The French novelist Marcel Proust once wrote, “The real voyage of discovery consists not in seeking new landscapes but in having new eyes.” Ocular allergy researchers are gaining a new perspective on an old problem with the recent discovery of a new addition to the histamine receptor family: the H4 histamine receptors.

As we are in the thick of the autumn allergy season, staying up to date with new technologies and therapies that may reduce itching and inflammation associated with allergic conjunctivitis is vitally important. Itching is caused by the H1 receptor, which shares many traits with the novel H4 receptor. My interest in this novel receptor and its potential in new therapies stems from my earlier work in the identification of H1 receptors, and in the evaluation of H1 antagonist actions in the eye. I also helped garner the approval of the first H1 receptor antagonist, levocabastine.1-4 I was able to observe firsthand the effects of the multiple inflammatory mediators in the eye, and have been involved in the development of many other therapeutics since then. Thus, a new target for potential ocular allergy therapy was bound to get my attention.

While the physiologic functions of histamine have been recognized for more than 100 years, the analysis of H4 has significantly impacted our understanding of histamine actions. It has become clear that a thorough knowledge of ocular allergy requires further investigation of this novel receptor and its role in inflammation and allergy.

All in the Family
Histamine, or 4-imidazole ethyl amine, plays a key role in physiological processes such as gastric acid secretion, smooth muscle modulation, allergy and inflammation. It works as a chemical messenger to exert numerous functions in both central and peripheral tissues. Its diverse biological effects are mediated through three distinct subtypes of receptors: the H1, H2 and H3 receptors.4

The ocular targets for histamine: Of the four types of histamine receptors, at least three are expressed in ocular tissues and participate in histamine-evoked responses. Most prominent is the combination of H1 plus H4 receptors, found in sensory neurons and in most immune cells. To date, no published studies have identified H3 receptors in the eye.
All four histamine receptor types are G-protein coupled, though there are significant differences between them. To be exact, each shows a distinct pattern of tissue expression.

• H1: The H1 receptor is expressed on endothelial cells, nerve cells, and smooth muscle cells.5 In the eye, these receptors are particularly important in mediating itch sensation. Antagonists of H1 receptors have been used for many years in the treatment of allergic inflammatory responses.

• H2: The second class of histamine receptors, H2, are localized to the blood vessels in the eye, and have a much more significant impact on redness associated with allergic conjunctivitis.6

• H3: This receptor has a 37.4% homology with the novel H4 receptor, and is expressed throughout the central nervous system.7,8 In addition to the brain, there is evidence that H3 receptors may be present in nasal mucosa, suggesting a role in histamine-mediated nasal inflammation.9 Thus, despite similar structure and related mechanisms, each receptor plays its own unique role.

What is H4?
The identification of a fourth receptor in 2,000 by the Human Genome Project has revealed a strong synergy between the H1 and H4 receptor in various inflammatory conditions.7 This new receptor—the H4 receptor—has a much higher affinity for histamine than the other receptors and is a lower abundance, higher sensitivity pathway.5 H4 is involved in chemotaxis and inflammatory mediator release by eosinophils and mast cells. These cells express histamine H4 receptors as well as histamine itself, which can be released to further enhance recruitment of these major effector cells into tissue sites, leading to possible chronic inflammation.10 Studies in animal models using selective antagonists or H4 deficient mice have shown a specific role for these receptors in inflammation in vivo.11 Correlations between these four receptors shows that the physiological response to histamine is an integrated response. New therapies are now in the pipeline to aim at targeting H4.

H4 and New Therapies
The initial efforts to develop H4-specific drugs have focused on treatment of disorders such as pruritus and urticaria. To date, no H4 specific antihistamines have been approved by the FDA for any indication. However, the newly-approved H1 antihistamine, Lastacaft (alcaftadine 0.25% ophthalmic solution, Allergan) has demonstrated H4 antagonism in vitro.10,12 While the connection between this in vitro effect and alcaftadine’s long duration of action in treating ocular allergy is unclear, it is possible that this new antihistamine acts by antagonism at multiple histamine receptors.

The newfound knowledge of the novel H4 receptor paves the way for even further exploration of the histamine family and its potential connections to ocular allergy therapies.  

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