation by histamine in allergic inflammation
The interaction of histamine with HR1 mediates a variety of effects, such as vasodilatation, bronchial smooth muscle contraction, mucus secretion, and pruritus, which lead to bronchial obstruction, increased vascular permeability, nasal blockade, sneezing, and itchy wheals and flares in urticaria.22 Although the classical effects of histamine are emphasized in allergy, an increasing amount of evidence suggest that it influences several immune-inflammatory and effector functions.23
Histamine and hr2 in peripheral T-cell tolerance
Considerable evidence has emerged to suggest that histamine participates in the immune regulation of the inflammatory response in several diseases. Peripheral T-cell tolerance characterized by immune deviation to regulatory-suppressor T cells represents a key event in the control of specific immune response during allergen-specific immunotherapy.52 Although multiple suppressor factors, including contact-dependent or contact-independent mechanisms, might be involved, IL-10 and transforming
Conclusion
Historical data and recent studies indicate an essential role of histamine in the immune dysregulation of allergy, asthma, autoimmunity, and malignancies. Histamine and so far 4 different HRs display a complex system with distinct functions of receptor subtypes and their differential expression, which changes according to the stage of cell differentiation, as well as microenvironmental influences. Although contrasting findings have been reported, HR1 activates the immune system cells,
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Supported by the Swiss National Foundation (grants 32.65661.01 and 31.65436.01).
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Reprint requests: Cezmi A. Akdis, MD, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, CH-7270 Davos, Switzerland.