MicroRNAs: Novel Regulators Involved in the Pathogenesis of Psoriasis?

MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases

Global Expression Profiling in Atopic Eczema Reveals Reciprocal Expression of Inflammatory and Lipid Genes

Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood.We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE.Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. The full data set is available at http://microarray-pubs.stanford.edu/eczema

Immunological mechanisms in atopic dermatitis : clinical and experimental studies

The aim of the study was to investigate immunological mechanisms in atopic dermatitis. Serum IgE levels are elevated in 80% of atopic dermatitis patients and CD4+ T cells and environmental allergens are known to be of importance in the pathogenesis of the disease. It was therefore of interest to further elucidate the role of these factors in atopic dermatitis. Cyclosporin A (CSA) was used as a tool for exploring the pathogenesis of atopic dermatitis, with emphasis on the expression of IgE, the low-affinity IgE receptor (CD23), intercellular adhesion molecule-1 (ICAM-1) and eosinophils in a placebo-controlled study of ten patients with persistent atopic dermatitis. CSA reduced the expression of epidermal and dermal IgE and CD23, ICAM-1 on keratinocytes, and the number of eosinophils in lesional skin. The effects are most likely due to a decrease in the amounts of T cell derived cytokines in the skin. The inflammatory and pruritogenic properties of interleukin-2 (IL-2) were explored by a single intradermal injection of IL-2 into eight atopic dermatitis patients and eight healthy individuals in a placebo-controlled study. IL-2 induced local itch, erythema, dermal infiltration of CD4+ T cells, spongiosis, exocytosis and activation of keratinocytes in atopic dermatitis patients, indicating that IL-2 may be of importance in skin inflammation in atopic dermatitis. The yeast Pityrosporum orbiculare, a member of the normal microflora of human skin, is considered to be one of the factors contributing to atopic dermatitis. Serum lgE antibodies or positive skin prick tests to P. orbiculare are found with a frequency of 14-71% in patients with atopic dermatitis, but rarely in atopic respiratory diseases without atopic dermatitis or in healthy controls. The proliferative response of peripheral blood mononuclear cells (PBMC) to P. orbiculare extract was investigated in ten patients with atopic dermatitis and six healthy individuals and was found to be significantly higher in the atopic dermatitis patients. From two atopic dermatitis patients, T-cell clones (TCCs) from skin and blood were established and characterized. The investigated TCCs were CD4+ and a majority of the skin derived T cells showed a Th2 or Th2/ThO-like cytokine profile. In addition, cytokine production was investigated in blood-derived P. orbiculare-stimulated T-cell lines (TCLs) from eleven atopic dermatitis patients and six healthy individuals. The TCLs derived from atopic dermatitis patients produced significantly higher levels of Th2 cytokines than those from the healthy individuals. Fifteen atopic dermatitis patients, eight seborrhoeic dermatitis patients and eight healthy individuals were patch tested with P. orbiculare extract on tape-stripped non-lesional skin. The seborrhoeic dermatitis patients and the healthy individuals were RAST and patch test negative for P. orbiculare. Thirteen out of fifteen atopic dermatitis patients had serum IgE antibodies to P. orbiculare and eight of them showed a positive patch test reaction to P. orbiculare, with a maximal intensity at 48 h. Significantly higher serum levels of P. orbiculare specific lgE were detected in patch test positive compared to the negative atopic dermatitis patients indicating that allergen-specific IgE is important for initiating an allergen-specific eczematous response. In the atopic dermatitis patients, an infiltration of CD4+ T cells and eosinophils was present at the P. orbiculare positive patch test sites along with an up-regulation of ICAM-1 and HLA-DR expression. The Th2-like cytokine profile of P. orbiculare reactive TCCs and TCLs together with the positive patch test response to R orbiculare in sensitized atopic dermatitis patients indicate that P. orbiculare may be of importance for triggering and maintaining IgE mediated skin inflammation in these patients. Patch tests with P. orbiculare extract may serve as a diagnostic tool in a subgroup of atopic dermatitis patients

Elevated levels of IgG and IgG4 to Malassezia allergens in atopic eczema patients with IgE reactivity to Malassezia

The opportunistic yeast Malassezia is considered to be one of the factors that can contribute to atopic eczema (AE). Elevated serum IgE levels, T-cell proliferation and positive skin prick test (SPT) and atopy patch test (APT) reactions to Malassezia are found among AE patients. Sera from 127 AE patients, 14 patients with seborrheic dermatitis (SD) and 33 healthy controls were investigated for IgE and IgG4 to M. sympodialis extract and four recombinant Malassezia allergens; rMala s 1, rMala s 5, rMala s 6, and rMala s 9. In addition, IgG to the recombinant allergens was analyzed. The IgG and IgG4 levels were compared to IgE levels and in vivo reactions (SPT and APT) to Malassezia. AE patients with serum IgE levels >0.35 kU/l to M. sympodialis extract had significantly higher IgG4 levels to M. sympodialis extract than AE patients without detectable serum IgE to M. sympodialis extract, SD patients and healthy controls. Among the AE patients with and without detectable serum IgE to M. sympodialis extract, respectively, there were no differences in IgG4 levels between patients with positive or negative in vivo reactions to M. sympodialis extract. IgG4 to the rMala s allergens was almost exclusively found among patients with IgE to the same allergen. Within the four tested rMala s allergens, most IgG4 reactions were found to rMala s 6, an allergen with homology to cyclophilin. Elevated serum IgG4 to M. sympodialis extract accompanies elevated serum IgE to the extract. This is further confirmed by the association between IgG/IgG4 and IgE to recombinant Malassezia allergen

Positive Atopy Patch Test Reaction to Malassezia furfur in Atopic Dermatitis Correlates with a T Helper 2-like Peripheral Blood Mononuclear Cells Response

The yeast Malassezia furfur belongs to the normal cutaneous flora, but is also a triggering allergen that can contribute to atopic dermatitis. To illuminate the effect of circulating allergen-specific T cells in atopic dermatitis, the peripheral mononuclear cell response was correlated with the in vivo skin prick test and atopy patch test reactivity to M. furfur. None of 16 healthy controls showed any positive in vivo reaction. The 40 atopic dermatitis patients, of whom 18 had serum IgE reactivity to M. furfur, were subdivided according to their in vivo reaction to M. furfur extract into three groups: skin prick test positive/atopy patch test positive (n = 12), skin prick test positive/atopy patch test negative (n = 12), and skin prick test negative/atopy patch test negative (n = 16). The skin prick test positive/atopy patch test positive and the skin prick test positive/atopy patch test negative groups had a significantly higher peripheral mononuclear cell stimulation index than the healthy controls. Interestingly, the stimulation index values in the skin prick test positive/atopy patch test positive group were significantly higher than in the skin prick test positive/atopy patch test negative group. In the M. furfur skin prick test positive atopic dermatitis patients (n = 24) a correlation was found between stimulation index and the M. furfur atopy patch test reactions, but not between stimulation index and M. furfur-specific serum IgE levels. Skin prick test positive and/or atopy patch test positive reactions to the recombinant M. furfur allergens rMal f 1, rMal f 5, and rMal f 6 were observed in 7, 14, and 16 of the 40 atopic dermatitis patients, respectively. Further, there was a correlation between production of the T helper 2-related cytokines interleukins 4, 5, and 13 and stimulation index to M. furfur extract, but not between the T helper 1-related interferon-γ and stimulation index to M. furfur extract. Our data strongly suggest a relationship between circulating specific T cells with a T helper 2-like cytokine profile and positive atopy patch test reactions