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  • Review Article
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The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines

Nature Reviews Drug Discovery volume 7, pages 41–53 (2008)Cite this article

Key Points

  • There are four known receptors for histamine. Antagonists for H1 and H2 receptors are currently in clinical use for the treatment of allergies, insomnia and gastric acid disorders. However, there are many conditions such as asthma and chronic pruritus in which histamine has been implicated in the disease pathology, but for which the currently marketed antihistamines have little, if any, effect.

  • The most recently discovered histamine receptor, the H4 receptor, has been shown to modulate the activity of numerous cell types associated with inflammation and has been shown to drive inflammatory processes in vivo.

  • As indicated, while evidence exists for a role of histamine in driving asthmatic responses, there is little evidence for clinical efficacy of H1 receptor antagonists for the disease. However, their use at high doses or early in the disease history is supported by recent animal data. Furthermore, preclinical models suggest that H4 receptors may account for other functions of histamine that are not blocked by the H1 receptor.

  • Histamine is also the best characterized pruritogen in humans and is known be involved in driving pruritic responses induced by mast-cell degranulation, such as acute urticaria. H1 receptor antagonists appear to be clinically effective in these conditions, but not so in more chronic pruritic conditions such as those associated with atopic dermatitis or psoriasis. Pruritus in these conditions may be mediated by the H4 receptor as preclinical models have shown that it is also involved in driving pruritic responses.

  • The recent data on the novel functions of H1 and H4 receptors have opened the possibility for new breakthrough therapies for the treatment of conditions such as asthma and pruritus. In addition, there seems to be some overlap in function between the receptors, suggesting that combining H1 and H4 receptor antagonism might bring added benefit over monotherapy.

Abstract

Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists — commonly known as antihistamines — have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions.

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Figure 1: The major classical physiological roles of histamine.
Figure 2
Figure 3: The effects of histamine on dendritic cell and T-cell interactions.
Figure 4: Potential role of histamine, and histamine H1 and H4 receptors in asthma.
Figure 5: Proposed role of histamine H1 and H4 receptors in peripheral and central transmission of itch responses.

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Authors and Affiliations

  1. Johnson & Johnson Pharmaceutical Research & Development, L.L.C, San Diego, 92121, California, USA

    Robin L. Thurmond & Paul J. Dunford

  2. Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Colorado, 80206, Denver, USA

    Erwin W. Gelfand

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DATABASES

IUPHAR Receptor Database

H1

H2

H3

H4

OMIM

Asthma

atopic dermatitis

multiple sclerosis

psoriatic arthritis

rheumatoid arthritis

Glossary

Mast cell

A cell found in connective tissue that contains numerous basophilic granules and releases substances such as leukotrienes and histamine in response to various stimuli, such as bacterial products or specific antigen binding to surface immunoglobulin E.

Wheal and flare

The characteristic immediate reaction to an injected allergen in a skin test, in which an irregular blanched wheal appears, surrounded by an area of redness (flare). First described by Lewis in 1927 and attributed as a response to histamine.

Antihistamines

Drugs that block the action of histamine and most commonly used to designate histamine H1 receptor antagonists. In general, first-generation antihistamines are classified as having CNS activity; second-generation antihistamines have little or no activity in the CNS.

Chronic urticaria

An inflammatory skin condition associated with chronic pruritus. Often the result of an autoimmune reaction to self-immunoglobulin E that causes degranulation of mast cells.

Monoamine GPCR

A monoamine G-protein-coupled receptor (GPCR) is a receptor whose ligand contains one amino acid; for example, serotonin, dopamine, noradrenaline or histamine.

Eosinophil

A white blood cell with a physiological role in the destruction of parasites. Eosinophils are strongly implicated in allergic inflammation with an ability to release an array of cytotoxic mediators.

Dendritic cell

An antigen-presenting leukocyte that is found in the skin, mucosa and lymphoid tissues and initiates a primary immune response by activating T lymphocytes and secreting cytokines.

Monocyte

A circulating, phagocytic white blood cell with the ability to release numerous inflammatory cytokines, such as tumour necrosis factor-α (TNFα) and interleukin 6. Monocytes can differentiate into tissue macrophages.

T-cell

A lymphocyte that matures in the thymus and has the ability to recognize specific peptide antigens through the receptors on its cell surface. Subdivided into CD4+ (T-helper) and CD8+ (T-cytotoxic) T cells.

Chemotaxis

The characteristic movement of a cell along a chemical concentration gradient formed by a chemokine or other chemotactic substance.

TH2 cell

A CD4+ T-helper cell that is strongly implicated in the pathogenesis of allergic disease.

Endothelial and epithelial cells

Endothelial cells line the closed spaces of the body such as the inside of blood vessels, lymphatic vessels, the heart and body cavities. By contrast, epithelial cells make up the outside layer of cells that covers all open surfaces of the body including the skin and mucous membranes.

Diapedesis

The movement or passage of blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue.

Airway mucosa

A membrane lining the respiratory tract and forming an interface with air. Also contains glands that secrete mucus.

Bronchial hyperresponsiveness

A symptom of asthma: an increase in sensitivity to airway-narrowing stimuli. This is often assessed experimentally, in humans and animals, by the measurement of airway function after inhalation of methacholine or histamine.

Sensitization

The immunization phase in experimental immune models in which animals are rendered reactive to specific antigens by administration of the antigen, normally in conjunction with an adjuvant. Specific T-cell and B-cell antibody responses ensue.

TH2 cytokines

Proteins such as interleukin 4 (IL4), IL5 and IL13 that are produced by TH2 cells and have a central role in key allergic responses, such as immunoglobulin E production, eosinophilia, mucus production and bronchial hyperresponsiveness.

Challenge

The effector phase in experimental immune models in which animals previously sensitized to a specific antigen are exposed to the antigen to cause 'disease'. Antigen is normally delivered to the site where the disease response is to be measured, for example, the lung to cause an asthma-like response.

C-fibres

Unmyelinated, slow-conducting nerve fibres identified as sensors and transmitters of pruritic signals.

Pruritogenic mediator

A stimulus or chemical mediator, such as histamine, known to cause itch.

Immunoglobulin E

(IgE). A class of immunoglobulin involved in allergic responses. IgE bound to mast cells can recognize allergens and cause their degranulation and activation.

Tachyphylaxis

The loss of response to an agonist or antagonist following repeated or prolonged exposure, most often due to downregulation or alteration of the specific receptor.

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Thurmond, R., Gelfand, E. & Dunford, P. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 7, 41–53 (2008). https://doi.org/10.1038/nrd2465

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