Risa Tamagawa-Mineoka

Increased serum levels of interleukin 33 in patients with atopic dermatitis

BACKGROUND Interleukin (IL)-33 is a new member of the IL-1 cytokine family and a promoter of T helper type 2 (Th2) inflammation. IL-33 may be involved in the pathogenesis of atopic dermatitis (AD), but its relationship with disease severity, laboratory markers, and eruption types in patients with AD are unclear. OBJECTIVE The aim of this study was to quantify serum IL-33 levels in patients with AD and to examine relationships with disease severity, laboratory markers, and eruption types. METHODS Serum IL-33 was measured by enzyme-linked immunosorbent assay in patients with AD, chronic idiopathic urticaria, and psoriasis and in healthy control subjects. RESULTS Serum levels of IL-33 were significantly higher in patients with AD compared with those in patients with urticaria and psoriasis and in healthy control subjects, and were correlated with the disease severity of AD. IL-33 levels were also significantly correlated with excoriation and xerosis scores, but not with blood eosinophilia, serum IgE, serum thymus and activation-related chemokine, and serum lactate dehydrogenase. Elevated IL-33 levels were significantly reduced after improvement of skin lesions by drug treatment. LIMITATION A limitation in the study was the small number of subjects. CONCLUSION Our results suggest that IL-33 released from mechanically injured or barrier-disrupted skin may increase inflammation in AD.

Platelet activation in patients with psoriasis: Increased plasma levels of platelet-derived microparticles and soluble P-selectin

BACKGROUND It has recently been established that platelets have an important role in increasing inflammation, in addition to their main role in hemostasis and thrombosis. An increased incidence of occlusive vascular disease has been reported in patients with psoriasis and the pathomechanism of psoriasis may involve platelet activation. OBJECTIVE The goal of the study was to establish a clearer explanation of the association between platelet activation and psoriasis activity by investigating the levels of markers of platelet activation in patients with psoriasis and examining the relationship between the marker levels and a severity score for psoriasis. METHODS Plasma levels of platelet-derived microparticles (PDMPs) and soluble P-selectin were measured by enzyme-linked immunosorbent assay as markers of platelet activation in 21 patients with psoriasis and 22 healthy control subjects. The relationships between the platelet activation markers and the Psoriasis Area and Severity Index score were investigated. RESULTS Plasma PDMPs and soluble P-selectin levels were markedly higher in patients with psoriasis compared with those in healthy control subjects. There was a significant correlation between the PDMPs levels and the Psoriasis Area and Severity Index score, and the increased plasma PDMPs and soluble P-selectin levels were markedly reduced after clinical improvement occurred. LIMITATIONS The number of people evaluated was relatively small. CONCLUSIONS Our results show that blood platelets are activated in patients with psoriasis, especially in those with extensive disease, and suggest a close association between platelet activation and psoriasis activity. Plasma PDMPs level may be a useful indicator of the severity of psoriasis.

Elevated Platelet Activation in Patients with Atopic Dermatitis and Psoriasis: Increased Plasma Levels of β-Thromboglobulin and Platelet Factor 4

BACKGROUND Beyond their role in hemostasis and thrombosis, platelets are important for modulating inflammatory reactions. Activated platelets play a role in the pathomechanism of inflammatory diseases such as asthma, but little is known about platelet activation in chronic skin inflammation, including atopic dermatitis (AD) and psoriasis. Furthermore, the relationship between platelet activation and disease severity is not understood. This work was performed to investigate plasma levels of β-thromboglobulin (β-TG) and platelet factor 4 (PF4) as platelet activation markers in patients with AD or psoriasis, and to determine the relationships between these markers and disease severity. METHODS Plasma levels of β-TG and PF4 were measured by enzyme-linked immunoassay in 22 healthy controls, 44 patients with AD, and 16 patients with psoriasis. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophilia, serum IgE and serum lactate dehydrogenase were investigated in AD patients, and relationships with the psoriasis area and severity index (PASI) score were examined in psoriatic patients. RESULTS Plasma β-TG and PF4 levels were significantly higher in patients with AD or psoriasis compared with healthy controls. β-TG and PF4 levels correlated with the SCORAD index, and PF4 levels correlated with PASI scores. Elevated β-TG and PF4 levels were significantly reduced after treatments. CONCLUSIONS Our results show that blood platelets are activated in patients with AD or psoriasis, suggesting that activated platelets play a role in the pathomechanism of chronic skin inflammation. Furthermore, plasma β-TG and PF4 may be markers for the severity of AD and psoriasis.

Effect of serotonin on the differentiation of human monocytes into dendritic cells

The local cytokine environment and presence of stimulatory signals determine whether monocytes acquire dendritic cell (DC) or macrophage characteristics and functions. Because enhanced platelet activation is reported in patients with many allergic disorders, such as atopic dermatitis, platelet‐derived factors may influence monocytic differentiation into DC. In this study we examined the effect of serotonin, a prototypic mediator of allergic inflammation released mainly by activated platelets at the inflammatory site, on the granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and interleukin (IL)‐4‐driven differentiation of monocytes into monocyte‐derived DC. Monocytes from healthy adult donors were cultured with GM‐CSF and IL‐4 in the presence or absence of serotonin, and the phenotypes and function of these cells were analysed. In the presence of serotonin, monocytes differentiated into DC with reduced expression of co‐stimulatory molecules and CD1a, whereas expression of CD14 was increased. These serotonin‐treated DC exhibited significantly reduced stimulatory activity toward allogeneic T cells. However, these cells showed enhanced cytokine‐producing capacity, including IL‐10 but not IL‐12. There was no significant difference between both types of DC in phagocytic activity. Experiments using agonists and antagonists indicated that serotonin 5‐hydroxytryptamine (5‐HT) induced the alteration of their phenotype and reduction in antigen‐presenting capacity were mediated via 5‐HTR1/7. It is therefore suggested that serotonin‐driven DC may have a regulatory function in the inflammatory process.

Platelets play important roles in the late phase of the immediate hypersensitivity reaction

BACKGROUND Recent studies have shown that platelets have a role in most inflammatory reactions, but involvement of platelets in the immediate hypersensitivity reaction (IHR) in skin has not been examined. OBJECTIVE To investigate the role of platelets in a mouse model of IgE-mediated IHR. METHODS Mice were sensitized by injecting ovalbumin intraperitoneally and challenged by injecting ovalbumin intradermally into ears, with or without platelet depletion. RESULTS Sensitized mice developed biphasic responses characterized by early-phase and late-phase reactions (LPRs). Degranulation of mast cells in skin did not differ between platelet-depleted mice and controls. The early phase reaction was not suppressed at 1 hour, but platelet depletion significantly reduced the LPR at 24 hours (P < .01). Flow cytometry showed that P-selectin expression on platelets and the number of platelet-leukocyte aggregates were both higher in the blood of ovalbumin-challenged mice compared with sham-sensitized mice at 24 hours (P < .05). In platelet-depleted mice, the LPR was restored by infusing platelets from normal mice (P < .01). This effect did not occur by infusing platelets from P-selectin-deficient mice or by pretreating platelets with anti-P-selectin antibody. Injection of activated platelet supernatant into ears led to increased leukocyte infiltration at 24 hours, and this effect was blocked by pretreating the supernatant with several antichemokine antibodies. Systemic administration of antiplatelet compounds also suppressed the LPR significantly. CONCLUSION These results show that platelets play important roles in the LPR of the IHR in skin by forming platelet-leukocyte complexes via P-selectin in blood and secreting several chemokines that attract leukocytes to skin.

DRESS syndrome caused by teicoplanin and vancomycin, associated with reactivation of human herpesvirus-6.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by high fever, facial edema, and maculopapular eruption, followed by lymphadenopathy, hypereosinophilia, atypical circulating lymphocytes, and multiorgan involvement. Recently, attention has been focused on the reactivation of human herpesvirus-6 (HHV-6) in DRESS syndrome. 1,2 Here, we describe a patient in whom fever, an eruption, and liver and renal dysfunction developed following teicoplanin and vancomycin, associated with reactivation of HHV-6.

Platelet-derived microparticles and soluble P-selectin as platelet activation markers in patients with atopic dermatitis☆

Plasma levels of platelet-derived microparticles (PDMPs) and soluble P-selectin (sP-selectin) were investigated as markers of platelet activation in 46 atopic dermatitis (AD) patients, 20 non-atopic urticaria patients and 22 healthy controls. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophil number, serum IgE, and serum lactate dehydrogenase were also investigated in AD patients. Plasma PDMPs and sP-selectin levels were significantly higher in AD patients compared with the other two groups. In multiple regression analysis, the SCORAD index was the most significant factor associated with the platelet activation markers. Among the SCORAD index components, excoriations were most closely related to the markers. The elevated levels of PDMPs and sP-selectin were significantly reduced following skin lesion improvement by drug treatment. Our results show that blood platelets are activated in AD patients upon aggravation of eruption, suggesting that activated platelets may be involved in the pathomechanism of AD.

Narrow‐band ultraviolet B phototherapy in patients with recalcitrant nodular prurigo

Management of nodular prurigo has been less than satisfactory. Conventional therapies such as systemic antihistamines and topical steroids have not been particularly successful. The effects of narrow‐band ultraviolet B (NB‐UVB) phototherapy in the treatment of various inflammatory dermatoses have been proven, however, no data exist on the efficacy and the duration of remission in NB‐UVB monotherapy for nodular prurigo. The aim of this study was to evaluate the effect of NB‐UVB phototherapy on recalcitrant nodular prurigo. NB‐UVB phototherapy was performed once a week on 10 patients with recalcitrant nodular prurigo. The initial dose was 0.4 J/cm2, and the dose was increased by 0.1 J/cm2 for each treatment. The treatment was performed until the eruption was almost clear. In each patient, a mean cumulative dose of 23.88 J/cm2 was applied over a mean of 24.3 irradiations. The mean maximum daily dose of ultraviolet B was 1.2 ± 0.4 J/cm2. NB‐UVB phototherapy notably improved the eruption of nodular prurigo in all patients. Follow up at 1 year revealed that only one patient had relapsed. The remaining nine patients continued to derive long‐term benefits. NB‐UVB phototherapy appears to be an effective treatment for recalcitrant nodular prurigo, offering long‐term benefits in the majority of those treated.

Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency

Background:Infants are vulnerable to zinc deficiency. Thus, abnormally low breast milk zinc levels cause transient neonatal zinc deficiency (TNZD) in breast-fed infants. TNZD has been considered to be rare because of a paucity of citations in the published literature. However, recent studies of affected mothers identified four missense mutations in the solute carrier family 30 member 2 gene (SLC30A2), which encodes the zinc transporter, ZnT2.Methods:Genetic analyses of SLC30A2/ZnT2 in three Japanese mothers secreting low-zinc milk (whose infants developed TNZD) were performed. The effects of identified mutations were examined in a cell-based assay. Furthermore, 31 single-nucleotide polymorphisms (SNPs) in SLC30A2/ZnT2 were evaluated for their potential involvement in low-zinc levels in milk.Results:Each mother had a different novel heterozygous mutation in SLC30A2/ZnT2. One mutation reduced splicing efficiency of the SLC30A2/ZnT2 transcript, and all ZnT2 mutants were defective in zinc transport and were unstable in cells. Moreover, four SNPs caused a significant loss of zinc-transport activity, similar to that in disease-causing ZnT2 mutants.Conclusion:Our results indicate that many SLC30A2/ZnT2 mutations cause or potentially cause TNZD. Genetic information concerning TNZD pathogenesis is limited, and our results suggest that the TNZD frequency may be higher than previously thought.

Toll-Like Receptor 3 Increases Allergic and Irritant Contact Dermatitis

There is increasing recognition of the role of Toll-like receptor 3 (TLR3) in noninfectious inflammatory diseases, but the function of TLR3 in inflammatory skin diseases is unclear. We investigated the functions of TLR3 in allergic and irritant contact dermatitis (ICD). The contact hypersensitivity (CHS) response was lower in Toll-like receptor 3 knockout (Tlr3 KO) mice, and was greater in TLR3 transgenic (Tg) mice than in wild-type (WT) mice after challenge with 2,4,6-trinitro-1-chlorobenzene. Adoptive transfer of immunized lymph node cells from Tlr3 KO mice induced CHS in WT recipients. In contrast, adoptive transfer of those from WT mice did not fully induce CHS in Tlr3 KO recipients. The ICD reaction following croton oil application was lower in Tlr3 KO mice, and was greater in TLR3 Tg mice than in WT mice. Maturation, migration, and antigen presentation of dendritic cells and proliferation of lymphocytes between WT mice and Tlr3 KO mice were comparable. These results show that TLR3 enhances antigen-independent skin inflammation in the elicitation phase of allergic contact dermatitis and in ICD.