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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., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)

At birth, commensal microbes penetrate into the skin of the human newborn, eliciting an acute rash, erythema toxicumn neonatorum. Histologically, the rash is characterized by an upregulation of proinflammatory activity and a local recruitment of immunocytes, including macrophages. High mobility group box chromosomal protein 1, a nuclear and cytosolic protein, is also a pro-inflammatory cytokine released by macrophages in response to microbial stimulation. Here, we reasoned that macrophages but also keratinocytes might upregulate this protein in response to the first colonization and that high mobility group box chromosomal protein 1 might play a role as a proinflammatory mediator in the development and progression of erythema toxicum. Punch biopsy specimens from 1-day-old healthy infants, seven with and four without erythema toxicum were analyzed with indirect immunohistochemistry and two different antihigh mobility group box chromosomal protein 1 antibodies, immunofluorescence, nuclear counterstaining, confocal and immunoelectron imaging. We found relocation of nuclear high mobility group box chromosomal protein 1 into the cytoplasm in keratinocytes and macrophages in erythema toxicum. Cytoplasmatic high mobility group box chromosomal protein 1 was also found in melanocytes and did neither co-locate with lysosomal-associated membrane proteins nor with melanosomes. We speculate that terrestrial adaptation triggers the induction of the endogenous "danger signal" high mobility group box chromosomal protein 1 in the skin of the newborn infant, perhaps in response to the first commensal colonization and that this signal may contribute to alert the immune system and promote a protective immune response.

Erythema toxicum neonatorum is a common rash of unknown etiology affecting healthy newborn infants. In this study, we postulated that the rash reflects a response to microbial colonization of the skin at birth, and that the hair follicle constitutes an "easily opened door" for microbes into the skin of the newborn. We collected microbial cultures from the skin of 69 healthy, 1-d-old infants with and without erythema toxicum to identify the colonizing flora and correlate culture results with clinical findings. We also analyzed biopsies from lesions of erythema toxicum with scanning and transmission electron microscopy in the search for microbes. Finally, each infant's body temperature was measured as a sign of acute phase response. We found that 84% of 1-d-old healthy infants, with and without erythema toxicum were colonized with coagulase-negative staphylococci. In all lesions of erythema toxicum, TEM identified cocci-like bacteria localized in the hair follicle epithelium and into recruited immune cells surrounding the hair follicle; morphology and dimension supported their identification as belonging to the genus Staphylococcus. SEM revealed 10 times more hair structures per skin surface unit in newborns compared with adults. Infants with erythema toxicum also had higher body temperature. In erythema toxicum, commensal microbes gain entry into the skin tissue, most probably through the hair canal. This triggers the local immune system and a systemic acute phase response, including an increase in body temperature. We speculate that early microbial exposure to the newborn may be important for the maturation of the immune system.

Erythema toxicum neonatorum is a common, inflammatory skin reaction in healthy newborn infants characterized by an accumulation of activated immune cells in the lesions. Its etiology and physiologic significance are still unclear. The purpose of this study was to extend the search for possible inflammatory mediators of the rash. We performed immunohistochemistry on punch biopsy cryosections from lesions of four, 1-day-old infants and from four matched controls without rash, using antibodies against the water channel proteins aquaporin-1 (AQP1) and aquaporin-3 (AQP3), psoriasin, and the nitric oxide synthase (NOS) enzymes, neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). All sections from the lesions showed a dense, nodular cellular infiltrate located near the hair follicle. The vessels in the dermis showed a high incidence of AQP1 and eNOS. Strong staining for AQP1, AQP3, and psoriasin, as well as nNOS, iNOS, and eNOS were seen in the entire epidermal layer. The infiltrate in the dermis contained numerous cells expressing AQP1, AQP3, nNOS, iNOS, and eNOS. Double immunofluorescence staining showed that AQP3 was located in CD1a-expressing Langerhans cells and other dendritic cells in the dermis, as well as in CD14-expressing macrophages, CD15-expressing neutrophils, and EG2-expressing eosinophils surrounding the hair follicle. Our findings show that AQP1 and AQP3, psoriasin, and NOSs are involved in the activation of the skin immune system at birth.

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.

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.