No abstract

Atopic dermatitis (AD) is a common inflammatory skin disease associated with the local infiltration of T helper type 2 (Th2) cells. The ST2 gene encodes both membrane-bound ST2L and soluble ST2 (sST2) proteins by alternative splicing. The orphan receptor ST2L is functionally indispensable for Th2 cells. We found a significant genetic association between AD and the -26999G/A single nucleotide polymorphism (SNP) (chi2-test, raw P-value=0.000007, odds ratio 1.86) in the distal promoter region of the ST2 gene (chromosome 2q12) in a study of 452 AD patients and 636 healthy controls. The -26999A allele common among AD patients positively regulates the transcriptional activity of the ST2 gene. In addition, having at least one -26999A allele correlated with high sST2 concentrations and high total IgE levels in the sera from AD patients. Thus, the -26999A allele is correlated with an increased risk for AD. We also found that the -26999G/A SNP predominantly affected the transcriptional activity of hematopoietic cells. Immunohistochemical staining of a skin biopsy specimen from an AD patient in the acute stage showed ST2 staining in the keratinocytes as well as in the infiltrating cells in the dermal layer. Our data show that functional SNPs in the ST2 distal promoter region regulate ST2 expression which induces preferential activation of the Th2 response. Our findings will contribute to the evaluation of one of the genetic risk factors for AD.

Our results, showing downregulation of the cornified envelope genes and upregulation of the alternative keratinization pathway, are the first to suggest abnormal epidermal differentiation and defective defences as key abnormalities in AD.

The density and fine structure of the peripheral nerve system in various skin lesions of 64 patients with atopic dermatitis (AD) was quantitatively analyzed by immunohistochemical staining with antibodies directed against protein gene product (PGP) and substance P (SP). The density of PGP-positive peripheral nerves was 2.5 x 10(3) microns2/delta s (delta s = 0.24 mm2 selected area) in early acute lesions, 3.8 x 10(3) microns2/delta s in subacute lesions, 4.9 x 10(3) microns2/delta s in lichenified lesions and 7.1 x 10(3) microns2/delta s in prurigo lesions of AD. The density of nerve fibers in subacute, lichenified and prurigo lesions was significantly higher than in uninvolved skin of AD patients (2.0 x 10(3) microns2/delta s). Electron microscopically, bulging of axons with many mitochondria and a loss of their surrounding sheath of Schwann cells suggests that the free nerve endings in skin lesions of AD are in an active state of excitation. Many pinocytotic vesicles in the periphery of basal keratinocytes facing nerve endings which contained many neurovesicles suggests reciprocal effects between keratinocytes and nerve endings. The number of SP-positive nerve fibers in AD lesions was far less than one-tenth of the number of PGP-positive nerve fibers.