The identification of the histamine H4 receptors has allowed new interest in the mechanism of action of an autacoid, which was originally identified in 1900s. Histamine is an important mediator of allergic disease, asthma and inflammation. The pharmacologic effects of histamine are mediated through four types of membrane histamine receptors, H1, H2, H3 and H4, which are all hepatohelical G-protein-coupled receptors. The H4 receptors, first considered to be present only on immunocompetent cells, are expressed on both the hematopoietic and non-hematopoietic cells. However, they are preferentially present on the cells, which are involved in the immune response, including eosinophils, basophils, mast cells, dendritic cells, helper T cells, cytolytic T cells and regulatory T cells. A number of other tissues including lung, heart, skin, small intestine and colon also express the H4 receptors. These receptors play a major role in the development of allergic diseases and asthma. The current understanding of allergic asthma is that it results from an abnormal TH2 production in response to environmental allergens, resulting in overproduction of IL-4, IL-5, and IL-13. The interaction of dendritic cells and allergen-specific T cells derives the polarization of naïve TH0 cells to the TH2 cells. Histamine along with other mediators plays a crucial role in this process. The H4 receptors have been identified as potential modulator for the activation of dendritic cells and polarization of T cells. In addition to their role in allergic asthma, these receptors are also involved in the inflammation of other tissues such as skin and the central nervous system. The vast body of evidence indicates a pro-inflammatory role for the H4 receptors, but there are reports where an antiinflammatory role for the H4 receptors, by their effects on regulatory T cells, has been reported. Agonist-biased signaling at the H4 receptors has added to the controversy regarding the role of these receptors. The histamine H1 receptor antagonists provide a limited relief in allergy and possess negligible to almost no efficacy in asthma. Consequently, the new histamine H4 receptor ligands may present an exciting opportunity to understand the etiology and pathogenesis of these disease states, along with new therapeutic opportunities.
Keywords: Airway hypersensitivity, airway remodeling, allergic contact dermatitis, allergic response, allergic rhinitis, asthma, atopic dermatitis, basophils, cytolytic T cells, dendritic cells, eosiophils, H4 receptor antagonists, H4 receptors, helper T cells, histamine, inflammation, mast cells, pruritus, regulatory T cells, TH1 cells, TH17 cells, TH2 cells.