Research from San Diego, published in the Annals of the Rheumatic Diseases, shows that histamine is not only involved in allergies but that it also has a role in potentiating inflammation in experimental inflammatory arthritis. As Robin Thurmond, the lead author on this paper explains: “There has been literature showing that histamine appears to be increased in arthritic joints, but I think this was dismissed as being unimportant. Our work shows that histamine, acting via the H4 receptor, amplifies both the innate and adaptive immune responses that underlie the disease.”
The researchers investigated the role of histamine4 receptor (H4R) in the development of autoimmune arthritis (CAIA; collagen antibody-induced arthritis) and inflammatory arthritis (CIA, collagen-induced arthritis) in studies involving H4R-deficient mice or an H4R antagonist (JNJ 28307474).
In the CAIA model, H4R-deficient and H4R-antagonist-treated mice developed less severe disease than the wild-type or vehicle-treated mice; disease scores were lower, and levels of inflammation, pannus formation, and bone and cartilage damage were reduced. Similar results were seen in the CIA model. Treatment with the H4R antagonist resulted in a dose-dependent reduction in disease severity compared with vehicle-treated mice, as confirmed by histological examination (see figure). Of 12 H4R-deficient mice, only seven developed inflammatory arthritis (score >2) in comparison with the wild-type mice who all developed disease. After 14 days, two of the H4R-deficient mice had fully recovered (score <2), whereas the disease scores remained unchanged in the wild-type mice. Disease severity in wild-type mice with established disease was reduced after treatment with an H4R-receptor antagonist.
These findings indicate a role for histamine, via the H4R, in the pathogenesis of experimental inflammatory arthritis, but how might H4R mediate its effects? The authors discovered that, in the CIA model, animals with disease had more lymph nodal IL-17+ CD4+ T cells than healthy mice and that treatment with an H4R antagonist reduced the number of these cells and the level of IL-17 produced. Therefore, H4R might, in part, act by influencing type 17 T helper cells.
“If the preclinical data translates into clinical efficacy, targeting H4R may provide novel oral treatment options for patients with RA,” states Thurmond. He concludes: “H4 R antagonists may become the antihistamines for autoimmune diseases.”
Cowden, J. M. et al. The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis. Ann. Rheum. Dis. 10.1136/annrheumdis-2013-203832
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Buckland, J. Antihistamines as treatments for autoimmune disease?. Nat Rev Rheumatol 9, 696 (2013). https://doi.org/10.1038/nrrheum.2013.169