Therefore, the decreased expression of APRIL and TWE-PRIL together with the increased BAFF expression in eczema skin could contribute to a reduced negative regulatory input on B-cells, which is more pronounced in the initiating acute stage of AE, resulting in dysregulation of over-activated B-cells in lesional skin of AE and SE. Our data of the down-regulation of APRIL and the up-regulation of BAFF in the eczema skin of AE and SE is also important for guiding potential clinical treatment. When targeting BAFF and APRIL in the therapy for AE and SE, the PR-171 agents neutralizing only BAFF but having no effect on APRIL might be more suitable than those targeting both BAFF and APRIL. The up-regulation of IL-18 in suprabasal keratinocytes in skin lesions has been described in psoriasis. Here we report that this phenomenon is also present in APT-AE, AE and SE. Indeed, IL-18 has been shown to play a harmful effect to enhance inflammation in several autoimmune and inflammatory diseases. Since B-cells are known to lack the expression of the IL-18 receptor, the effect of IL-18 on B-cell related activation has not been well studied. We suggest that there might be a direct or indirect interplay between IL-18 and BAFF/APRIL in AE, since the mRNA level of BAFF/APRIL correlates with that of IL-18 in lesional skin of AE and APT-AE. A connection between these factors is supported by a mouse model where daily i.p. injections of IL-18 for 10 days induce production of both IgE and BAFF. Furthermore, we demonstrated that although IL-18 itself had no direct effect on the regulation of BAFF and APRIL production in cultured keratinocytes, IFN-c dramatically increased the BAFF mRNA level in these cells. Since IL-18 is known to be a powerful stimulator of IFN-c production, we therefore suggest that IL18 could be produced locally by inflammatory cells and indirectly regulate the production of BAFF and APRIL in keratinocytes through IFN-c. Elevated serum levels of TWEAK have been found in patients with chronic inflammatory diseases and been suggested to be playing either a protective or harmful role. For example, in systemic sclerosis where TWEAK is associated with a low frequency of pulmonary fibrosis and in rheumatoid arthritis where the levels of TWEAK reflect disease activity. In our patient cohort, we found no difference in the serum level of TWEAK in patients with AE or SE compared with HCs. This is in agreement with a recent study, where the serum level of TWEAK was reported to be similar among patients with AE or psoriasis and HCs. Thus, unlike other chronic inflammatory diseases, increased level of TWEAK is not a candidate for a systemic role in the pathogenesis of AE and SE. Zimmermann et al also found that the TWEAK mRNA expression in healthy keratinocytes was not influenced by various eczema related stimuli in agreement with our results.