Search

Atopic dermatitis(AD) is a common allergic skin disease, characterized by a complex, heterogeneous pathogenesis, including non-allergic factors (skin barrier dysfunctions), and allergic factors. Recently, the skin barrier dysfunction induced by the filaggrin gene mutation has been demonstrated the most important factors, however, there are close interaction between non-allergic factors and allergic factors. The barrier dysfunction shifts Th1 to Th2 response. On the other hand, Th2 cytokines decrease filaggrin expressions by keratinocytes. In this review, I demonstrate the highly complex interplay among skin barrier abnormality and immune dysregulation in the pathogenesis of AD.

It is reported that antimycotic agents are effective for the treatment of patients with atopic dermatitis (AD). We studied in vitro effects of antimycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from AD patients and normal donors. The amounts of interleukin-4 (IL-4) and IL-5 secreted by anti-CD3/CD28-stimulated T cells were higher in AD patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole and non-azole terbinafine hydrochloride and tolnaftate reduced IL-4 and IL-5 secretion without altering that of IFN-gamma and IL-2 in anti-CD3/CD28-stimulated T cells from both AD patients and normal donors. The azole derivatives were more inhibitory than non-azole antimycotics. These antimycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for IL-4 and IL-5. The cAMP analogue dibutyryl cAMP reversed the inhibitory effects of the antimycotics on IL-4 and IL-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular cAMP in T cells, and the increase was greater in AD patients than in normal donors. The increase of cAMP by anti-CD3/CD28 correlated with IL-4 and IL-5 secretion by anti-CD3/CD28. The transient cAMP increase was suppressed by antimycotics, and azole derivatives were more suppressive than non-azoles. Azole derivatives inhibited the activity of cAMP-synthesizing adenylate cyclase while terbinafine hydrochloride and tolnaftate enhanced the activity of cAMP-hydrolyzing cyclic nucleotide phosphodiesterase in AD and normal T cells. These results suggest that the antimycotics may suppress IL-4 and IL-5 production by reducing cAMP signal, and strengthen the concept of their potential use for the suppression of T helper-2-mediated allergic reactions.

To elucidate the active process of eosinophil infiltration in atopic dermatitis (AD), we performed patch testing using crude mite allergens on normal-appearing skin in adult AD patients with high levels of mite-specific IgE antibodies and analyzed positive reaction sites chronologically by histological and immunohistological methods. Positive reactions were observed in 6 out of 9 AD patients (66.7%), whereas none of 7 non-AD control subjects showed positive reactions. Skin biopsies were obtained from positive reaction sites at 2,6,12,24 and 48 hours after allergen challenge. Eosinophils were seen within postcapillary venules at 2 hours, followed by increased perivascular eosinophil infiltration at 6 hours which peaked at 24 and 48 hours. Epidermal eosinophilic spongiosis was also observed at 48 hours. The majority of infiltrating eosinophils showed positive reactions for BMK-13 and 15-59% of them were EG2 positive activated eosinophils. BMK-13, EG2 and anti-EP positive reactions were scattered throughout connective tissue and their areas were time-dependently increased. These findings suggest that eosinophil transmigration and activation play an important role in initiating early AD lesions induced by transepidermal mite allergen permeation.