Histamine, a low-molecular amine, is produced by the reaction of histidine decarboxylase on L-histidine (1,2). This enzyme is located in cells found throughout the body including the central nervous system, gastric parietal cells, mast cells, and basophils (1,2). As a result of its ubiquitous presence in the body, it is not surprising that histamine has a wide range of biologic effects. Currently it is known that histamine exerts these effects through four histamine receptors (HRs). Histamine is involved in sleeping and waking, energy and endocrine homeostasis, cognition and memory through histamine receptor 1 (H₁R), regulation of gastric acid secretion through H₂R, modulation of neurotransmitter release through H₃R, and facilitation of pro-inflammatory activities through H₄R (Table 33.1) (1). HR antagonists (antihistamines) can be categorized in terms of their structure, pharmacokinetics, pharmacodynamics, and clinical utility (Table 33.1) (1). Histamine binding to H₁Rs causes itching, pain, vasodilatation, vascular permeability, hypotension, flushing, headache, tachycardia, bronchoconstriction, stimulation of airway vagal afferent nerves and cough receptors, and decreased atrioventricular-node conduction time (1,2). Histamine binding to H₂Rs causes increased gastric acid secretion, vascular permeability, hypotension, flushing, headache, tachycardia, chronotropic and inotropic activity, bronchodilation, and airway mucus production (1,2). Histamine binding to H₃Rs prevents excessive bronchoconstriction and mediates pruritus through nonmast cell pathways (1,2). Finally, histamine binding to H₄Rs is important for differentiation of myeloblasts and promyelocytes. Histamine has been shown to have a number of immunomodulatory effects through these various receptors. Clinically, selective antagonists are available for blocking H₁ and H₂ receptors (Table 33.1) (1). Nonselective H₃– and H₄-receptor antagonists are available as research tools but not for clinical use at the present time (Table 33.1) (1). Second-generation antihistamines, many of which have been derived from first-generation agents, are more selective for H₁Rs and have added a new dimension to the treatment of allergic disorders. Over the last several years, additional second-generation antihistamines have been introduced to the market and others, still under investigation may become available in the near future. This chapter will provide an overview of the immunologic and clinical effects of histamine so that the reader can appreciate the evolving role of histamine-antagonists in a broad spectrum of clinical disorders.

Histamine or β-imidazolylethylamine was first synthesized by Windaus and Vogt in 1907 (3). The term histamine was adopted because of its prevalence in animal and human tissues (hist: relating to tissue) and its amine structure (Figure 33.1) (4,5). Dale and Laidlaw (6) in 1910 were the first to report histamine’s role in anaphylaxis when they observed a dramatic bronchospastic and
vasodilatory effect in animals injected intravenously with this compound. Subsequently, histamine was found to be synthesized from L-histidine by L-histidine decarboxylase and metabolized by histamine N-methyltransferase to form N-methylhistidine or by diamine oxidase to form imidazole acetic acid (7). However, only the N-methyltransferase pathway is active in the central nervous system. Originally, histamine’s classic physiologic actions of bronchoconstriction and vasodilation were believed responsible for the symptoms of allergic diseases through its action at one type of HR. In 1966, Ash and Schild were the first to recognize that histamine-mediated reactions occurred through more than one receptor based on observations that histamine had an array of actions such as contraction of guinea pig ileal smooth muscle, inhibition of rat uterine contractions, and suppression of gastric acid secretion (8). This speculation was confirmed in 1972 by Black et al., who used the experimental histamine antagonists, mepyramine and burimamide, to block histamine-induced reactions in animals (9). They observed that each of these antagonists inhibited different physiologic responses, suggesting that there were at least two histamine receptors, now referred to as H₁ and H₂ (9). Arrang et al., discovered a third histamine receptor (H₃) with unique physiologic properties, raising the possibility that additional, yet unrecognized, histamine receptors exist (10). Table 33.1 summarizes the pharmacodynamic effects after activation of the known histamine receptors and their common agonists and antagonists (5,10,11). Characterizing histamine receptors has been essential in discovering histamine’s physiologic actions on target cells which include increased mucus secretion, increased nitrous oxide formation, endothelial cell contraction leading to increased vascular permeability, gastric acid secretion, bronchial relaxation, and suppressor T-cell stimulation. Finally, the H₄R was discovered based on a genomic approach using the H₃R sequence.
As mentioned, this receptor is expressed more selectively on dendritic cells, mast cells, eosinophils, monocytes, basophils, and T cells; therefore, it is believed to have an important immunoregulatory role (12). Figure 33.1 illustrates the actions of histamine on histamine receptors in allergic inflammation (13).

Histamine is stored in the cytoplasm of mast cells and basophils, attached to anionic carboxylate and sulfate groups on secretory granules (13,14). Histamine is released from mast cell and basophil secretory granules after aggregation of high-affinity immunoglobulin E (IgE) receptors. IgE receptors are coupled to G-proteins which when activated lead to a sequence of chemical reactions with the end result being histamine release. However, histamine can be released spontaneously by activation of mast cells and basophils by histamine releasing factors, which include chemokines (RANTES, MCP-1, and MIP-1 α) and several cytokines (IL-1, IL-3, IL-5, IL-6, IL-7) (7).

Histamine’s inflammatory action depends on which histamine receptors are activated, the level of histamine receptor expression, and the effector cells involved (1,2). For example, H₁R expression is increased during the differentiation of monocytes to macrophages and H₁R expression can be increased by a number of inflammatory stimuli (1,2,12,13). Furthermore, histamine has varying effects on different inflammatory cells. For example, mast cells express H₁, H₂, and H₄ receptors (1,2,12,13). Although histamine does not appear to have a direct effect on mast cell degranulation, by binding to H₄Rs it can act synergistically with chemoattractants such as CXCL12 (1). In contrast, histamine binding to H₂ receptors on mast cells can act to inhibit histamine release and modulate cytokine production (1,2,13).

Low concentrations of histamine via H₄ receptors can induce eosinophil chemotaxis but at higher concentrations via H₂ receptors can attenuate this effect (1,2,14). Histamine binding to H₄ receptors can stimulate upregulation of adhesion molecules and reorganization of actin polymers, whereas binding to H₁ receptors can induce superoxide production and complement receptor upregulation in eosinophils (1,2,12,13).

Dendritic cells express H₁, H₂, and H₄ receptors (1,13). Histamine can cause chemotaxis of dendritic cells by binding primarily to H₄Rs and to a lesser extent to H₁Rs (1). Furthermore, T-cell polarization may be regulated by histamine binding via H₁ and H₄ receptors on dendritic cells in conjunction with other chemokines: CCL17, thymus and activation regulated chemokine (TARC); CCL22; CCL3 macrophage inflammatory protein 1 α (MIP1α).

Histamine can have direct effects on T cells via H₁, H₂, and H₄ receptors which are expressed on CD4⁺ and CD8⁺ T cells (1). The effect of histamine on T-cell
proliferation varies (1). It can increase T-cell proliferation by binding to H₁Rs and inhibit proliferation by binding to H₂Rs. Binding to H₂Rs has been demonstrated to inhibit T-cell production of IL-2, IL-4, IL-13, and interferon γ (1). However, the role of histamine in regulating T-cell proliferation is likely much more complicated than can be explained by the counter-regulatory roles of cytokine production (1).