Koji Habe

Human Mast Cell Chymase Cleaves Pro-IL-18 and Generates a Novel and Biologically Active IL-18 Fragment

Increased release of IL-18 in the skin causes atopic dermatitis (AD)-like skin lesions, suggesting a role of IL-18 in the pathogenesis of AD. Caspase-1 is a well-known activator of IL-18, but caspase-1 knockout mice still have biologically active IL-18. Normal human keratinocyte constitutively produces pro-IL-18, but it is unable to activate it, suggesting the existence of an alternative pathway for IL-18 in the skin. Dermal accumulation of mast cells is commonly observed in AD patients and in experimental mouse models of AD. Connective tissue mast cells contain high amounts of chymase and tryptase in their cytoplasmic granules. In the present study, we demonstrated that activation of IL-18 is a novel function of human mast cell chymase. Human mast cell chymase rapidly cleaves recombinant pro-IL-18 at 56-phenylalanine and produces a biologically active IL-18 fragment that is smaller than any other reported IL-18-derived species. The human mast cell chymase and the novel IL-18-derived active peptide may be novel therapeutic targets in AD- and IL-18-associated diseases

Plasma ADAMTS13, von Willebrand factor (VWF) and VWF propeptide profiles in patients with DIC and related diseases.

ADAMTS13, endothelial von Willebrand factor (VWF) and related proteins are involved in the pathogenesis of some life threatening systemic thrombotic coagulopathies. Changes of plasma ADAMTS13 activity in thrombotic thrombocytopenic purpura (TTP) is well known but is also involved in septic disseminated intravascular coagulation (DIC). Here we investigated the ADAMTS13 activity, VWF and VWF propeptide (VWFpp) antigens in 69 patients with DIC, 143 with non-DIC, 21 with thrombotic thrombocytopenic purpura (TTP) and 23 with atypical hemolytic uremic syndrome (aHUS) for diagnosis of DIC. The plasma ADAMTS13 activity was significantly low in patients with DIC, and the plasma levels of VWF and VWFpp antigens, were the highest in these patients, but there were no significant differences in the plasma VWFpp levels between the patients with DIC and those with aHUS. The difference in the plasma ADAMTS13 activity, the VWF and VWFpp antigens between DIC and non-DIC cases was significant in those with infectious and malignant diseases, but the difference in the VWFpp/ VWF ratio were significant only in subjects with infectious diseases. As an indicator for prognosis, the plasma levels of VWFpp were significantly higher in non-survivors than in survivors. Then, VWFpp/ VWF ratio and VWFpp/ADAMATS13 ratio will be potent informative indicators in DIC. These findings suggest that ADAMTS13/VWF profiles may have important roles in the pathogenesis of DIC, and that ADAMTS13 and VWFpp are useful indicators for the diagnosis and prognosis of DIC.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

BACKGROUND Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Relapse of Dermatomyositis after 10 Years in Remission Following Curative Surgical Treatment of Lung Cancer

A 55‐year‐old woman with dermatomyositis and small cell lung cancer was successfully treated with surgery followed by combination chemotherapy in 1987. She had been in remission without further immunosuppressive therapy for 10 years. However, myositis with cutaneous manifestations specific for dermatomyositis relapsed when the patient was 69 years old. Intensive examinations revealed no neoplasm, and she responded to a moderate dose of systemic corticosteroids. This case suggests a long‐lasting autoimmune abnormality in dermatomyositis and that a neoplasm is an important factor in eliciting an occult dermatomyositis.

Presence of Antiphospholipid Antibodies as a Risk Factor for Thrombotic Events in Patients with Connective Tissue Diseases and Idiopathic Thrombocytopenic Purpura

OBJECTIVE Antiphospholipid syndrome (APS) is a well-known complication of habitual abortion and/or thrombosis and is frequently associated with autoimmune diseases. METHODS We retrospectively investigated the relationships between the presence of antiphospholipid antibodies (aPLs) and the incidence of thrombotic events (THEs) in 147 patients with various connective tissue diseases (CTD) suspected of having APS and 86 patients with idiopathic thrombocytopenic purpura (ITP). THEs were observed in 41 patients, including 14 cases of venous thrombosis, 21 cases of arterial thrombosis and eight cases of complications of pregnancy. RESULTS The prevalence of THE was significantly high in the systemic lupus erythematosus (SLE) patients compared with the other CTD patients and ITP patients. The frequency of lupus anticoagulant (LA), anticardiolipin antibodies (aCL)-β2-glycoprotein (GPI) complex IgG and aPL was significantly high in the SLE patients compared with the ITP patients. Subsequently, the rate of development of THE was significantly high in the patients with aPLs. In particular, the incidence of THE was significantly high in the SLE or ITP patients with LA, aCL-β2GPI IgG or aPL. The optimal cut-off values for LA, aCL IgG and aCL-β2GPI complex IgG for the risk of THEs were higher in the SLE patients in comparison to the values obtained when using the kit provided by the manufacturer. CONCLUSION Although aPLs is frequently associated with SLE and is a causative factor for thrombosis, the optimal cut-off value for aPL for predicting the occurrence of THEs varies among different underlying diseases.

Complete remission of advanced extramammary Paget's disease treated with docetaxel: a case report.

reported; however, its effects on metastatic tumours are limited. Interestingly, we found an increase in antitumour cytokine levels in PBMCs, which indicates a similar activation of the immunocytes as seen in the injected lesion. The locally administered BRM successfully augmented the systemic antitumour immune responses. It is likely that the induced cytokines contribute in part to control of local and distant metastasis. Of course, this single case result cannot be generalized, but this patient has survived for 5 years without distant metastasis, with a high quality of life. In conclusion, we found that intratumoral administration of OK-432 had a beneficial effect on SCC metastases, with systemic IFN-c and TNF-a production. Intratumoral injection of OK-432 could be a potent therapeutic candidate for patients with advanced cancer.

Magnetic resonance (MR) imaging‐induced deep second‐degree burns of lower extremities by conducting loop

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Presence of antiphospholipid antibody is a risk factor in thrombotic events in patients with antiphospholipid syndrome or relevant diseases

Antiphospholipid antibodies (aPL) including lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG and aCL-β2-glycoprotein I (β2GPI) complex IG are causative factors for thrombotic event (THE). We retrospectively investigated relationships between aPLs and THE in 458 patients suspected of having antiphospholipid syndrome. THEs were observed in 232 of 458 patients, including 148 cases of venous thrombosis, 59 of arterial thrombosis, 18 of microthrombosis, and 20 of complications of pregnancy. The frequency of THE was significantly high in patients positive for LA and/or aPL. In patients with autoimmune disease (AID), the frequency of THE was significantly high in patients with any types of aPLs. Additionally, risk of THE was significantly increased in patients with more than two types of aPLs. Prolonged activated partial thromboplastin time indicated a high risk for THE. However, neither thrombocytopenia nor AID was a risk for THE. In conclusion, the presence of aPL is an indicator for high risk of THE in patients in whom THE was suspected. However, the risk of THE in aPL-positive patients varied among patients with different underlying diseases.

Neutrophils are not the dominant interleukin-17 producer in psoriasis

Dear Editor, In the psoriasis field, the blockade of interleukin (IL)-17A and its receptor by specific monoclonal antibodies shows dramatic improvement of skin and joint symptoms. However, the main source of IL-17 in psoriasis is still controversial. Neutrophils have been suggested as a major producer of IL-17 as well as T-helper (Th)17, cd T cells, mast cells and, recently, the focus has been on innate lymphoid cell 3 (ILC3). Histopathologically, neutrophils are the dominant skin infiltrating immune cells, but IL-17 production from neutrophils is still a topic of debate. IL-17 immunoreactive neutrophils are detectable in the psoriatic skin lesions as well as in the peripheral blood by histopathological and flow cytometric analysis, which is explained by extracellular trap formation. IL-17 mRNA expression from neutrophils was undetectable by reverse transcription polymerase chain reaction (RT–PCR) in a report, but was slightly detectable in severe psoriasis patients in another report (M. J. Kaplan, unpubl. obs.). Is there a technical issue to address this inconsistency? In the current study, venous blood was drawn after obtaining written informed consent from all subjects, and the investigational protocol was approved by the institutional review board of Mie University Hospital (#2870). This unpublished data is quoted from the Journal of Allergy and Clinical Immunology: “Although our Western blot and

A Case of a Large Dermatofibrosarcoma Protuberans Successfully Treated with Radiofrequency Ablation and Transcatheter Arterial Embolization

We present a large dermatofibrosarcoma protuberans on a 52 years‐old womans back that was successfully treated with transcatheter arterial embolization and radiofrequency ablation. The tumor developed on her back at the age of 14. Surgical treatment was not complete, and it relapsed at age 17 and again at age 24. The tumor enlarged to over 20 × 20 × 10 cm and flooded intermittently. The tumor cells with atypical nuclei were CD34 positive and proliferated in a storiform pattern. These findings were compatible with dermatofibrosarcoma protuberans. She was treated with blood transfusion for severe anemia. Two large feeding arteries were embolized, and the bottom of the tumor was treated with radiofrequency ablation. The tumor reduced in volume by more than 50%. It was then surgically removed and reconstructed with a free mesh skin graft. The combination pretreatment enabled radical resections of a large DFSP without severe complications.