Background Although the cytokine, interleukin-31 (IL-31), has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear. Objective To determine whether immune cell-derived IL-31 directly stimulates sensory neurons, and to identify the molecular basis of IL-31-induced itch. Methods We used immunohistochemistry and qRTPCR to determine IL-31 expression levels in mice and humans. Immunohistochemistry, immunofluorescence, qRTPCR, in vivo pharmacology, western blotting, single cell calcium and electrophysiology were used to examine the distribution, functionality and cellular basis of the neuronal IL-31 receptor (IL-31RA) in mice and humans. Results Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and to a significantly lesser extend by mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentration increased significantly in murine atopic-like dermatitis skin. Both human and mouse DRG neurons express IL-31RA, largely in neurons that co-express TRPV1. IL-31-induced itch was significantly reduced in TRPV1- and TRPA1-deficient mice, not c-kit or PAR-2 mice. In cultured primary sensory neurons, IL-31 triggered Ca2+-release and ERK1/2 phosphorylation, Inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo. Conclusion IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA+/TRPV1+/TRPA1+ neurons, and is a critical neuro-immune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus, targeting neuronal IL-31RA may be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T cell lymphoma.

Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi-or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.

of vitamin D3 deficiency related diseases. 7 Recommendations to prevent sun exposure especially in immunosuppressed patients further complicate this situation.

SummaryAtopic dermatitis (AD) is a common, chronic inflammatory skin disease with a highly variable clinical phenotype and heterogeneous pathophysiology. Its pathogenesis is associated with alterations to both the skin barrier and the immune system, which may in turn be influenced by genetic mutations and the patient's environment. Basic and translational research, as well as clinical trials, have helped broaden our knowledge of the molecular mechanisms underlying the development of AD and to identify potential treatment targets and approaches. These include new ways of reducing transepidermal water loss and the shedding of corneocytes, new ways of interacting with established molecular targets (such as histamine receptors and interleukins and other T-cell cytokines), and the identification of new molecular targets (such as toll-like receptors and tight junction proteins). Well-established treatment options such as emollients, corticosteroids and topical calcineurin inhibitors will clearly continue to have a role in treating AD. Among the new agents that could be joining them in the near future are sphinganin (a precursor of ceramides 1 and 3), cannabinoids, highly targeted monoclonal antibodies and subcutaneous immunotherapy.Atopic dermatitis (AD) is a common, clinically defined, chronic inflammatory skin disease frequently associated with allergic rhinitis, asthma and immunoglobulin E (IgE)-mediated food reactions.1 The high variability of the clinical phenotype and severity, genetic background and known pathomechanisms strongly suggest a high degree of pathophysiological heterogeneity. 2 The clinical pattern of eczematous skin lesions is relatively uniform and results from interactive alterations of the skin barrier and the innate and adaptive immune systems. 3Some of the mechanisms linking specific reaction patterns in these three major areas of AD pathogenesis are well understood on a molecular level. A number of these alterations are caused by mutations in the genes encoding immune and barrier function proteins, which may alter the regulation or the structure of the gene product itself. Other alterations may be consequences of environmental factors such as stress, scratching behaviour, allergen exposure or washing habits. Hence, the development of AD can be understood as a result of gene-environment interaction. This paper reviews selected aspects of AD pathogenesis and highlights current and future treatment targets for AD. Barrier function in atopic dermatitisThe epidermal barrier consists of a thin layer of vital keratinocytes, which slowly differentiate into flat corneocytes while moving upwards in the epidermis. The thin layer of dead keratinocytes that make up the stratum corneum covers the vital parts of the epidermis and protects it against water loss and microbe invasion. The complex process of epidermal differentiation is disturbed in AD lesions, and offers many potential targets for therapeutic intervention. 4,5 The corneocytes are attached to one another by corneodesmosomes. Stratum corneum chy...