Objective To identify pathoaetiological neuroimmune mechanisms in patients with atopic dermatitis (AD) and chronic stress, focusing at nerve density, sensory neuropeptides, and the serotonergic system. Methods Eleven patients with AD with histories of stress worsening were included. Biopsies from involved and non-involved skin were processed for immunohistochemistry. Salivary cortisol test was done as a marker for chronic stress. Results There were more acanthosis and fewer nerve fibres in epidermis and papillary dermis of involved compared with non-involved skin. Whereas there was no significant change in the number of substance P and calcitonin generelated peptide-positive nerve fibres between the involved and non-involved skin, there was an increase in the epidermal fraction of 5-hydroxtrytamine 1A (5-HT1A) receptor and serotonin transporter protein (SERT) immunoreactivity in the involved skin. The number of 5-HT2AR, CD3-positive cells, and SERTpositive cells, most of them being CD3 positive, was increased in involved skin. There was an increase in mast cells in the involved skin, and these cells were often located close to the basement membrane. There was a strong tendency to a correlation between 5-HT2AR positive cells in the papillary dermis of involved skin and low cortisol ratios, being an indicator of chronic stress. Conclusion A changed innervation and modulation of the serotonergic system are indicated in chronic atopic eczema also during chronic stress.
Expression of serotonin (5-hydroxytryptamine; 5-HT), 5-HT receptors 1A (5-HT1AR) and 2A, and serotonin transporter protein (SERT) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients, at 72 h post-challenge with the antigen. In addition, the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), and the selective serotonin reuptake inhibitors (SSRIs) citalopram and fluoxetine, were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients, regarding their proliferation and interleukin (IL)-2 production, as well as the effect of these SSRIs on a murine Langerhans' cell-like line (XS52), regarding its IL-1beta production. Serotonin-positive platelets were increased in the inflamed skin compared with control skin. A decrease (p <0.01) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin, whereas 5-HT2AR- and SERT-positive cells were increased (p <0.001 for both) in the eczematous skin. Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited (p <0.01) the proliferation of nickel-stimulated peripheral blood mononuclear cells, while no effect was found regarding IL-2 production. Citalopram at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line. These results indicate the implication of the serotonergic system in the contact allergic reaction.
Stress and anxiety may worsen atopic dermatitis (AD) through the serotonin system. Serotonergic expression was measured in 28 patients with AD in relation to extent of the disease (SCORing of Atopic Dermatitis; SCORAD), pruritus intensity (visual analogue scale; VAS), anxiety traits (Swedish Universities Scales of Personality; SSP) and depression (Montgomery-Åsberg Depression Rating Scale-Self assessment; MADRS-S). Biopsies were taken from lesional and non-lesional AD skin, and investigated for expression of serotonin, its receptors 5-HT1A and 5-HT2, and serotonin transporter protein (SERT), using immunohistochemistry. 5-HT1AR-immunoreactivity (ir) was higher in lesional skin in apical epidermis and in mast cell-like cells in dermis, and 5-HT2AR-ir in apical epidermis and on blood vessels. In contrast, a basement membrane 5-HT2AR-ir signal was higher in non-lesional skin. The distribution of SERT-ir in the basal epidermal layer was higher in lesional skin. Positive and negative correlations were found between serotonergic markers and SCORAD, inflammation, pruritus intensity, anxiety traits, and depression score, indicating that serotonergic mechanisms are involved in AD.
Nerve fibers and sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) have been reported to be involved in allergic contact dermatitis (ACD). In the present study, we investigated the general innervation (using antibody against protein gene product 9.5, PGP 9.5), axonal growth (using antibody against growth associated protein, GAP-43), CGRP, and substance P with its receptor neurokinin 1 (NK1), in positive epicutaneous reactions to nickel sulphate from nickel-allergic patients, at the peak of inflammation, 72 hr after challenge with the antigen. There was an increased (p < 0.01) number of GAP-43 positive fibers in the eczematous compared with control skin, indicating an increased axonal growth already at 72 hr postchallenge. Double staining revealed a coexpression of CGRP and GAP-43 on dermal nerve fibers. There was no difference in the number of substance P and CGRP positive nerve fibers between eczematous and control skin. However, semiquantification analyses showed an increased expression of substance P positive inflammatory cells, being CD3, CD4, or CD8 positive, and NK1R positive inflammatory cells, being tryptase or CD3 positive. These results indicate a contribution of regenerating nerve fibers and substance P to the contact allergic reaction.
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