Substance P alterations in skin and brain of chronically stressed atopic-like mice.

BACKGROUND: Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. OBJECTIVE: To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic-like mice. METHODS: The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. RESULTS: In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. A decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. CONCLUSION: Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus.

Neuroimmune mechanisms in patients with atopic dermatitis during chronic stress.

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 gene-related 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 SERT-positive 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.

Upregulation of the axonal growth and the expression of substance P and its NK1 receptor in human allergic contact dermatitis.

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.

The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa.

BACKGROUND: Peptide antibiotics are part of the surface defences against microbial intruders. However, the presence and significance of these innate immune effectors in the skin barrier of the newborn infant have not yet been appreciated. Erythema toxicum neonatorum is an inflammatory skin reaction of unknown aetiology and significance, commonly present in the healthy newborn infant. OBJECTIVES: As peptide antibiotics are upregulated in inflammatory skin disorders, we hypothesized that this also could be the case in erythema toxicum. We also investigated if the vernix caseosa, a cream-like white substance present on the skin of the infant at birth, might contribute to host defences. METHODS: The presence of the human antibacterial peptide LL-37 was investigated by immunohistochemistry and confocal imaging of skin biopsies from four 1-day-old infants with an erythema toxicum rash and four matched newborns without the rash. In addition, we analysed the expression of LL-37 and human beta defensin-1, an antibacterial peptide of epithelial origin, by reverse transcriptase-polymerase chain reaction. Finally, we screened for antibacterial components in vernix material obtained from six healthy newborns by inhibition zone assays. RESULTS: All biopsies from the lesions of erythema toxicum showed a dense, nodular infiltrate with numerous LL-37-expressing cells located in the dermal layer and a clear localization of the peptide within CD15-expressing neutrophils, EG2-expressing eosinophils and CD1a-expressing dendritic cells. LL-37 was also found to be located in CD1a-expressing Langerhans cells and a positive staining for the peptide was seen throughout the whole epidermal layer, both in infants with and without the rash. Skin samples from infants with the rash of erythema toxicum showed a constitutive expression of human beta defensin-1, while the expression of LL-37 seemed to be induced. Furthermore, LL-37 and lysozyme were detected in the protein fractions derived from the vernix caseosa, and these fractions exhibited a clear antibacterial activity. CONCLUSIONS: Peptide antibiotics are present in the vernix caseosa and in the skin of the healthy newborn infant, indicating effective innate immune protection already during fetal and neonatal life.

[Botryomycosis--peculiar bacterial granuloma]. / Botryomykos--besynnerligt bakteriellt granulom.

Botryomycosis is a chronic granulomatous infection, usually of skin or mucous membranes in predisposed individuals. Infection in internal organs may occur in immunosuppressed persons and is serious but uncommon. Trauma or foreign bodies and defective immune defense mechanisms predispose for the disease, which is mainly caused by Staphylococcus aureus, but also by other bacteria. The histopathological picture is diagnostic and biopsy is encouraged in granulomatous infections. Differential diagnoses may be mycobacteriosis, mycosis and parasitosis. If excision, the preferred treatment, is not radical, prolonged antibiotic treatment is required. The disease may become more widespread in connection with the common use of piercing in young immunocompetent persons.

Erythema toxicum neonatorum: an immunohistochemical analysis.

Erythema toxicum neonatorum is a benign rash of unknown etiology, present to various degrees in most term newborns and characterized by an accumulation of eosinophils in dermal lesions. The recruitment of leukocytes to tissues implicates the involvement of adhesion molecules, cytokines, and chemokines. We therefore performed immunohistochemistry on punch biopsy specimens from cutaneous lesions of ten 1-day-old infants with erythema toxicum using specific monoclonal antibodies directed against a variety of adhesion molecules, cytokines, chemokines, and cell type-specific membrane markers. Biopsy specimens of noninflamed skin from four matched newborns and four adults served as controls. The immunohistologic features of erythema toxicum in all 10 infants included a strong staining of the adhesion molecule E-selectin in the vessel wall and the presence of numerous inflammatory cells that were identified as dendritic cells (CD1a, CD83, HLA-DR, CD40, and ICAM-1 positive), eosinophils (EG2 positive), neutrophils (CD15 positive), macrophages (CD14, CD68, and Mac387 positive), and E-selectin-expressing cells. Furthermore, the lesions showed a high incidence of the proinflammatory cytokines interleukin (IL)-1alpha and IL-1beta and of the chemokines IL-8 and eotaxin. This immunologic activity was reduced or absent in noninflamed skin from newborn controls and adults. We conclude that there is an accumulation and activation of immune cells in the lesions of erythema toxicum, also present in noninflamed skin of 1-day-old infants, but to a lower level. The physiologic significance of the rash remains to be elucidated.

Provocation with stress and electricity of patients with "sensitivity to electricity".

Twenty-four patients with self-reported "sensitivity to electricity" were divided into two groups and tested in a double-blind provocation study. These patients, who reported increased skin symptoms when exposed to electromagnetic fields, were compared with 12 age- and sex-matched controls. Both groups were exposed to 30-minute periods of high or low stress situations, with and without simultaneous exposure to electromagnetic fields from a visual display unit. The matched controls were tested twice and given the same exposure as the patients but had the fields turned on every time. Stress was induced by requiring the participants to act in accordance with a random sequence of flashing lights while simultaneously solving complicated mathematical problems. Blood samples were analyzed for levels of the stress-related hormones melatonin, prolactin, adrenocorticotrophic hormone, neuropeptide Y, and growth hormone, and the expression of different peptides, cellular markers, and cytokines (somatostatin, CD1, factor XIIIa, and tumor necrosis factor-alpha). Skin biopsies were also analyzed for the occurrence of mast cells. Stress provocation resulted in feelings of more intense mental stress and elevated heart rate. The patients reported increased skin symptoms when they knew or believed that the electromagnetic field was turned on. With the blind conditions there were no differences between "on" or "off." Inflammatory mediators and mast cells in the skin were not affected by the stress exposure or by exposure to electromagnetic fields. The main conclusion was that the patients did not react to the fields.

Stinging and rosacea.

A total of 32 rosacea patients (25 with the papulopustular type of rosacea and 7 with the erythematotelangiectatic type) and 32 healthy persons were single-blind tested with a solution of 5% lactic acid and pure water applied to their cheeks. Twenty-four patients and 6 controls reacted positively as "stingers" (p<0.001) in this objective test of sensitive skin. All 7 of the patients with erythematotelangiectatic rosacea, but only 17/25 with the papulopustular type, were stingers (n.s.). The reason why some patients react with subjective symptoms, such as itching, burning, stinging, prickling or tingling, is unclear. The findings in this study are not surprising, but do support the theory that impairment due to different stimuli, most likely because of vascular sensitivity, is a central mechanism in the aetiology of rosacea. The correlation between sensitive vessels and sensitive skin has, however, not yet been determined.

Patients with visual display unit-related facial symptoms are stingers.

Thirty patients without obvious skin disease but with subjective skin symptoms related to work with visual display units (VDUs) and 32 healthy persons were single-blind-tested with a solution of 5% lactic acid and pure water on their cheeks. Thirteen of the patients and 6 control persons reacted positively as "stingers" (p < 0.05) in this objective test of sensitive skin. The reason why some patients react with subjective symptoms like itching, burning, stinging, prickling or tingling is unclear. The result of this study, that patients with VDU-related skin symptoms have sensitive skin, does not tell anything about the aetiology of the symptoms. Former studies speak against the role of electric and magnetic fields and indicate that "techno-stress", cognitive factors or flickering from the VDUs or fluorescent tubes could be of importance, as could the Swedish mass media debate.