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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.

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.

Galanin is a neuropeptide widely distributed in the nervous system. The expression of galanin was investigated in murine contact allergy using immunohistochemistry, radioimmunoassay and in situ hybridization. Female BALB/c mice were sensitized with oxazolone and 6 days later challenged on the dorsal surface of ears, while control mice received vehicle. After 24 h, one ear was processed for immunostaining using a biotinylated fluorescence technique, while the other ear was frozen and processed for radioimmunoassay or in situ hybridization. Galanin immunoreactive nerve fibres were more numerous (p < 0.01) in the eczematous compared with control ears. Double-staining with antibody to the nerve fibre marker PGP (protein gene product) 9.5 revealed colocalization of PGP 9.5 and galanin in nerve fibres. Radioimmunoassay demonstrated a decrease (p < 0.04) in galanin concentration in eczematous compared with control ears. Our results suggest a role for galanin in murine contact allergy.

Ninety-five percent of patients with palmoplantar pustulosis are smokers at onset of the disease. The aim of this study was to determine whether these patients have serum antibodies to nicotinic acetylcholine receptors (nAChR ab) and if their sera induce a specific immunofluorescence in normal palmar skin. Sera from 45 patients with palmoplantar pustulosis and 23 patients with chronic hand eczema were analysed for muscle nAChR ab, and immunofluorescence was performed on healthy palmar skin. Forty-two percent of the patients with palmoplantar pustulosis but none of the eczema patients had raised levels of nAChR ab. Immunofluorescence showed staining on endothelial cells in the papillary dermis in 47% of all sera from patients with palmoplantar pustulosis and in those with nAChR ab in 68%. On palmar skin from smokers there was also a staining of the sweat duct. Sera from patients with chronic hand eczema were negative. Our findings indicate that palmoplantar pustulosis is an autoimmune disease, possibly induced by smoking.

There is increasing evidence that the nervous system has influence on the immune response. The effect of vasoactive intestinal peptide (VIP) and of serotonin and its antagonists on the challenge phase of allergic contact dermatitis in humans were tested. The substances were injected intracutaneously shortly before and 6 h after application of patch tests with nickel sulphate in nickel-allergic patients and the test areas were measured after a further 18 h. Biopsy specimens were also taken for immunohistochemistry. The diameter of the nickel sulphate-induced test reaction was significantly reduced after injection of VIP at 10(-6)-10(-5) mol/l, but was not affected by serotonin or ketanserin. Also tested was the influence of the substances on the response of peripheral blood mononuclear cells from nickel-allergic subjects to nickel sulphate, when added at the same time as the antigen. No effect on the cell proliferative rate was seen, except for an inhibitory effect of serotonin and its antagonists at 10(-5)-10(-4) mol/l. VIP, at 10(-5) mol/l and serotonin at 10(-4) mol/l stimulated the secretion of interferon gamma. The interleukin-2 soluble receptor secretion was slightly stimulated by 5-HT at 10(-4) mol/l and by ketanserin at 10(-6) mol/l. In conclusion, our results show that when injected intracutaneously in the challenge phase of allergic contact dermatitis, VIP has an inhibitory effect, which might be explained by enhanced leukocyte production of interferon gamma.

The cross-talk between the immune and nervous systems is becoming an interesting field of research and there is accumulating evidence supporting this notion. In the present study we investigated the levels of nerve growth factor in a murine model of cutaneous leishmaniasis, using a two-site ELISA. Two strains of inbred mice were used for this purpose, namely BALB/c and C57BL/6, genetically susceptible and resistant, respectively, to infection with Leishmania major. This work demonstrates a difference in expression of nerve growth factor in the skin and secondary lymphoid organ microenvironment, as well as in the serum, between these mouse strains. The high nerve growth factor levels in the microenvironment seem to be important and possibly critical for the outcome of the disease. Compared with controls, the resistant strain, C57BL/6, expressed significantly increased nerve growth factor levels in the skin, secondary lymphoid organs and serum at 1 week post-infection, whereas the susceptible strain, BALB/c, showed no change in the skin and a slight increase in the lymphoid organs and serum at this time-point. These high nerve growth factor levels in the early stage of the disease, whether produced directly by the inflammatory cells or indirectly through its induction by other cytokines or both, might indicate a contribution of this neurotrophic factor to differentiation of naive T lymphocytes into either Th1 or Th2 subsets that fundamentally govern the disease outcome. The expression of significantly elevated nerve growth factor levels in the skin and lymphoid organs of C57BL/6 at the late studied time points might suggest a role for nerve growth factor in the resolution of the disease process, which is usually evident from 6 weeks post-infection in this model. The high nerve growth factor levels expressed in the skin, lymph nodes and serum of BALB/c at late stages of the disease may be explained as an attempt to counteract the progression and dissemination of the disease. This investigation adds further experimental evidence for an anti-inflammatory effect of nerve growth factor, possibly through its action as a link between the nervous and immune systems.

Immunoreactivity to interleukin-1 alpha, interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha and their receptors, as well as the endogenous interleukin-1 receptor antagonist, was investigated in hair follicles in paraffin-embedded normal human skin. Interleukin-1 beta- and tumour necrosis factor-alpha-like immunoreactivities were found in the inner root sheath layer of hair follicles, at the suprapapillary level. Interleukin-1 receptor-like immunoreactivity was also found in this layer, while there was a variable immunoreactivity to the interleukin-1 receptor antagonist. In the outer root sheath there was a weak to moderate staining for the four cytokines, in addition to intense staining for their receptors and a weak staining for the antagonist. The fibrous root sheath had a moderate immunoreactivity for interleukin-1 alpha and interleukin-6. The distribution patterns suggest that these cytokines, particularly interleukin-1 beta and tumour necrosis factor-alpha, may have a protective role in hair formation, while all the investigated proinflammatory cytokines may have a role in the differentiation process.

Neuromediators may influence the immune response. To investigate their potential immunomodulating role in established allergic contact dermatitis in man, the following neuromediators were tested: vasoactive intestinal polypeptide (VIP), serotonin, and the serotonin antagonists ketanserin, methiotepine and ICS-205-930. Positive patch test reactions were elicited by application of nickel sulphate for 48 h. The neuromediators were applied under patch test conditions after another 24 h. The test areas were measured before and 24 h after application of the neuromediators and biopsy specimens were taken for immunohistochemistry. After application of VIP at a concentration of 10(-5) mol/l, and of ketanserin at a concentration of 10(-4) mol/l, there was a significant reduction in the diameter of the test reaction. In addition, with VIP there was a reduction in the number of Leu 3a+ cells. Also tested was the influence of the neuromediators on the proliferative response of peripheral blood mononuclear cells from nickel-allergic subjects to nickel sulphate. The cells were cultured for 6 days and the neuromediators were added after 3 days. There was no effect on the proliferative response, except for slight inhibition by serotonin and by ketanserin at 10(-4) mol/l. More interferon gamma was found in the supernatants when VIP was added at 10(-5) and 10(-6) mol/l than in the control cultures. Thus, VIP and ketanserin may have an inhibitory effect on established allergic contact dermatitis. The effect of VIP is possibly mediated by an increased production of interferon gamma.

Paraformaldehyde-fixed tissue of chronic granulomatous skin conditions, such as cutaneous leishmaniasis, granuloma annulare, leprosy and hidroadenitis, was investigated for the presence of interleukin-1 alpha-, interleukin-1 beta-, interleukin-6- and tumour necrosis factor-alpha-like immunoreactivities among the cellular infiltrates. There was a weak to strong cytoplasmic labelling of plasma cells for interleukin-6 and tumour necrosis factor-alpha at the periphery of the granulomatous mass and around the skin appendages. The interleukin-6-like immunoreactivity seemed to be correlated with the coarseness of the chromatin material of the cells, being more intense with coarse chromatin. The cytoplasmic labelling for interleukin-1 alpha and interleukin-1 beta in the plasma cells was less intense. Epitheloid, Langhans' giant cells and small round cells exhibited a weak to moderate cytoplasmic labelling for interleukin-1 alpha and interleukin-1 beta, whereas the staining intensity for interleukin-6 and tumour necrosis factor-alpha was weak to strong. In addition, there was staining of the stroma in the centre of granuloma with antisera against interleukin-1 alpha, interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. This area contained few cells, suggesting that the granuloma was in a resolution process. A contribution of interleukin-6 and tumour necrosis factor-alpha to the granulomatous reaction, at least during the maintenance period, is suggested by the occurrence of these cytokines in the skin conditions studied. The findings are also consistent with a suggested role of B cells in the late stages of the granulomatous reaction. In addition, they are in line with the reported declining role of interleukin-1 in the maintenance of granuloma.