These data document for the first time itch-related local markers in psoriasis, and suggest complex and multifactorial mechanisms of pruritus in the disease. These results provide the groundwork for further studies to evaluate the efficacy of antipruritic treatment for psoriatic patients.

These data represent the first reported evidence of increased plasma levels of NGF and SP in an allergic human skin disease. They suggest that these neurogenic factors systemically modulate the allergic response in AD, probably through interactions with cells of the immune-inflammatory component. In addition, NGF and SP may be useful markers of disease activity in patients with AD.

Acne vulgaris is a skin disorder of the sebaceous follicles that commonly occurs in adolescence and in young adulthood. The major pathogenic factors involved are hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. The clinical presentation of acne can range from a mild comedonal form to severe inflammatory cystic acne of the face, chest, and back. At the ultrastructural level, follicular keratinocytes in comedones can be seen to possess increased numbers of desmosomes and tonofilaments, which result in ductal hypercornification. The increased activity of sebaceous glands elicited by androgen causes proliferation of P. acnes, an anaerobe present within the retained sebum in the pilosebaceous ducts. The organism possesses a ribosome-rich cytoplasm and a relatively thick cell wall, and produces several biologically active mediators that may contribute to inflammation, for instance, by promoting leukocyte migration and follicular rupture. In inflamed lesions, numerous neutrophils and macrophages infiltrate around hair follicles and sometimes phagocytose P. acnes. To examine the participation of neurogenic factors in the pathogenesis of acne, we quantitatively assessed the effects of neuropeptides on the morphology of sebaceous glands in vitro using electron microscopy. Substance P, which can be elicited by stress, promoted the development of cytoplasmic organelles in sebaceous cells, stimulated sebaceous germinative cells, and induced significant increases in the area of sebaceous glands. It also increased the size of individual sebaceous cells and the number of sebum vacuoles for each differentiated sebaceous cell, all of which suggests that substance P promotes both the proliferation and the differentiation of sebaceous glands. In this review, we introduce the general concept of pathogenic factors involved in acne, including typical electron microscopic findings and recent evidence of stress-induced exacerbation of acne from a neurological point of view. An improved understanding of the pathogenesis of acne should lead to a rational therapy to successfully treat this skin disease.

SummaryCommunication between the nervous system and epidermal melanocytes has been suspected on the basis of their common embryologic origin and apparent parallel involvement in several disease processes, but never proven. In this study, confocal microscopic analysis of human skin sections stained with antibodies specific for melanocytes and nerve fibers showed intraepiderreal nerve endings in contact with melanocytes. This intimate contact was confirmed by electron microscopy, which further demonstrated thickening of apposing plasma membranes between melanocytes and nerve fibers, similar to synaptic contacts seen in nervous tissue. Since many intraepidermal nerve fibers are afferent nerves that act in a "neurosecretory" fashion through their terminals, cultured human melanocytes were stimulated with calcitonin generelated peptide (CGRP), substance P, or vasoactive intestinal peptide, neuropeptides known to be present in cutaneous nerves, to examine their possible functions in the epidermal melanin unit. CGRP increased DNA synthesis rate ofmelanocytes in a concentration-and time-dependent manner. Cell yields after 5 d were increased 25% compared with controls maintained in an otherwise optimized medium. Furthermore, stimulation by CGRP induced rapid and dosedependent accumulation of intracellular cAMP, suggesting that the mitogenic effect is mediated by the cAMP pathway. These studies confirm and expand a single earlier report in an animal model of physical contact between melanocytes and cutaneous nerves and for the first time strongly suggest that the nervous system may exert a tonic effect on melanocytes in normal or diseased human skin (Mihara, K., K. Hashimoto, and M. Kumakiri. 1982. J. Dermatol. 19:1-43).

There is ample clinical evidence suggesting that the nervous system such as emotional stress can influence the course of acne. We examined possible participation of cutaneous neurogenic factors including neuropeptides, neuropeptide-degrading enzymes and neurotrophic factors, in association with inflammation in the pathogenesis of acne. Immunohistochemical studies revealed that substance P (SP)-immunoreactive nerve fibers were in close apposition to the sebaceous glands, and that neutral endopeptidase (NEP) was expressed in the germinative cells of the sebaceous glands in the skin from acne patients. Nerve growth factor showed immunoreactivity only within the germinative cells. In addition, an increase in the number of mast cells and a strong expression of endothelial leukocyte adhesion molecule-1 on the postcapillary venules were observed in adjacent areas to the sebaceous glands. In vitro, the levels and the expression of stem cell factor by fibroblasts were upregulated by SP. When organ-cultured normal skin specimens were exposed to SP, we observed significant increases in the sizes of the sebaceous glands and in the number of sebum vacuoles in sebaceous cells. Furthermore, supplementation of SP to organ-cultured skin induced expression of NEP, and we demonstrated the subcellular localization of NEP in the endoplasmic reticulum and the Golgi apparatus within the sebaceous germinative cells using preembedding immunoelectron microscopy. These findings suggest that SP may stimulate lipogenesis of the sebaceous glands which may be followed by proliferation of Propionibacterium acnes, and may yield a potent influence on the sebaceous glands by provocation of inflammatory reactions via mast cells. Thus, cutaneous neurogenic factors should contribute to onset and/or exacerbation of acne inflammation.