There is increasing evidence that histamine as an important mediator of immediate type allergic reactions also effects professional APCs. Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R. We show here that MoDC also express H3R and H4R at the mRNA and protein level. mRNA of the H3R is down-regulated and mRNA of the H4R is up-regulated during the differentiation from monocytes to MoDC. H4R or H2R stimulation suppressed IL-12p70 production in MoDC. Induction of cAMP was necessary for IL-12p70 inhibition mediated via the H2R. In contrast, H4R stimulation did not affect cAMP production but induced the transcription factor AP-1, and U0126, an inhibitor of AP-1 transactivation and MEK, rescued H4R mediated IL-12p70 suppression. Moreover, MoDC responded to a H4R agonist (and also to a H2R agonist) with increased F-actin polymerization and migration in modified Boyden chamber assays, suggesting a chemotactic effect of histamine via the H2R and the H4R. Thus, H4R stimulation on MoDC results in immunomodulatory and chemotactic effects. Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases.

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

Significance: IL-36γ is a potent cytokine that drives and orchestrates inflammation. It is strongly expressed at barrier tissues such as the skin and thus is particularly relevant to inflammatory diseases that affect these tissues, including psoriasis. IL-36γ is expressed as an inactive precursor that requires precise N-terminal truncation for activation. In these investigations, we demonstrate that cathepsin S is the major IL-36γ–activating protease expressed by barrier tissues. Moreover, we show that both cathepsin S and IL-36γ are strongly up-regulated in psoriatic inflammation. These findings are important as they both identify the mechanism of IL-36γ activation and highlight that this mechanism may play a central role in the development of psoriatic inflammation.

Objective: We compared ultrasonography (US) with the modified nail psoriasis severity index (mNAPSI) to investigate the nail plate, nail matrix and adjacent tendons in subjects with psoriatic nail disease and to test the hypothesis that nail involvement was specifically linked to extensor tendon enthesopathy. Methods: 86 psoriatic patients (169 nails) and 20 healthy controls (HC) (40 nails) were assessed with both the mNAPSI and US. The thickness of the nail plate, nail matrix region and adjacent extensor tendon were assessed and compared with physical examination findings. Results: A good agreement between clinical and sonographic nail findings was noted (kappa value = 0.52, p < 0.0001). Entheseal thickening of the extensor tendon on US was more frequent in patients with clinical nail disease compared to patients without clinical nail disease in both psoriasis and psoriatic arthritis (38 vs. 16%, p = 0.03, and 47 vs. 19%, p = 0.008, respectively). Nail thickness, nail matrix and adjacent skin thickness were higher in psoriatic patients compared to HC. Conclusion: US and clinical findings show good correlation for the assessment of the nail in psoriatic disease. The demonstration of extensor tendon enthesopathy in both psoriasis and psoriatic arthritis supports the importance of enthesopathy in nail disease pathogenesis whether or not clinical arthritis is present.