Brief Report: First identification of H4 histamine receptor in healthy salivary glands and in focal sialadenitis in Sjögren's syndrome

Objective

The conventional H₁ and H₂ histamine receptors have >10,000‐fold lower avidity for histamine than H₄ histamine receptor, which has been implicated in autoimmune diseases. This study was undertaken to compare H₄ histamine receptor levels in the salivary glands (SGs) of healthy controls with those in the SGs of patients with primary Sjögren's syndrome (SS).

Methods

H₄ histamine receptor messenger RNA (mRNA) was analyzed using real‐time quantitative polymerase chain reaction, and the receptor protein was examined using immunostaining. Effects of the H₄ histamine receptor agonist ST‐1006 on cytokine synthesis by human SG (HSG) cells were analyzed using xMAP technology and enzyme‐linked immunosorbent assay.

Results

Healthy SGs contained H₄ histamine receptor mRNA. The receptor protein was localized to the acinar and ductal epithelial cells. H₄ histamine receptor agonist stimulated HSG cells to produce the cytokines interleukin‐8 and vascular endothelial growth factor. SS patients had low H₄ histamine receptor levels.

Conclusion

H₁ and H₂ histamine receptor antagonists are not effective in the treatment of autoimmune diseases. However, such antagonists do not affect the newly discovered H₄ histamine receptor. Dendritic cells and lymphocytes are nonprofessional histamine‐producing cells, which produce histamine at 100–1,000‐fold lower rates than mast cells do. Saliva contains only 0.31–12.4 ng/ml histamine, which is too low to stimulate H₁ or H₂ histamine receptor, but stimulates H₄ histamine receptor half maximally. Our findings show that H₄ histamine receptor is strongly expressed in tubuloacinar SG cells, which emphasizes the role of these cells in the pathogenesis of SS.