Histamine release

Histamine release DEFAULT

Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19

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The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets

Introduction

Allergic diseases, for example, allergic asthma, pruritus, atopic dermatitis, and allergic rhinitis are due to a complex interaction between several inflammatory cells, including basophils, mast cells, lymphocytes, dendritic cells, neutrophils, and eosinophils in response to various environmental/allergic stimuli (1, 2). These cells produce a plethora of inflammatory mediators, such as histamine, eicosanoids, chemokines, cytokines, and reactive oxygen species (3, 4). Among these, mast cell histamine is an axial player in stimulating the development of allergic-related inflammatory diseases by regulating the maturation and activation of leukocytes and directing their migration to target sites where they cause chronic inflammation (5–8). Histamine also exerts a various other immune regulatory functions by modulating the functions of monocytes (9), T cells (10, 11), macrophages (12), neutrophils (13), eosinophils (14), B cells, and dendritic cells (15). The biological impact of histamine follow their interaction with four types histamine receptors, H1R, H2R, H3R, and H4R, all of which belong to the G protein coupled receptor family (8, 16–20).

In this review, we focus on the importance and present knowledge about the histamine and histamine receptor-mediated activation in mast cell-mediated allergic disorders.

Mast Cells: Source of Histamine

Mast cells are the major producer of histamine and express a vast array of receptors on their surface such as FcεR1, FcγRI, and receptors for complement components (C3aR and C5aR), nerve growth factor (NGF) (Trk A), substance P, vasoactive intestinal peptide (MrgX2), adenosine phosphate, etc. (21–24). Activation through these receptors by their respective stimulants, such as allergens, complement peptides C3a, C5a (25, 26), NGF (27), neuropeptides, adenosine mono-phosphate activate human cord blood-derived mast cells to release various inflammatory mediators including histamine. Histamine can also be produced by basophils and other immune cells (28) but much higher concentrations of histamine may be found in intestinal mucosa, skin, and bronchial tissues. Histamine regulates a plethora of pathophysiological and physiological processes, such as secretion of gastric acid, inflammation, and the regulation of vasodilatation and bronchoconstriction (29, 30). In addition, it can also serve as a neurotransmitter (31).

Role of Histamine in Allergic Disease

Histamine plays a central role in the pathogenesis of several allergic diseases, such as atopic dermatitis, allergic rhinitis, and allergic asthma through differential regulation of T helper lymphocytes. Enhancement of Th2 cytokine secretion [such as interleukin (IL)-5, IL-4, IL-10, and IL-13] and inhibition of Th1 cytokine production [interferon-γ (IFN-γ), monokine IL-12, and IL-2] are mediated by histamine. Thereby, histamine regulates the effective balance between Th1 and Th2 cells by assisting a shift toward Th2 (32). Histamine-mediated mast cell activation plays a critical role in various allergic diseases. Histamine may induce the release of leukotrienes, cytokines, and chemokines via H4R in CD34+ cord blood-derived human mast cells (33). In mouse mast cells, both histamine and 4-methylhistamine can induce IL-6 production individually, an effect that is potentiated by LPS stimulation. This effect can be blocked by H4R antagonists and does not occur in H4R-deficient allergic mice (34). Recent findings have shown that activation of H4 receptors by histamine stimulates the synthesis of IL-4 and IL-5 in human cord blood mast cells and tumor necrosis factor (TNF)-α in bone marrow-derived murine mast cells (BMMCs), both of which have a potential role in inducing allergic inflammation (33, 35).

Histamine Receptors and Their Role in Allergic Inflammation

Histamine receptors (H1R–H4R) are characterized by their function, structure, distribution, and their affinity to histamine (36, 37). Histamine has diverse effects, both pro-inflammatory and anti-inflammatory, which are determined by both the histamine receptor subtype and the cells stimulated types (38). The H1-receptor drives cellular migration, nociception, vasodilatation, and bronchoconstriction (39), whereas the H2-receptor modifies gastric acid secretion, airway mucus production, and vascular permeability (40). The H3-receptor plays an important role in neuro-inflammatory diseases (37). The H4-receptor has also been shown to be involved in allergy and inflammation (38, 41). H4R-mediated mast cell activation can regulate a powerful inflammatory cascade by releasing several inflammatory mediators; these mediators may stimulate the migration of different inflammatory cells into the inflammatory site (33). Likewise, the activation of H1R also regulates allergic responses by enhancing the migration of Th2 cells toward the allergen during lung inflammation (42). A more detailed summary of histamine receptor expression is shown in Table 1.

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Table 1. Expression of different histamine receptors on various cells.

The H1-Receptor

The H1R is ubiquitously expressed and is involved in allergy and inflammation. H1R is expressed in many tissues and cells, including nerves, respiratory epithelium, endothelial cells, hepatic cells, vascular smooth muscle cells, dendritic cells, and lymphocytes (8, 19). Histamine activates H1R through Gαq/11, which then activates phospholipase C and increases intracellular Ca++ levels. As a consequence, histamine elicits the contraction of smooth muscle of the respiratory tract, increases vascular permeability, and induces the production of prostacyclin and platelet activating factor by activating H1R (Figure 1) (58). Thus, almost all immediate hypersensitivity reactions, including symptoms observed in the skin, such as erythema, pruritus, and edema, may be elicited by the activation of H1R (59).

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Figure 1. Schematic representation of the expression of histamine receptors on mast cells and their potential response to histamine: binding of histamine to H1R induces vasodilatation, bronchoconstriction, platelet aggregation, and mucus hyper-secretion. Stimulation of H2R by histamine causes gastric acid secretion, increase heart rate, and cardiac output. Activation of H3R is involved in sleep-wake cycle, cognition, homeostatic regulation of energy levels, and neurotransmission. H4R activation leads to Ca++ release from endoplasmic reticulum, degranulation, chemotaxis, and immuno-modulation whereas inhibitors of histamine receptors (H1R–H4R) inhibit specific responses.

Activation via H1R may also enhance both Th1- and Th2-type immune responses (11). In mice, deletion of H1R leads to the release of Th2 cytokines (IL-4 and IL-13) and inhibition of IFN-γ (60). Similarly, Bryce et al. (42) demonstrated that allergen-challenged H1R-deficient mice had attenuated lung allergic responses. They also demonstrated that histamine may act as a chemotactic factor for Th2 cells, stimulating their migration into lung tissues (42).

In addition, IL-3 activation can increase H1R expression on Th1 cells (61, 62), and histamine can enhance B cell proliferation, which is absent in H1R-deficient mice (63). The role of H1R activation in asthma may be further corroborated by observations showing that use of H1R-antagonists can significantly decrease asthma symptoms and improve pulmonary function in persistent asthma (58, 64, 65).

Histamine H1 receptor is also expressed in dermal dendritic cells and keratinocytes in the skin tissue, and histamine increases the NGF production via H1R in human keratinocytes (66). The secretion of NGF is caused by the phosphorylation of protein kinase C, extracellular signal-regulated kinases (ERK), and the activation of AP-1 resulting from H1R stimulation. Similarly, histamine, acting via H1R, has also been shown to enhance the production of chemokines, such as granulocyte macrophage colony stimulating factor, regulated on activation T cell expressed and secreted (RANTES), and monocyte chemotactic protein-1 (MCP-1) in IFN-γ-stimulated keratinocytes. It also upregulates the antigen-presenting capability of dendritic cells, and leads to Th1 polarization through H1R (67).

Histamine induces IL-31 production, which plays an important and crucial role in pruritus and skin barrier function in allergic dermatitis (54). Administration of an H1R antagonist decreased IL-31 levels in the serum of atopic dermatitis patients (68). These data therefore suggest that H1R activation by histamine has the ability to induce various symptoms related with allergic skin diseases such as pruritus and atopic dermatitis.

The H2-Receptor

The Gαs-coupled H2R is highly expressed in various cells and tissues, such as B cells, T cells, dendritic cells, gastricparietal cells, smooth muscle cells, and the brain and cardiac tissues (Table 1). Activation of the receptor can induce airway mucus production, vascular permeability, and secretion of gastric acid (69). The role of the H2R is well studied in histidine decarboxylase knockout mice (HDC−/−) models which suggest that the lack of histamine can enhance downregulation of H2R expression in a tissue-specific manner (70). Furthermore, the H2R is importantly accountable for the relaxation of the airways, uterus, and smooth muscle cells in the blood vessels. Moreover, the H2R is involved in the activation of the immune system, such as Th1 cytokine production, reduction of basophil degranulation, T-cell proliferation, and antibody synthesis (71, 72). Knockdown of H2R−/− mice show impaired immune functions, gastric acid secretion, and cognitive function associated with hippocampal potentiation impairments (73, 74) and nociception abnormalities (75).

The H3-Receptor

The H3R is coupled to Gαi/o and exclusively expressed in neurones. It is important for homeostatic regulation of energy levels, sleep-wake cycle, cognition, and inflammation (76) (Figure 1). H3R-deficient mice exhibit altered behavior and locomotion (77) and display a metabolic syndrome characterized by obesity, hyperphagia, and increased leptin and insulin levels (78, 79). Similarly, several studies suggest that H3R knockout can also lead to an increase in severity of neuro-inflammatory diseases and can enhance the expression of IFN-inducible protein 10, MIP 2, and CXCR3 in T cells (80). These investigators also showed that H3R can be involved in blood–brain barrier function.

The H3R has also been associated with rhinitis (81). This is likely because it is expressed on presynaptic nerves in the peripheral sympathetic adrenergic system and also on nasal sub-mucosal glands. Stimulation of H3R suppressed norepinephrine release at presynaptic nerve endings and stimulated nasal sub-mucosal gland secretion (82).

Currently, several H3R ligands are available, but not in clinical use. H3R antagonists, such as clobenpropit and thioperamide, were extensively used as a research tools and few early stage clinical trial reports are also available for H3R antagonists (83). However, these antagonists are used to treat obesity, myocardial ischemic arrhythmias, cognition disorders, and insomnia (84).

The H4-Receptor

The histamine H4R is coupled to Gα/io proteins (85) and is expressed on a variety of immune cells as well as on other cells such as spleen, intestinal epithelia, lung, synovial tissue, central nervous system, sensory neurons, and cancer cells (86–94). Stimulation of H4R reduces forskolin-induced cyclic AMP formation, which leads to the activation of MAPK and enhanced Ca++ release (6, 95). H4R mediates the pro-inflammatory responses of histamine in both autocrine and paracrine manners. Histamine enhances adhesion molecule expression, cell shape change, and cytoskeletal rearrangement via H4R, leading to the increased migration of eosinophils (5).

In various allergic diseases allergen cross linkage of FcεRI is the primary driver of mast cell activation. However, H4R is constitutively expressed on human mast cells such as LAD-2 and HMC-1 (33, 43). H4R-mediated activation of mast cells leads to the expression of various pro-inflammatory cytokine and chemokines, such as IL-6, TNF-α, TGF-β1, RANTES, IL-8, MIP-1α, and MCP-1 (33). Histamine H4R stimulation of mast cells may have three positive effects. First, it increases chemotaxis of mast cells thus encouraging their accumulation at the site of an allergic response (6). Second, it upregulates the expression of FcεRI on mast cells, thereby priming them for allergen-induced activation (96). Third, it mobilizes intracellular calcium to either prime mast cells for activation or, indeed, induce degranulation. These effects have been studied using histamine, the H4R-agonist 4-methylhistamine, the H4R-antagonists thioperamide or JNJ 7777120 and mast cells from H4R-deficient mice.

Basophils also express H4R on their surface and release histamine following antigen stimulation (55). However, basophils and mast cells differ in several important aspects, such as anatomical localization, the production of cytokines, and antigen-presenting activity. Histamine, acting via H4R, induces chemotaxis of bone marrow-derived basophils. H4R may play significant roles in basophil regulation in allergic dermatitis (97).

Among the Th subsets, the mRNA and protein of H4R are preferentially expressed in Th2 cells over naive T cells and Th1 cells. H4R may be involved in the pathogenesis of allergy and inflammation by activating Th2 as well as Th17 cells (68, 98). In human Th17 cells, H4R antagonists inhibit the IL-17 production, induced by H4R agonist (68).

Stimulation of H4R can also enhance the migration of eosinophils and the recruitment of mast cells leading to the amplification of immune responses and chronic inflammation. Similarly, H4R are involved in T cell differentiation and dendritic cell activation and its immunomodulatory function (6). Histamine and selective H4R agonists were shown to induce the shape change of eosinophils, an effect that maybe blocked by selective H4R antagonists (5). Treatment with JNJ 39758979 (H4R antagonist) resulted in a statistically significant inhibition of eosinophil shape change. These results showed that administration of H4R antagonists may have an impact on eosinophil function (38).

Finally, the activation of H4R involves several signaling cascades for the release of various allergic inflammatory mediators. ERK is a member of MAPK family and mediates the proliferation, differentiation, anti-apoptosis, regulation, and cytokine expression at gene level. There are reports showing that histamine can induce phosphorylation of ERK through H4R in peripheral blood derived CD34+ human mast cells as well as in mouse BMMCs (34) and HEK-293 cells (99). H4R-involved ERK and PI3 kinase pathways have been shown to be involved in the release of IL-6 in mouse BMMCs (34) and JAK/STAT signaling pathways for the release of TNF-α in a rat model (100). Recent studies (101) demonstrated that the activation of NFκB through H4R has followed the JAK/STAT signaling pathway.

H4R: A Novel Drug Target for Allergic Diseases

In addition to H1R, H4R is considered as a novel drug target for the treatment of allergy and inflammation. Recently, the H4R antagonists such as JNJ 7777120 and JNJ 39758979 have been extensively used as a tools to understand the pathophysiological involvement of H4R and have been studied extensively in both cell culture and in vivo animal models (102, 103). Furthermore, H4R antagonists have been used to explore the role of H4R in allergic inflammatory disorders, such as allergic asthma, allergic rhinitis, and chronic pruritus (31).

Role of Antihistamines in Mast Cell-Associated Diseases

Mast cells play an active role in various allergic diseases such as acute pruritus, atopic dermatitis, allergic asthma, allergic rhinitis, and pulmonary fibrosis (104, 105). H1-antihistamines, such as azatadine, cetirizine, and mizolastine are used for the treatment mast cell activated diseases (106). Cimetidine, ranitidine, famotidine, and nizatidine are H2R selective antihistamines that reduce gastric acid secretion (107). H3R antihistamines include thioperamide, clobenpropit, BF2. 649, PF-03654746, JNJ-17216498, and MK 0249.

JNJ 7777120 is a selective H4R antihistamine that is widely used in inflammation and pruritus (108). There are some H4R antihistamines which are under clinical trial, such as JNJ 39758979, NCT 01068223, UK-63325, PF-3893787, and JNJ 38518168 (Figure 1) (108, 109). H1-antihistamines are a standard treatment for mast cell-mediated allergic diseases. There is increasing evidence that histamine binding to H4 receptors exacerbates allergy and inflammation. Indeed, mast cells themselves have H4 receptors which when stimulated increased degranulation and cytokine production. Therefore, antihistamines targeting both the H1 and H4 receptor could be an effective treatment for mast cell-mediated allergic diseases (110).

Clinical Trials Targeting Histamine Receptors

Pharmacological properties of H4R have been exhibited by various H4R transfected cells (87, 89, 99, 111, 112). It was observed that H1R and H2R specific agonist/antagonists cannot bind to the H4R. However, some H3R ligands such as imetit, clobenpropit, thioperamide, and R-methylhistamine are also able to bind to the H4R with different affinities. Currently, a number of H4R antagonists have been developed but only a few are undergoing clinical trials. JNJ 39758979, a potent and selective H4R antagonist, has shown impressive results in different allergic inflammatory diseases such as dermatitis, asthma, pruritus, and arthritis (102, 103).

Recent clinical trials (NCT01068223) with the H4R antagonist JNJ 39758979 help to demonstrate a significant role of the H4 receptor in pruritus in humans. Interestingly, the combination therapy of this H4R antagonist and the H1R antihistamine, cetirizine, showed a more beneficial effect in the treatment of pruritus as compared with H1R alone (113–116). Furthermore, a study was carried out by using JNJ 39758979 to treat persistent asthma (NCT00946569), but no results have yet been reported. There are some H4R antagonists under the clinical trial including toreforant (JNJ 38518168), PF-3893787, and UR-63325. Toreforant (JNJ 38518168) has been used for the treatment of rheumatoid arthritis (clinical trial numbers: NCT01679951, NCT00941707, and NCT01862224). However, a study in rheumatoid arthritis (NCT01679951) was terminated due to issues related to efficacy. Even though, studies are still going on with the H4R antagonist toreforant (JNJ 38518168) in patients with asthma and psoriasis (clinical trial numbers NCT01823016 and NCT02295865, respectively) (38).

Conclusion and Future Prospective

The recent developments in research on histamine pathway underscore the importance of histamine in allergic inflammation through its effects on the H1R and H4R. Although, drugs targeting H1R are being explored for the treatment of various mast cell-associated allergic disorders, they are not always clinically effective. Several H4R antagonists have entered the later stages of clinical trials for a different range of allergic and inflammatory diseases. However, their clinical efficacy reports are not yet published. Furthermore, there appears to be some overlap in function between H1R and H4R, opening up the possibility for using synergistic strategies for therapeutic approaches. As such, we suggest the combination therapies by using both H4R together with H1R antagonists may provide a potential benefit in the treatment of various allergic and inflammatory diseases.

Author Contributions

ET, EJ, HS, MB, MK, CM, MC, and RS designed the manuscript; were involved in drafting/revising the manuscript; and read and approved the final manuscript. ET, EJ, and RS wrote the first draft.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This work was primarily supported by DBT, Government of India, Ref. No: BT/PR3230/BRB/10/965/2011. ET and EJ thank SRM Institute of Science and Technology for the constant support and institutional facilities throughout the study. RS (BT/RLF/Re-entry/53/2013) and MB (BT/RLF/Re-entry/26/2013) acknowledge support from the Department of Biotechnology, India for Ramalingaswami Re-entry Fellowship.

Abbreviations

BMMCs, bone marrow-derived murine mast cells; ERK, extracellular signal-regulated kinases; GM-CSF, granulocyte macrophage colony stimulating factor; H1R, histamine H1 receptor; H2R, histamine H2 receptor; H3R, histamine H3 receptor; H4R, histamine H4 receptor; IFN-γ, interferon-γ; IL, interleukin; MCP-1, monocyte chemotactic protein-1; NGF, nerve growth factor; PKC, protein kinase C; TNF, tumor necrosis factor; RANTES, regulated on activation T cell expressed and secreted; PBMC, peripheral blood mononuclear cells; THP-1, Tamm–Horsfall protein 1.

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Keywords: histamine, histamine receptors, mast cells, allergy, inflammation, antihistamines

Citation: Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, Church MK and Saluja R (2018) The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Front. Immunol. 9:1873. doi: 10.3389/fimmu.2018.01873

Received: 14 March 2018; Accepted: 30 July 2018;
Published: 13 August 2018

Edited by:

Carlo Pucillo, Università degli Studi di Udine, Italy

Reviewed by:

Axel Lorentz, University of Hohenheim, Germany
Meenu Sharma, University of Texas MD Anderson Cancer Center, United States

Copyright: © 2018 Thangam, Jemima, Singh, Baig, Khan, Mathias, Church and Saluja. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Rohit Saluja, drrohitsaluja@gmail.com, rohit.biochemistry@aiimsbhopal.edu.in

Sours: https://www.frontiersin.org/articles/10.3389/fimmu.2018.01873/full
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Histamine

For the use as an immunostimulant drug, see Histamine dihydrochloride.

Histamine.svg
Histamine 3D ball.png
Names
IUPAC name

2-(1H-Imidazol-4-yl)ethanamine

Identifiers

CAS Number

3D model (JSmol)

ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard100.000.092Edit this at Wikidata

IUPHAR/BPS

KEGG
MeSHHistamine

PubChemCID

UNII

CompTox Dashboard(EPA)

InChI

  • InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8) checkY
    Key: NTYJJOPFIAHURM-UHFFFAOYSA-N checkY
  • InChI=1/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8)

    Key: NTYJJOPFIAHURM-UHFFFAOYAP

Properties

Chemical formula

C5H9N3
Molar mass111.148 g·mol−1
Melting point 83.5 °C (182.3 °F; 356.6 K)
Boiling point 209.5 °C (409.1 °F; 482.6 K)

Solubility in water

Easily soluble in cold water, hot water[1]
Solubility in other solvents Easily soluble in methanol. Very slightly soluble in diethyl ether.[1] Easily soluble in ethanol.
log P−0.7[2]
Acidity (pKa) Imidazole: 6.04
Terminal NH2: 9.75[2]
Pharmacology

ATC code

L03AX14 (WHO) V04CG03 (WHO) (phosphate)

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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Infobox references

Chemical compound

Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus.[3][4] Since histamine was discovered in 1910, it has been considered as a local hormone (autocoid) because it lacks the classic endocrineglands to secrete it, however, in recent years, histamine has been recognized as a central neurotransmitter.[5] Histamine is involved in the inflammatory response and has a central role as a mediator of itching.[6] As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.[7] It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

Properties[edit]

Histamine base, obtained as a mineral oil mull, melts at 83–84 °C.[8] Hydrochloride[9] and phosphorus[10] salts form white hygroscopiccrystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, the imidazole ring of histamine exists in two tautomeric forms, identified by which of the two nitrogen atoms is protonated. The nitrogen farther away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign and the nitrogen closer to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The tele tautomer, Nτ-H-histamine, is preferred in solution as compared to the pros tautomer, Nπ-H-histamine.

The tele tautomer (Nτ-H-histamine), on the left is more stable than the pros tautomer (Nπ-H-histamine) on the right.

Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated.[11] Thus, histamine is normally protonated to a singly charged cation. Since human blood is slightly basic (with a normal pH range of 7.35 to 7.45) therefore the predominant form of histamine present in human blood is monoprotic at the aliphatic nitrogen. Histamine is a monoamine neurotransmitter.

Synthesis and metabolism[edit]

Histamine is derived from the decarboxylation of the amino acidhistidine, a reaction catalyzed by the enzymeL-histidine decarboxylase. It is a hydrophilicvasoactiveamine.

Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling.

Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish. Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L range; wines contain it in the 2–10 mg/L range.[12]

Storage and release[edit]

Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes) called basophils. Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the hypothalamus region of the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgEantibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.

Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.

Degradation[edit]

Histamine is released by mast cells as an immune response and is later degraded primarily by two enzymes: diamine oxidase (DAO), coded by AOC1 genes, and histamine-N-methyltransferase (HNMT), coded by the HNMT gene. The presence of single nucleotide polymorphisms (SNPs) at these genes are associated with a wide variety of disorders caused by an overactive immune system, from ulcerative colitis to autism spectrum disorder (ASD). Histamine degradation is crucial to the prevention of allergic reactions to otherwise harmless substances.

DAO is typically expressed in epithelial cells at the tip of the villus of the small intestine mucosa.[13] Reduced DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to an increase in histamine absorption through enterocytes, which increases histamine concentration in the bloodstream.[14] One study found that migraine patients with gluten sensitivity were positively correlated with having lower DAO serum levels.[15] Low DAO activity can have more severe consequences as mutations in the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis.[16]Heterozygous or homozygous recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 alleles increased the risk for reduced DAO activity.[17] People with genotypes for reduced DAO activity can avoid foods high in histamine, such as alcohol, fermented foods, and aged foods, to attenuate any allergic reactions. Additionally, they should be aware whether any probiotics they are taking contain any histamine-producing strains and consult with their doctor to receive proper support.

HNMT is expressed in the central nervous system, where deficiencies have been shown to lead to aggressive behavior and abnormal sleep-wake cycles in mice.[18] Since brain histamine as a neurotransmitter regulates a number of neurophysiological functions, emphasis has been placed on the development of drugs to target histamine regulation. Yoshikawa et al. explores how the C314T, A939G, G179A, and T632C polymorphisms all impact HNMT enzymatic activity and the pathogenesis of various neurological disorders.[19] These mutations can have either a positive or negative impact. Some patients with ADHD have been shown to exhibit exacerbated symptoms in response to food additives and preservatives, due in part to histamine release. In a double-blind placebo-controlled crossover trial, children with ADHD who responded with aggravated symptoms after consuming a challenge beverage were more likely to have HNMT polymorphisms at T939C and Thr105Ile.[20] Histamine’s role in neuroinflammation and cognition has made it a target of study for many neurological disorders, including autism spectrum disorder (ASD). De novo deletions in the HNMT gene have also been associated with ASD.[21]

Mast cells serve an important immunological role by defending the body from antigens and maintaining homeostasis in the gut microbiome. They act as an alarm to trigger inflammatory responses by the immune system. Their presence in the digestive system enables them to serve as an early barrier to pathogens entering the body. People who suffer from widespread sensitivities and allergic reactions may have mast cell activation syndrome (MCAS), in which excessive amounts of histamine are released from mast cells, and cannot be properly degraded. The abnormal release of histamine can be caused by either dysfunctional internal signals from defective mast cells or by the development of clonal mast cell populations through mutations occurring in the tyrosine kinaseKit.[22] In such cases, the body may not be able to produce sufficient degradative enzymes to properly eliminate the excess histamine. Since MCAS is symptomatically characterized as such a broad disorder, it is difficult to diagnose and can be mislabeled as a variety of diseases, including irritable bowel syndrome and fibromyalgia.[22]

Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune system. In patients with asthma, abnormal histamine receptor activation in the lungs is associated with bronchospasm, airway obstruction, and production of excess mucus. Mutations in histamine degradation are more common in patients with a combination of asthma and allergen hypersensitivity than in those with just asthma. The HNMT-464 TT and HNMT-1639 TT are significantly more common among children with allergic asthma, the latter of which is overrepresented in African-American children.[23]

Mechanism of action[edit]

In humans, histamine exerts its effects primarily by binding to G protein-coupledhistamine receptors, designated H1 through H4.[24] As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.[24][25]

G-protein coupled receptorLocationFunctionSources
Histamine H1 receptor

 • CNS: Expressed on the dendrites of the output neurons of the histaminergic tuberomammillary nucleus, which projects to the dorsal raphe, locus coeruleus, and additional structures.
 • Periphery: Smooth muscle, endothelium, sensory nerves

 • CNS: Sleep-wake cycle (promotes wakefulness), body temperature, nociception, endocrine homeostasis, regulates appetite, involved in cognition
 • Periphery: Causes bronchoconstriction, bronchial smooth muscle contraction, urinary bladder contractions, vasodilation, promotes hypernociception (visceral hypersensitivity), involved in itch perception and urticaria.

[24][25][26][27]
Histamine H2 receptor

 • CNS: Dorsal striatum (caudate nucleus and putamen), cerebral cortex (external layers), hippocampal formation, dentate nucleus of the cerebellum
 • Periphery: Located on parietal cells, vascular smooth muscle cells, neutrophils, mast cells, as well as on cells in the heart and uterus

 • CNS: Not established (note: most known H2 receptor ligands are unable to cross the blood–brain barrier in sufficient concentrations to allow for neuropsychological and behavioral testing)
 • Periphery: Primarily involved in vasodilation and stimulation of gastric acid secretion. Urinary bladder relaxation. Modulates gastrointestinal function.

[24][25][28][27]
Histamine H3 receptorLocated in the central nervous system and to a lesser extent peripheral nervous system tissue Autoreceptor and heteroreceptor functions: decreased neurotransmitter release of histamine, acetylcholine, norepinephrine, serotonin. Modulates nociception, gastric acid secretion, and food intake. [24]
Histamine H4 receptorLocated primarily on basophils and in the bone marrow. It is also expressed in the thymus, small intestine, spleen, and colon. Plays a role in mast cell chemotaxis, itch perception, cytokine production and secretion, and visceral hypersensitivity. Other putative functions (e.g., inflammation, allergy, cognition, etc.) have not been fully characterized.[24]
Ligand-gated ion channelLocationFunctionSources
Histamine-gatedchloride channelPutatively: CNS (hypothalamus, thalamus) and intestinal epithelium Brain: Produces fast inhibitory postsynaptic potentials
Intestinal epithelium: chloride secretion (associated with secretory diarrhea)
[24][25]

Roles in the body[edit]

Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.[29]

Vasodilation and fall in blood pressure[edit]

It has been known for more than one hundred years that an intravenous injection of histamine causes a fall in the blood pressure.[30] The underlying mechanism concerns both vascular hyperpermeability and vasodilation. Histamine binding to endothelial cells causes them to contract, thus increasing vascular leak. It also stimulates synthesis and release of various vascular smooth muscle cell relaxants, such as nitric oxide, endothelium-derived hyperpolarizing factors and other compounds, resulting in blood vessel dilation.[31] These two mechanisms play a key role in the pathophysiology of anaphylaxis.

Effects on nasal mucous membrane [edit]

Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:[32]

  1. sneezing due to histamine-associated sensory neural stimulation
  2. hyper-secretion from glandular tissue
  3. nasal congestion due to vascular engorgement associated with vasodilation and increased capillarypermeability

Sleep-wake regulation[edit]

Further information: Ascending reticular activating system

Histamine is a neurotransmitter that is released from histaminergic neurons which project out of the mammalianhypothalamus. The cell bodies of these neurons are located in a portion of the posterior hypothalamus known as the tuberomammillary nucleus (TMN). The histamine neurons in this region comprise the brain's histamine system, which projects widely throughout the brain and includes axonal projections to the cortex, medial forebrain bundle, other hypothalamic nuclei, medial septum, the nucleus of the diagonal band, ventral tegmental area , amygdala, striatum, substantia nigra, hippocampus, thalamus and elsewhere.[33] The histamine neurons in the TMN are involved in regulating the sleep-wake cycle and promote arousal when activated.[34] The neural firing rate of histamine neurons in the TMN is strongly positively correlated with an individual's state of arousal. These neurons fire rapidly during periods of wakefulness, fire more slowly during periods of relaxation/tiredness, and stop firing altogether during REM and NREM (non-REM) sleep[citation needed].

First-generation H1 antihistamines (i.e., antagonists of histamine receptor H1) are capable of crossing the blood–brain barrier and produce drowsiness by antagonizing histamine H1 receptors in the tuberomammillary nucleus. The newer class of second-generation H1 antihistamines do not readily permeate the blood–brain barrier and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the likelihood of a sedating effect. In contrast, histamine H3 receptor antagonists increase wakefulness. Similar to the sedative effect of first-generation H1 antihistamines, an inability to maintain vigilance can occur from the inhibition of histamine biosynthesis or the loss (i.e., degeneration or destruction) of histamine-releasing neurons in the TMN.

Gastric acid release[edit]

Enterochromaffin-like cells, located within the gastric glands of the stomach, release histamine that stimulates nearby parietal cells by binding to the apical H2 receptor. Stimulation of the parietal cell induces the uptake of carbon dioxide and water from the blood, which is then converted to carbonic acid by the enzyme carbonic anhydrase. Inside the cytoplasm of the parietal cell, the carbonic acid readily dissociates into hydrogen and bicarbonate ions. The bicarbonate ions diffuse back through the basilar membrane and into the bloodstream, while the hydrogen ions are pumped into the lumen of the stomach via a K+/H+ ATPase pump. Histamine release is halted when the pH of the stomach starts to decrease. Antagonist molecules, like ranitidine, block the H2 receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.

Protective effects[edit]

While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress.[35] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[36]

Erection and sexual function[edit]

Libido loss and erectile failure can occur during treatment with histamine H2 receptor antagonists such as cimetidine, ranitidine, and risperidone.[37] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[38] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the functional binding of testosterone to its endogenous receptors.[37]

Schizophrenia[edit]

Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H1 receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine production, because histamine levels seem to be imbalanced in people with that disorder.[39]

Multiple sclerosis[edit]

Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4 receptors are thought to increase permeability in the blood-brain barrier, thus increasing infiltration of unwanted cells in the central nervous system. This can cause inflammation, and MS symptom worsening. The H2 and H3 receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the body's immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead, attack invaders.[40]

Disorders[edit]

As an integral part of the immune system, histamine may be involved in immune system disorders[41] and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.[42]

Some people may accumulate excessive dietary histamine in their bodies as a result of histamine intolerance. This may lead to sympthoms such as hives, itchy or flushed skin, red eyes, facial swelling, runny nose and congestion, headaches, or asthma attacks.[43]

History[edit]

The properties of histamine, then called β-iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw.[44] By 1913 the name histamine was in use, using combining forms of histo- + amine, yielding "tissue amine".

"H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.

See also[edit]

References[edit]

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  30. ^Dale HH, Laidlaw PP (December 1910). "The physiological action of beta-iminazolylethylamine". The Journal of Physiology. 41 (5): 318–44. doi:10.1113/jphysiol.1910.sp001406. PMC 1512903. PMID 16993030.
  31. ^Abbas A (2018). Cellular and molecular immunology. Elsevier. p. 447. ISBN .
  32. ^Monroe EW, Daly AF, Shalhoub RF (February 1997). "Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines". The Journal of Allergy and Clinical Immunology. 99 (2): S798-806. doi:10.1016/s0091-6749(97)70128-3. PMID 9042073.
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External links[edit]

Histamine receptormodulators

H1
  • Others:Atypical antipsychotics (e.g., aripiprazole, asenapine, brexpiprazole, brilaroxazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, zotepine)
  • Phenylpiperazineantidepressants (e.g., hydroxynefazodone, nefazodone, trazodone, triazoledione)
  • Tetracyclic antidepressants (e.g., amoxapine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline)
  • Tricyclic antidepressants (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, trimipramine)
  • Typical antipsychotics (e.g., chlorpromazine, flupenthixol, fluphenazine, loxapine, perphenazine, prochlorperazine, thioridazine, thiothixene)
H2
H3
H4

See also:Receptor/signaling modulators • Monoamine metabolism modulators • Monoamine reuptake inhibitors

Sours: https://en.wikipedia.org/wiki/Histamine
Histamine Synthesis and Metabolism Pathway

Histamine Intolerance

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What is histamine intolerance?

Histamine intolerance is not a sensitivity to histamine, but an indication that you’ve developed too much of it.

Histamine is a chemical responsible for a few major functions:

  • communicates messages to your brain
  • triggers release of stomach acid to help digestion
  • releases after injury or allergic reaction as part of your immune response

When histamine levels get too high or when it can’t break down properly, it can affect your normal bodily functions.

Symptoms of histamine intolerance

Histamine is associated with common allergic responses and symptoms. Many of these are similar to those from a histamine intolerance.

While they may vary, some common reactions associated with this intolerance include:

In more severe cases of histamine intolerance, you may experience:

What causes high histamine levels?

You naturally produce histamine along with the enzyme diamine oxidase (DAO). DAO is responsible for breaking down histamine that you take in from foods.

If you develop a DAO deficiency and are unable to break down histamine, you could develop an intolerance.

Some reasons your DAO enzyme levels could be affected include:

  • medications that block DAO functions or prevent production
  • gastrointestinal disorders, such as leaky gut syndrome and inflammatory bowel disease
  • histamine-rich foods that cause DAO enzymes to function improperly
  • foods that block DAO enzymes or trigger histamine release

Bacterial overgrowth is another contributing factor for developing a histamine intolerance. Bacteria grows when food isn’t digested properly, causing histamine overproduction. Normal levels of DAO enzymes can’t break down the increased levels of histamine in your body, causing a reaction.

Controlling histamine levels with diet

Foods to avoid

A healthy diet contains moderate levels of histamine. However, there are some foods high in histamine that can trigger inflammatory reactions and other negative symptoms.

Histamine-rich foods are:

There are also a number of foods that trigger histamine release in the body, such as:

Foods that block DAO production include:

Foods to eat

If you have a histamine intolerance, incorporating low-histamine foods into your diet can help reduce symptoms. There’s no such thing as a histamine-free diet. Consult with a dietician before you eliminate foods from your diet.

Some foods low in histamine include:

Shop for olive oil.

Diagnosing histamine intolerance

Before reaching a diagnosis, your doctor will eliminate other possible disorders or allergies that cause similar symptoms.

Doctors may also suggest following an elimination diet for 14 to 30 days. This diet requires you to remove any foods high in histamine or histamine triggers, and slowly reintroduce them to watch for new reactions.

Your doctor might also take a blood sample to analyze if you have a DAO deficiency.

Another way to diagnose histamine intolerance is through a prick test. A examined the effectiveness of a prick test to diagnose histamine intolerance. Researchers pricked the skin of 156 people and applied a 1 percent histamine solution.

For those with suspected histamine intolerance, the prick test was positive for 79 percent, revealing a small red, itchy bump on the tested area that didn’t resolve within 50 minutes.

Outlook

Histamine intolerance can cause uncomfortable symptoms, but a low-histamine diet may help ease symptoms.

Histamine intolerance shouldn’t be self-diagnosed since symptoms are similar to other allergens, disorders, or infections. If you think you might have an intolerance or are experiencing irregular symptoms, talk with your doctor.

Sours: https://www.healthline.com/health/histamine-intolerance

Release histamine

Imperceptibly, we somehow split into two companies. And at some point, the company, which included my boyfriend, decided that there was not enough booze, and it was high time to go for more. On the clock, the time was moving towards night and this situation did not suit me, and stupidly, because of excitement, I did.

Not want to let me in. But he didn't care, the alcohol had already hit his head and he invited me to have some fun in the company of the.

Mast cells part 1 - activation and histamine

His hands were on my chest, which he massaged. A minute later I stopped. We needed rest. The husband took out a member. He gave me freedom of action.

Similar news:

Nevertheless, there were no other characters for the next hundred meters of unfamiliar place and I could not ignore Red. Well, hello, - he said in a language. I understand, - I will accompany you. We'll be there soon.



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