Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus.

BACKGROUND: Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high-affinity histamine H4 receptor (H4 R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4 R pattern, which is deranged in oral lichen planus (OLP). OBJECTIVES: To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP. METHODS: Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real-time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high-performance liquid chromatography. RESULTS: l-histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N-methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate-to-high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon-γ upregulated HDC-gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor-α. LPS induced a dose-dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins. CONCLUSIONS: HOKs are histamine-producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low-affinity H1 R and H2 R, but high enough to stimulate the high-affinity H4 R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.

Sjögren's syndome and extragonadal sex steroid formation: a clue to a better disease control?

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphoplasmacytoid focal adenitis leading to mucosal dryness, with 9:1 female dominance and peak incidence at menopause. Due to autoimmune adenitis it can be speculated that the normal epithelial cell renewal has failed, possibly as a result of local intracrine failure to process dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). Local intracrine/-cellular DHT deficiency seems to predispose to SS if estrogens are low, in menopausal women and in men. This intracrine failure could be the initial noxious stimulus, factor X, initiating the development of SS. Abnormal release and presentation of exocrine gland-derived antigens (Ag-epitopes), in a complex with major histocompatibility complex class II (MHC II), by migratory dendritic cells (DC) activates T-cells in the regional lymph nodes. B-cells with the same specificity capture and present self-Ag to Th-cells which provide T-cell help. B-cells transform to plasma cells and start to produce autoantibodies (Ab) against these T-cell-dependent Ag. Ab against SS-A/Ro and SS-B/La ribonucleoproteins occur only in HLA-DQw2.1/DQw6 heterozygous individuals, but hY-RNA and RNA polymerase III transcripts in these Ag may in all SS patients stimulate toll-like receptors (TLR) 7 and 9 of the plasmacytoid DCs, because IFN-α and IFN-signature are produced. CD8+αEß7+cytotoxic T-cells activated via cross-presentation recirculate to attack intracrine-deficient, apoptotic epithelial cells expressing self-Ag on their surface. Exocrine glands fall into the sphere of mucosal/gut-associated lymphatic tissue. This together with immune complexes spreads the immunological memory/aggression to extra-glandular sites explaining the systemic nature of the syndrome. Secondary SS could be explained by disturbed lymphocyte recirculation. There is no conclusive evidence that SS in those few men affected is more severe than in women, suggesting that sex steroid endo-/intracrinology has its major impact on the target tissue, not on immune modulation. This article is part of a Special Issue entitled 'Essential role of DHEA'.

Histamine H4 receptor in oral lichen planus.

OBJECTIVES: Oral lichen planus (OLP) is an autoimmune disease characterized by a band-like T-cell infiltrate below the apoptotic epithelial cells and degenerated basement membrane. We tested the hypothesis that the high-affinity histamine H4 receptors (H4 Rs) are downregulated in OLP by high histamine concentrations and proinflammatory T-cell cytokines. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence staining, image analysis and quantitative real-time polymerase chain reaction of tissue samples and cytokine-stimulated cultured SCC-25 and primary human oral keratinocytes. RESULTS: H4 R immunoreactivity was weak in OLP and characterized by mast cell (MC) hyperplasia and degranulation. In contrast to controls, H4 R immunostaining and MC counts were negatively correlated in OLP (P = 0.003). H4 R agonist at nanomolar levels led to a rapid internalization of H4 Rs, whereas high histamine concentration and interferon-γ decreased HRH4 -gene transcripts. CONCLUSION: Healthy oral epithelial cells are equipped with H4 R, which displays a uniform staining pattern in a MC-independent fashion. In contrast, in OLP, increased numbers of activated MCs associate with increasing loss of epithelial H4 R. Cell culture experiments suggest a rapid H4 R stimulation-dependent receptor internalization and a slow cytokine-driven decrease in H4 R synthesis. H4 R may be involved in the maintenance of healthy oral mucosa. In OLP, this maintenance might be impaired by MC degranulation and inflammatory cytokines.