Notes: Connections between nerve fibres and cutaneous cells have been studied using confocal and electron microscopy. In the skin, nerve fibres may secrete neuromediators, i.e. substance P, vasoactive intestinal peptide, somatostatin, calcitonin-gene-related peptide, gastrin-releasing peptide, neuropeptide Y, peptide histidine-isoleucine, neurotensin, neurokinins A and B, bradykinin, acetylcholine, catecholamines, endorphins and enkephalins. Neurohormones such as prolactin, melanocyte-stimulating hormone and adrenocorticotrophic hormone are also expressed in the skin. Neuromediators and neurohormones may be secreted by cutaneous cells, which also express receptors. Functions of epidermal and dermal cells are modulated by these substances. Immune cells transiently present in the skin (e.g. macrophages and lymphocytes) are modulated by neuromediators through receptors. During the course of skin disorders, especially inflammatory reactions, the neuroimmunocutaneous system is destabilized. This is particularly true in psoriasis. This destabilization may be secondary, although evidence shows it can also be responsible for the induction and maintenance of the inflammatory process. The skin, the nervous system and immunity are not independent systems but are closely associated and use the same language of cytokines and neurotransmitters. A new concept is suggested: the neuroimmunocutaneous system.

Notes: Skin innervation is extremely dense and reaches the most superficial layers of the epidermis (but not into the stratum corneum). The relationship between skin and the nervous system was neglected for a long time. Nowadays, this represents one of the most widely investigated fields of skin biology.Associations between nerve fibres and skin are so close that these can be observed at the cellular level. They are anatomical and physiological. Neurotransmitters are naturally synthesized by nerve endings, but cells from the skin and the immune system are also able to produce them. They are mediators for transmission of information between skin and the nervous system. All cutaneous and immune cells express specific receptors for these neuromediators, and enzymes for degrading them. Binding of the neurotransmitter to its receptor induces modulation of cell properties and skin functions (immunity, cell differentiation and proliferation, pigmentation, etc.). Hence, keratinocytes, Langerhans cells, melanocytes, endothelial cells, fibroblasts and the other cells of the skin or the immune system are modulated and controlled by the nerves. Reciprocally, skin is able to modulate neuronal activity and growth. All these data suggest that skin, nervous and immune systems are integrated in a unique system that we could name the neuro-immuno-cutaneous system (NICS).Hence, we can understand how the nervous system, and further the psychism, are involved in the maintenance of cutaneous homeostasis. In dermatological diseases or in cosmetological disorders, this equilibrium is broken. New fields of research are open: neuro-dermatology and of course neuro-cosmetics. Neuro-cosmetic products are supposed to modulate NICS functioning at the epidermal level. The French expression ‘avoir les nerfs à fleur de peau’ means that nervosity is so tense that one feels his nerves closely under or within skin, ready to explode. In fact, nerves are always ‘à fleur de peau’. Skin is an organ whose dense innervation involves the outermost skin layers, stratum corneum excepted. Long time neglected, the relation between skin and the nervous system are, today, a growing field of research within cutaneous biology.

Notes: We report the case of a 50-year-old male homosexual suffering from AIDS, who developed diffuse annular hyperkeratotic lesions on the arms and legs. Histopathological examination revealed typical features of porokeratosis, which clinically was of the disseminated superficial type. Ultrastructural examination showed a paucity of keratohyalin granules and lamellar bodies. Immunohistochemical studies showed an almost complete absence of Langerhans cells in lesional epidermis. Involucrin and filaggrin expression were altered in areas of cornoid lamella formation, whereas basal keratinocytes in these areas expressed PCNA/cyclin and, to a lesser degree, p53 protein. Porokeratosis may affect immunocompetent patients, but has also been reported in the setting of immunosuppression following organ transplantation. As far as we are aware, the development of porokeratosis during the course of HIV infection has not been reported previously.

Notes: While the enormous clinical and psychosocial importance of pruritus in many areas of medicine and the detrimental effects of chronic ‘itch’ on the quality of life of an affected individual are widely appreciated, the complexity of this sensation is still often grossly underestimated. The current Controversies feature highlights this complexity by portraying pruritus as a truly interdisciplinary problem at the crossroads of neurophysiology, neuroimmunology, neuropharmacology, protease research, internal medicine, and dermatology, which is combated most successfully if one keeps the multilayered nature of ‘itch’ in mind and adopts a holistic treatment approach – beyond the customary, frequently frustrane monotherapy with histamine receptor antagonists. In view of the often unsatisfactory, unidimensional, and altogether rather crude standard instruments for pruritus management that we still tend to use in clinical practice today, an interdisciplinary team of pruritus experts here critically examines recent progress in pruritus research that future itch management must take into consideration. Focusing on new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus, and discussing available neuropharmacological tools, specific research avenues are highlighted, whose pursuit promises to lead to novel, and hopefully more effective, forms of pruritus management.

Notes: Abstract:  All three-dimensional in vitro mucosal models constructed, thus far, have only been reconstituted by epithelial cells. We have developed a reconstructed oral and vaginal epithelium that integrates Langerhans' cells (LC), the dendritic cells (DC) of malpighian epithelia. The epithelium was composed of gingival or vaginal keratinocytes seeded on a de-epidermized dermis (DED) and grown in submerged culture for 2 weeks. LC precursors, obtained after differentiation of cord blood-derived CD34+ hematopoietic progenitor cells (CD34+HPC) by granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and Flt3-ligand (Flt3-L), were introduced after 6–8 days of culture into the reconstituted epithelium. The in vitro reconstituted mucosal epithelium formed a multilayered, well-differentiated epithelial structure, confirmed by the immunohistochemical expression of cytokeratins 4, 6, 10, 13, 14, 16 and involucrin. LC were identified in the basal and suprabasal epithelial layers by CD1a antigen, S100 protein and Langerin/CD207 expression, and by transmission electron microscopy. Type IV collagen was expressed at the chorio–epithelial junction, and most ultrastructural features of this junction were visualized by electron microscopy. This in vitro reconstructed gingiva or vagina integrating LC represents interesting models very similar to native tissues. Because LC play an important role in the mucosal immune system, our models could be useful for conducting studies on interactions with pathogenic agents (viruses, bacteria etc.), as well as in pharmacological, toxicological and clinical research.

Notes: In order to provide a model for in vitro studies of the interactions between skin and the nervous system, we have performed a co-culture of epidermal cells and neurons. We used a tri-compartmented box with separated domains. In the central part of this box, we put an epidermal suspension (4 millions cells/ml) obtained from biopsies of human skin. Around this central domain, we disposed sensorial neurons from the dorsal root ganglia of rats. The periphery was occupied by neurons from the dorsal horn of spinal cord. Sensorial neurons grew in low density (500 cells), on a glial layer, in a medium conditioned by astrocytes. After 15 days of culture, cells were fixed and stained with monoclonal antibodies directed against PGP 9.5, keratins, or cytokeratin 20 (Merkel cells). We obtained a co-culture with three identifiable territories, equivalents of epidermis, root ganglia, and spinal cord. Nervous fibers specifically grew from the sensorial neurons to epidermal cells or to the spinal cord equivalent. We observed synapse-like contacts between nerve endings and Merkel cells or keratinocytes. This model allows us to reconstruct in vitro an equivalent of sensitive nerve fibers, connected for one part to a spinal cord equivalent and on the other part to an epidermis equivalent. Such a model could be used to understand the origin and the function of Merkel cells in the epidermis and to study synapses in the skin.