Kazumoto Katagiri

Increased levels of IL-13 mRNA, but not IL-4 mRNA, are found in vivo in peripheral blood mononuclear cells (PBMC) of patients with atopic dermatitis (AD)

Previous studies using in vitro systems with various stimuli have shown that PBMC from patients with AD show increased levels of IL‐4 but decreased levels of interferon‐gamma (IFN‐γ) compared with PBMC from normal controls. However, in vitro conditions do not always mimic the in vivo condition. We therefore believe that it is important to quantify the expression of these cytokines in freshly isolated PBMC. This study examines the expression of IFN‐γ, IL‐4 and IL‐13 mRNA in freshly isolated PBMC from adult patients with AD, from patients with psoriasis vulgaris and from healthy adults, using the semiquantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) method. Levels of IFN‐γ mRNA were significantly lower in PBMC of patients with AD than in controls. IL‐4 mRNA levels did not differ significantly between groups. Conversely, levels of mRNA for IL‐13 were significantly greater in PBMC of patients with AD than in controls. An increase in IL‐13 expression may regulate the in vivo synthesis of IgE in patients with AD.

Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signalling in peripheral blood mononuclear cells of patients with atopic dermatitis

Atopic dermatitis is characterized by Th2‐dominant immunity. Recently many intracellular molecules have been reported to regulate cytokine expression and T cell differentiation. GATA‐3 and T‐box expressed in T cells (T‐bet) are transcription factors that play a critical role in the development of Th2 and Th1 immunity, respectively. Suppressor of cytokine signalling (SOCS)‐3 and SOCS‐5, are negative regulators of the cytokine signalling induced by IL‐12 and IL‐4, respectively. Txk is a transcription factor that activates IFN‐γ gene directly. The present study was designed to identify intracellular molecules that are responsible for the pathogenesis and the imbalance of cytokines in atopic dermatitis. Semi‐quantitative RT‐PCR revealed that in peripheral blood mononuclear cells without any stimulation the levels of mRNA for GATA‐3 and SOCS‐3 were elevated, the levels of mRNA for Txk were depressed and the levels of mRNA for T‐bet and SOCS‐5 were comparable in patients with atopic dermatitis as compared with healthy controls. In addition, successful therapy normalized levels of mRNA for GATA‐3 and Txk, although those for the others including IL‐4, IL‐5, IL‐10, IL‐13 and IFN‐γ did not change. Levels of Txk mRNA correlated with those of IFN‐γ, while the mRNA levels of the other regulators did not correlate with those of any of the cytokines. These results suggest GATA‐3 and Txk might be involved in skin lesions, while SOCS‐3 might be associated with an imbalance of cytokines that is difficult to normalize in atopic dermatitis.

The Th2 cytokine, interleukin‐4, abrogates the cohesion of normal stratum corneum in mice: implications for pathogenesis of atopic dermatitis

There is mounting evidence that Th2 cytokines adversely affect skin barrier functions and contribute to the pathogenesis of atopic dermatitis (AD). AD is also characterized by abnormal cohesion in the stratum corneum (SC). However, the contribution of Th2 cytokines to this abnormality remains unknown. This study examined the effects of IL‐4, a prototypic Th2 cytokine, on the cohesion of the SC. Structural and physiological assessments revealed that repeated intradermal injections of IL‐4 compromised the cohesion of the SC of normal hairless mice. Two potential mechanisms were explored to account for the altered cohesion. First, IL‐4 decreased the amount of corneodesmosomes and down‐regulated the expression of desmoglein 1, but not of corneodesmosin (CDSN) or loricrin expression, in murine skin and in cultured human keratinocytes (KC). IL‐4 did not affect the skin surface pH, and in situ zymography revealed no net change in total serine protease activity in the IL‐4‐treated SC. Yet, IL‐4 enhanced expression of kallikrein (KLK)7, while simultaneously down‐regulating KLK5 and KLK14. Finally, IL‐4 did not alter the expression of the lympho‐epithelial Kazal‐type inhibitor (LEKTI) in KC. This study suggests that IL‐4 abrogates the cohesion of SC primarily by reducing epidermal differentiation.

Increased levels in vivo of mRNAs for IL-8 and macrophage inflammatory protein-1α (MIP-1α), but not of RANTES mRNA in peripheral blood mononuclear cells of patients with atopic dermatitis (AD)

Chemokines play an important role in the selective movement of leucocytes into inflammatory areas and they also activate various cells in inflamed tissues. However, it is unclear which cells are the main sources of chemokines in actual inflammatory diseases, even though both mononuclear cells and non‐inflammatory resident cells are able to produce chemokines in vitro and the former cells are also the main target of chemokines. To clarify the roles of chemokines that are produced by mononuclear cells in AD, we measured levels in vivo of mRNA for IL‐8 and MIP‐1α, as well as the level of regulated upon activation normal T cell expressed and secreted (RANTES) mRNA in freshly isolated peripheral blood mononuclear cells from patients with AD. We compared the results with those from psoriatic patients, and patients without AD who were suffering from other cutaneous diseases and eosinophilia. Levels of mRNAs were determined by semiquantitative reverse transcriptase‐polymerase chain reactions. Levels of IL‐8 and MIP‐1α mRNA were elevated not only in atopic patients but also in non‐atopic patients with inflammatory skin disease associated with eosinophilia, compared with levels in psoriatic patients and healthy controls. Levels of RANTES mRNA were similar in atopic patients but they were lower in the other two groups of patients when compared with levels in healthy controls. In atopic patients, the levels of both IL‐8 and MIP‐1α mRNAs but not of RANTES mRNA decreased with improvements in symptom scores after therapy. These findings suggest that mononuclear cells are not only the target of chemokines but might also play an important role in the pathogenesis of AD by producing IL‐8 and MIP‐1α.

Perineural and Neural Involvement in Skin Cancers

BACKGROUND Malignant skin tumors rarely spread along nerves. Complete resection of involved nerves is often unsuccessful. OBJECTIVE In the treatment of tumors with perineural invasion, surgeons should accurately estimate the extent of distant spread. METHODS We report six cases of skin cancers, including two basal cell carcinomas, two squamous cell carcinomas, and two neurotropic malignant melanomas, that invaded nerve or perineural spaces. RESULTS In three of the cases, the tumors developed on the face and involved the infraorbital nerves or its branches. Two patients suffered from tumors on aid burn scars of lower legs. Branches of posttibal nerves were involved in both cases. In the last case, tumor invasion of a branch of the greater occipital nerve was detected. CONCLUSION The extent of surgical excision should include the area of skin supplied by the affected nerve, which must be resected in continuity.

Efficacy of Combined Peroxisome Proliferator-Activated Receptor-α Ligand and Glucocorticoid Therapy in a Murine Model of Atopic Dermatitis

Although topical glucocorticoids (GCs) display potent anti-inflammatory activity in inflamed skin, they also can exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-α (PPARα) not only reduce inflammation, and also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPARα) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone)-induced, murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced: i) epidermal thinning; ii) reduced expression of involucrin, loricrin and filaggrin; and iii) allowed outside-to-inside penetration of an epicutaneous tracer. While Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical applications of Wy14643 after GC was not only significantly effective comparable to GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPARα ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD.

In vivo levels of IL-4, IL-10, TGF-β1 and IFN-γ mRNA of the peripheral blood mononuclear cells in patients with alopecia areata in comparison to those in patients with atopic dermatitis

Alopecia areata (AA) has been considered to be supported by an aberrant expression of IFN-γ as a result of antigen dependent immune response. On the other hand, AA sometimes concurs with atopic diseases, although the mechanism of the concurrence is not clear. This study was designed to elucidate the immune status of AA and the similarity between AA and atopic dermatitis (AD) by analysis of in vivo levels of mRNA of Th1, Th2, and suppressive cytokines of peripheral blood mononuclear cells (PBMC). Using semiquantitative RT-PCR, the levels of cytokine mRNA were measured in freshly isolated PBMC of 47 patients with AA, 15 patients with AD, and 12 healthy controls (HC). The levels of IL-4, IFN-γ, and TGF-β1 mRNA were lower in patients with AA than those in HC. The levels of IL-10 mRNA in AA were comparable with those in HC. Decreased levels of IFN–γ and TGF-β1 were also shown in patients with AD. These results indicated a similarity (decreased levels of IFN-γ and TGF-β1) between AD and AA based on the cytokine profile. In addition, decreased levels of IL-4 mRNA in AA might also explain the experience that the severity of atopic disease coincident with AA is mild in the most of cases. Next, we compared the levels of these cytokine mRNA among the three subgroups of AA that were categorized based on the severity of the symptoms: mild, severe and totalis. Although there was no significant difference between any combinations of the subgroups, there was a tendency to increase the levels of IFN-γ mRNA and to decrease the levels of IL-4 mRNA according to the severity of alopecia. However, the levels of IFN-γ mRNA in any subgroups were less than those of HC. These results suggest that IFN-γ is therefore involved in the pathogenesis of AA, although the information from PBMC is limited. In conclusion, AA might be induced by an aberrant expression of IFN-γ in individuals whose PBMC produce low amounts of IFN-γ and TGF-β1. Further analysis is therefore required to investigate the phenotypes of the population in PBMC with or without reference to regulatory T cells.

An outbreak of hand-foot-and-mouth disease mimicking chicken pox, with a frequent association of onychomadesis in Japan in 2009: A new phenotype caused by coxsackievirus A6

Hand-foot-and-mouth disease (HFMD) is primarily caused by coxsackievirus (CV) A16 and enterovirus 71 [1], whereas sporadic outbreaks have been caused by other viruses [2]. CVA6 is known to be a major pathogen of herpangina [3] and an outbreak of CVA6-associated HFMD followed by onychomadesis was reported in Finland in 2008 [4].We experienced an outbreak of HFMD with a new phenotype (N-HFMD; 133 patients; 52.4%, 79 males and 54 females) mimicking chicken pox and an outbreak of the common type (C-HFMD; [...]

Paraneoplastic pemphigus associated with corneal perforation and cutaneous alternariosis: A case report and review of cases treated with rituximab

Hisashi KOKUBA, Masakazu TAKAHARA, Bungo OHYAMA, Takashi HASHIMOTO, Masutaka FURUE Department of Dermatology, Hiroshima Red Cross Hospital, Atomic-bomb Survivors Hospital, Hiroshima, Department of Dermatology, Kyushu Central Hospital, Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, and Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan

Drug Induced Acute Generalized Exanthematous Pustulosis

A 62‐year‐old woman with diabetic triopathy developed widespread erythematous macules, numerous pustules, and a high fever after she underwent electric coagulation for vitreous hemorrhage. She was administered several drugs at that time. After discontinuation of the drugs, the eruption disappeared, and the fever returned to normal within two weeks. A positive patch test with isepamicin sulfate highly suggested that the symptoms described above were due to drug allergy. Cadralazine, which was positive in the drug lymphocyte stimulation test (DLST), could not be excluded from the causative drugs. A false‐positive DLST with ofloxacin was confirmed by an accidental challenge test. To our knowledge, this is the first report of acute generalized exanthematous pustulosis due to isepamicin sulfate and/or cadralazine.