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 H4R may be involved in the pathogenesis of allergy and inflammation by activating Th2 as well as Th17 cells 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 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 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. 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 and JNJ 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 , 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 Mast cells play an active role in various allergic diseases such as acute pruritus, atopic dermatitis, allergic asthma, allergic rhinitis, and pulmonary fibrosis , H 1 -antihistamines, such as azatadine, cetirizine, and mizolastine are used for the treatment mast cell activated diseases Cimetidine, ranitidine, famotidine, and nizatidine are H2R selective antihistamines that reduce gastric acid secretion H3R antihistamines include thioperamide, clobenpropit, BF2.
JNJ is a selective H4R antihistamine that is widely used in inflammation and pruritus H 1 -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 Pharmacological properties of H4R have been exhibited by various H4R transfected cells 87 , 89 , 99 , , 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 , a potent and selective H4R antagonist, has shown impressive results in different allergic inflammatory diseases such as dermatitis, asthma, pruritus, and arthritis , 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 — Furthermore, a study was carried out by using JNJ to treat persistent asthma NCT , but no results have yet been reported.
However, a study in rheumatoid arthritis NCT was terminated due to issues related to efficacy. 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. 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. Rothenberg ME. N Engl J Med — Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med —7. Nature —6. Identification, purification, and characterization of a mast cell-associated cytolytic factor related to tumor necrosis factor.
Histamine induces cytoskeletal changes in human eosinophils via the H 4 receptor. Br J Pharmacol — Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells.
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Clin Exp Allergy — Functional characterization of histamine H4 receptor on human mast cells. Mol Immunol — Desai P, Thurmond RL. Eur J Immunol — Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis. A local histamine pool is physiologically relevant only if it is within the diffusion distance of the parietal cells, if it is effectively mobilized by gastrin, and if it is endowed with the machinery for a rapid replenishment of the histamine that has been released.
Histamine in the stomach occurs in endocrine cells so-called enterochromaffin-like ECL cells , mast cells, and neurons. The ECL cells are peptide hormone-producing cells. In mammals they are located basally in the oxyntic gland area, in the chief-cell-rich region. Histamine is a small molecule derived from the decarboxylation of the amino acid histidine.
It is destroyed by the enzyme diamine oxidase histiminase , which is also involved in the metabolism of other bioactive amines. Histamine is synthesized in all tissues, but is particularly abundant in skin, lung and gastrointestinal tract.
Mast cells, which are present in many tissues, are a prominent source of histamine, but histamine is also secreted by a number of other immune cells. Mast cells have surface receptors that bind immunoglobulin E, and when antigen crosslinks IgE on the mast cell surface, they respond by secreting histamine, along with a variety of other bioactive mediators. Histamine is best known as a mediator of allergic reactions, but it is now recognized to participate in numerous other normal and pathologic processes.
The sensitivity and response of a particular cell to histamine depends upon which type of histamine receptor is present on that cell. An interesting illustration of the systemic effects of histamine is scombroid fish poisoning. Essentially histamine poisoning, this disorder is seen following consumption of fish, commonly tuna or mackerel, that have spoiled and within which bacteria have generated abundant quantities of histamine from histidine in muscle protein.
Consumption of such spoiled fish results in the rapid development of a variety of clinical signs, including headache, sweating, diarrhea, a flushed face, and vomiting, all resulting from systemic exposure to histamine.
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