Basophils infiltrate into skin lesions more commonly than previously thought, and thus they may play important roles in a variety of inflammatory skin diseases.

PGD2 plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35–55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD2-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.

Acquired idiopathic generalized anhidrosis (AIGA) is characterized by an acquired impairment in total body sweating despite exposure to heat or exercise. Severe cases may result in heatstroke. Most cases of AIGA have been reported in Asia, especially in Japan. However, there is limited information on the epidemiology of this condition, and no diagnostic criteria or appropriate treatment options have been established. This guideline was developed to fill this gap. It contains information on the etiology, diagnosis, evaluation of disease severity and evidencebased recommendations for the treatment of AIGA. Appropriate treatment according to disease severity may relieve the clinical manifestations and emotional distress experienced by patients with AIGA.

Contact hypersensitivity (CHS) is thought to be mainly associated with the activation of T helper type 1 (Th1) cells. However, there is also evidence that Th2 cells or Th2 cytokines play a role in the development of CHS. To analyze the functional contribution of Th2 cytokines interleukin (IL)-4 and IL-13, signal transducer and activator of transcription 6 (STAT6)-deficient (STAT6−/−) and wild-type (wt) control C57BL/6 mice were contact sensitized with 5% 2,4,6-trinitrochlorobenzene (TNCB), 0.5% 2,4-dinitrofluorobenzene, or 5% 4-ethoxyl methylene-2-phenyl-2-oxazolin-5-one, and any skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6−/− mice compared with wt mice.A histological analysis revealed that the infiltration of both eosinophils and neutrophils in the skin challenged after 24 h in STAT6−/− mice decreased substantially compared with that in wt mice. The expression of Th2 cytokines (IL-4, IL-5) in TNCB-challenged skin tissues and the supernatants from T cells stimulated by 2,4,6-trinitrobenzene sulfonate–modified spleen cells, as well as the immunoglobulin (Ig)E and IgG1 response after challenge, were also profoundly reduced in STAT6−/− mice, whereas the expression of interferon γ was the same in STAT6−/− and wt mice after challenge. Furthermore, adoptive transfer experiments revealed that STAT6−/− mice induced CHS after injection of lymph node cells obtained from sensitized wt mice. Our data suggest that the STAT6 signal plays a critical role in the induction phase of CHS.

Rationale: The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear. Objective: Here, we examined the hypothesis that phosphorylation of iabetes mellitus not only accelerates atherosclerosis of the coronary artery but also induces functional and structural abnormalities in the myocardium. In addition, recent studies have shown that myocardial response to ischemic preconditioning (IPC) and its mimetics is blunted or lost in diabetic hearts. 1-3 Protection afforded by IPC is triggered by activation of G protein-coupled receptors 5 and impaired activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) in models of diabetes mellitus have been reported. 1-3 Our recent study 3 showed impaired activation of Jak2 and endoplasmic reticulum (ER) stress-mediated disruption of signaling from ERK to glycogen synthase kinase (GSK)-3␤ in diabetic hearts. However, the mechanism by which Jak2-mediated signaling is disabled in diabetic hearts remains unclear. In the present study, we tested the hypothesis that Jak2-mediated protection is impaired in diabetic myocardium by an angiotensin II type 1 (AT 1 ) receptor-mediated mechanism via upregulation of SOCS3 (suppressor of cytokine signaling 3)-Jak2 interaction or calcineurin. MethodsMale Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, which spontaneously develop obesity and type 2 diabetes, and their controls (Long-Evans-Tokushima-Otsuka [LETO] rats) were used. Preparation of myocardial infarction, immunoblotting, quantitative real-time RT-PCR, calcineurin activity assay, and determination of insulin sensitivity were performed by standard methods (see the expanded Methods section in the Online Data Supplement, available at

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Abbreviations: Ab, antibody; AD, atopic dermatitis; Ag, antigen; Arg1, arginase 1; CCR4, C-C chemokine receptor type 4; CD, cluster of differentiation; CXCR3, C-X-C chemokine receptor type 3; ELISA, enzyme-linked immunosorbent assay; IENFD, intraepidermal nerve fiber density; Ig, immunoglobulin; IL, interleukin; IL-7Rα, IL-7 receptor α; iNOS, inducible nitric oxide synthase; OSMRβ, oncostatin M receptor β; PAR-2, protease-activated receptor 2; PGP9.5, protein gene product 9.5; pM, peritoneal macrophages; TARC, thymus and activationregulated chemokine; TSLP, thymic stromal lymphopoietin; TSLPR, thymic stromal lymphopoietin receptor. Abstract Background: Scabies is a common contagious skin disease caused by an infestation of the skin by Sarcoptes scabiei var. hominis. A hallmark symptom of scabies is severe itch. Methods: We sought to determine the generation of a pruritogenic cytokine, interleukin (IL)-31, together with immune profiles in skin lesions of ordinary scabies through immunohistochemical and immunofluorescent studies. To elucidate the pathological mechanisms of IL-31 generation, murine peritoneal macrophages were stimulated with various T helper 2 (Th2) cytokines and proteins ex vivo. Results: A large number of CCR4(+) Th2 cells, eosinophils, and basophils infiltrated in scabies lesions. Increased generation of IL-31, thymic stromal lymphopoietin (TSLP), and periostin was also observed. A major population of IL-31(+) cells were Arginase-1(+)/CD163(+) M2 macrophages. Murine peritoneal macrophages showed an M2 phenotype and generated IL-31 when stimulated with TSLP and periostin.Conclusion: IL-31 appeared to be largely generated by M2 macrophages in ordinary scabies lesions. This IL-31 induction was mediated by TSLP and periostin. K E Y W O R D SIL-31, macrophage, periostin, scabies, thymic stromal lymphopoietin

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