Bungo Ohyama

Kurume University, Куруме, Fukuoka, Japan

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Publications (56)170.42 Total impact

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    ABSTRACT: Despite established pathogenic role of anti-desmoglein (Dsg) antibodies in classical pemphigus, significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc), is at present unknown. No consistent immunoassay for IgG autoantibodies to Dscs has been developed. The aim of this study was to develop reliable assays to detect anti-Dsc autoantibodies. We expressed soluble recombinant proteins of human Dsc1-Dsc3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus sera, by novel enzyme-linked immunosorbent assays (ELISAs) using the recombinant proteins. We also performed ELISAs of Dsc baculoproteins and cDNA transfection method, and compared the results with those of mammalian ELISAs. By mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16.5%, 36.7% and 59.5% of paraneoplastic pemphigus sera, respectively, and considerable numbers of pemphigus herpetiformis and pemphigus vegetans sera strongly reacted with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or cDNA transfection method. Several Dsc-positive sera, particularly pemphigus herpetiformis sera, showed no reactivity with Dsgs. Reactivity of a paraneoplastic pemhigus serum and a pemphigus vegetans serum with Dscs was not abolished by pre-absorption with Dsg receombinant proteins. The results of these novel ELISAs indicated that IgG anti-Dsc autoantibodies were frequently detected and potentially pathogenic in non-classical pemphigus. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 02/2015; DOI:10.1111/bjd.13711 · 4.10 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are potentially useful for treatment of skin diseases, because they stimulate keratinocyte differentiation, exert anti-inflammatory effects and improve barrier function. We examined five PPAR-γ agonists, including four thiazolidinediones (ciglitazone, troglitazone, rosiglitazone and pioglitazone) and an angiotensin-II receptor blocker (telmisartan), for their ability to up-regulate filaggrin and loricrin expression at both mRNA and protein levels in cultured normal human keratinocytes (NHKs). Troglitazone, rosiglitazone, pioglitazone and telmisartan significantly increased filaggrin expression at both mRNA and protein levels in calcium-induced differentiated NHKs. Rosiglitazone and pioglitazone, but not troglitazone nor telmisartan, also significantly increased loricrin expression at both mRNA and protein levels in differentiated NHKs. These effects were not found in undifferentiated NHKs nor differentiated NHKs treated with ciglitazone. This study revealed differential effects of various PPAR-γ agonists on epidermal differentiation, and the most potent of those are rosiglitazone and pioglitazone.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 10/2014; 24(1). DOI:10.1111/exd.12571 · 4.12 Impact Factor
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    ABSTRACT: Abstract Background: Adalimumab is an anti-tumor necrosis factor-? agent, and is widely used to treat moderate to severe psoriasis in Japan. The drug survival rate of adalimumab is shorter than that of other biological agents used for psoriatic patients in Europe. Objective: To study the long-term drug survival rate of adalimumab used for Japanese psoriatic patients. Methods: We studied 36 patients with moderate to severe psoriasis for whom adalimumab was administered between February 2010 and April 2013. Results: Thirty three patients had psoriasis vulgaris, and 3 patients had psoriatic arthritis. At the end of the observational period, 16 patients continued adalimumab therapy, while 20 patients discontinued. Six patients had adverse events, and 14 patients self-injected adalimumab. The mean probability of drug survival was 20.0 months (median, 18 months); it was shorter than the previously reported data from European countries. Gender, age, and the Psoriasis Area and Severity Index at baseline were not significant predictors of drug survival rates. Frequent visits for biweekly adalimumab injections were a burden for 40% of drop-out patients. Conclusion: The shorter drug survival rate of adalimumab in the present study may be attributed to the lower rate of self-injection than that in European patients.
    Journal of Dermatological Treatment 09/2014; DOI:10.3109/09546634.2014.962470 · 1.76 Impact Factor
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    ABSTRACT: Background: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two blistering skin diseases mediated by antibodies to desmoglein 3 (Dsg3) and/or Dsg1. Phenotypic transition from PV to PF is rarely reported. Objectives: To determine the immune response to extracellular (EC) domains of Dsgs during this transition. Materials and Methods: We report two PV patients who subsequently developed a PF phenotype. To map the conformational epitopes in these cases, we examined the reactivity of the sera of two patients by immunoprecipitation-immunoblotting analysis, using five Dsg1/Dsg3 domain-swapped molecules on a backbone of Dsg2. Results: Reactivity exclusively with the EC1 domain of Dsg1 was maintained in both PV and PF stages. No reactivity to Dsg3 in the PF stage was found in patient 1. Various changes in immunoreactivity to Dsg3 were found and the EC1 and EC2 domains of Dsg3 reacted weakly to serum taken at remission and PF stages in patient 2. Conclusions: Our findings suggest that amino-terminal pathogenic antibodies to the EC domain of Dsg1 were retained, while considerable epitope changes occurred in response to Dsg3 during the shift from PV to PF, with an absolute or significant decrease in pathogenic antibodies to the EC1 domain of Dsg3.
    04/2014; 24(2). DOI:10.1684/ejd.2014.2277
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    ABSTRACT: B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells and monocytes, BAFF expression on B-cells has not been well documented. In the present study, BAFF molecules on dendritic cells and naïve and memory B-cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, were analyzed by flow cytometry. Compared to healthy controls, BAFF expression on naïve and memory B-cells increased significantly in bullous pemphigoid. No difference in BAFF receptor expression in naïve and memory B-cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B-cells of bullous pemphigoid, but not healthy controls, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B-cells may play a pathogenic role in autoimmune bullous diseases, particularly bullous pemphigoid.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 04/2014; 23(8). DOI:10.1111/exd.12421 · 4.12 Impact Factor
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    ABSTRACT: We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrheic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein. Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 04/2014; 23(6). DOI:10.1111/exd.12418 · 4.12 Impact Factor
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    ABSTRACT: Drug-induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP. To characterize clinical and immunological profiles in DIP patients. We studied 17 Japanese DIP patients who were treated in Kurume University Hospital or consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence (IF), enzyme-linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analyzed. Eight of the 17 DIP patients showed pemphigus foliaceus-like appearance, three showed pemphigus herpetiformis-like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol-containing drugs in 16 patients (bucillamine in 9 cases, d-penicillamine in 4 case, and cetapril, thiopronine and captopril in one case each.), and non-thiol drug, azalfidine in one patient. By ELISAs and/or IB analyses, 9 patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, 4 patients with no detectable malignancy showed paraneoplastic pemphigus-like reactivity with the 210 kDa envoplakin and the 190 kDa periplakin. Four cases showed anti-Dsg3 antibodies without mucosal lesions. While 11 cases recovered by discontinuation of the causative drugs, six patients had very protracted or intractable disease course, who might develop true pemphigus. The present study indicated that the majority of the DIP cases studied showed pemphigus foliaceus-type phenotype with anti-Dsg1 autoantibodies, caused by thiol-containing drugs. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 03/2014; 171(3). DOI:10.1111/bjd.12925 · 4.10 Impact Factor
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    ABSTRACT: Abstract is missing (Short).
    Acta Dermato-Venereologica 01/2014; 94(5). DOI:10.2340/00015555-1776 · 4.24 Impact Factor
  • The Journal of Dermatology 10/2013; 40(11). DOI:10.1111/1346-8138.12261 · 2.35 Impact Factor
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    ABSTRACT: In this study, we report on the efficacy of combination therapy of second-generation antihistamine antagonist, fexofenadine hydrochloride, and leukotriene receptor inhibitor, montelukast sodium, for the treatment of 15 prurigo nodularis or pemphigoid nodularis patients, in whom conventional therapy was ineffective. All patients received 10 mg montelukast once a day and 240 mg fexofenadine twice a day for 4 weeks in addition to other medications they had been taking. We assessed the manifestations of the lesions and itching intensity before and after the therapy, and we evaluated each patient as (i) markedly improved, (ii) improved, (iii) slightly improved, (iv) no change, (v) worse. Two patients (13.3%) were evaluated as markedly improved, and the lesions of one patient completely disappeared. Three patients (20.0%) were evaluated as improved, and six patients (40.0%) as slightly improved. Thus, 11 of 15 cases (73.3%) improved by combination therapy of fexofenadine and montelukast, in which nine cases (75.0%) of prurigo nodularis and two cases (66.7%) of pemphigoid nodularis were involved. No patients revealed any side effects. This study revealed that combination therapy of fexofenadine and montelukast was effective for some patients with conventional therapy-resistant prurigo nodularis and pemphigoid nodularis.
    Dermatologic Therapy 09/2013; 27(3). DOI:10.1111/dth.12094 · 1.48 Impact Factor
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    ABSTRACT: IMPORTANCE Pemphigus vegetans shows clinically vegetating and/or pustular skin lesions mainly on the intertriginous areas and histopathologically neutrophilic and eosinophilic pustules in the epidermis. Pemphigus vegetans shows IgG reactivity mainly with desmoglein (Dsg) 3, but also with other autoantigens, including Dsg1 and desmocollins (Dscs). OBSERVATIONS We examined antigen profiles in 2 cases of pemphigus vegetans. (1) A women in her 80s presented with typical vegetating skin lesions on the right inguinal region with typical histopathological features. Immunoblotting using normal human epidermal extracts detected IgG antibodies to Dsg1 and Dscs. Enzyme-linked immunosorbent assays (ELISAs) revealed IgG antibodies to Dsg1 but not to Dsg3. Complementary DNA (cDNA) transfection method to COS-7 cells and novel ELISAs using eukaryotic recombinant proteins of human Dsc1, Dsc2, and Dsc3 confirmed specific IgG reactivity with Dsc3. (2) A women in her 70s presented with pustular skin lesions on the left fingers with typical histopathological features. Immunoblotting and ELISAs did not detect antibodies to either Dsg1 or Dsg3. Conversely, immunoblotting detected IgG antibodies to Dscs, cDNA transfection method revealed IgG reactivity only with Dsc3, and findings from ELISAs showed that IgG reacted weakly with Dsc2 and strongly with Dsc3. CONCLUSIONS AND RELEVANCE Autoantibodies to Dscs, particularly to Dsc3, may play a pathogenic role in some cases of pemphigus vegetans.
    08/2013; 149(10). DOI:10.1001/jamadermatol.2013.5244
  • 06/2013; 23(3). DOI:10.1684/ejd.2013.2026
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    ABSTRACT: Pemphigus is an autoimmune bullous disease showing intraepidermal blisters and IgG autoantibodies to desmogleins (Dsgs).(1) Dsg1 and Dsg3 are autoantigens for pemphigus foliaceus and mucosal-dominant type pemphigus vulgaris, respectively.(1) In addition, antibodies to desmocollins (Dscs), another group of desmosomal cadherin, are rarely detected in variants of pemphigus.(2-5) Dsc1 is autoantigen for subcorneal pustular dermatosis-type IgA pemphigus.(2) In addition, anti-Dsc antibodies were detected in some pemphigus cases with or without anti-Dsg autoantibodies.(3-5) This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 04/2013; DOI:10.1111/bjd.12398 · 4.10 Impact Factor
  • Journal of Dermatological Science 02/2013; 69(2):e11-e12. DOI:10.1016/j.jdermsci.2012.11.331 · 3.34 Impact Factor
  • 01/2013; 23(1). DOI:10.1684/ejd.2012.1891
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    ABSTRACT: Introduction: Desmoglein 3 (Dsg3) is one of desmosomal cadherins and functions in epidermal keratinocyte adhesion. IgG anti-Dsg3 autoantibodies are detected in pemphigus vulgaris, an autoimmune bullous disease showing blisters and erosions on the skin and oral mucosa. Other types of pemphigus also show anti-Dsg3 antibodies. Genetic disease of Dsg3 has not been reported. Areas covered: Many in vitro and in vivo studies have indicated pathogenic role of anti-Dsg3 antibodies. Blisters in pemphigus vulgaris are thought to be developed by loss of keratinocyte adhesions by binding of anti-Dsg3 antibodies to Dsg3 through steric hindrance, internalization of Dsg3, changes in molecular integrity or signal transduction. There are pathogenic and nonpathogenic anti-Dsg3 antibodies reactive with different epitopes. Recent studies of pemphigus vulgaris include existence of non-Dsg3 autoantibodies, B cells and T cells reactive with Dsg3, involvement of TNF-α and IL-1 and activation of intracellular signaling. Expert opinion: Although systemic corticosteroids and immunosuppressive agents are mainstays for treatment of pemphigus, intravenous immunoglobulin, plasmapheresis, immunoadsorption, rituximab and TNF-α inhibitors are emerging. Anti-Dsg3 antibody-targeting therapies are reported in mouse model, but they are not yet available clinically. Clarification of pathogenic role of anti-Dsg3 antibodies in pemphigus should provide us with safer and more effective therapies.
    Expert Opinion on Therapeutic Targets 01/2013; DOI:10.1517/14728222.2013.744823 · 4.90 Impact Factor
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    ABSTRACT: The patient was a 47-year-old female who presented with skin and oral mucosal lesions. Edematous erythema and pigmentation with crusts were observed on the sinciput, precordium and upper back, and gingival erosion and redness were seen in the oral cavity. Clinically, pemphigus vulgaris (PV) was suspected. However, blood examination results were positive for antidesmoglein 1 antibody, but negative for anti-Dsg 3 antibody. Histopathological examination and direct immunofluorescence microscopic observation revealed superficial vesicular formation and IgG and C3 deposits in the epithelial cell membranes. A diagnosis of pemphigus foliaceus (PF) was made. Regarding the gingival lesions, histopathological cleavage of the suprabasal cell layer was detected, and direct immunofluorescence microscopy found intercellular IgG and C3 deposits in almost the entire epithelial cell layer. These findings were compatible with PV. As there was a contradiction between the clinical features and laboratory data, we further performed immunoblotting analysis. Autoantibodies against periplakin and C-terminal of the 180-kDa bullous pemphigoid antigen (BP 180) were detected. However, these autoantibodies were not considered to pathogenic. We report a rare case of anti-Dsg 1 antibody-positive and anti-Dsg 3 negative pemphigus with oral mucosal lesions.
    01/2013; DOI:10.1016/j.ajoms.2013.10.004
  • 11/2012; 22(6). DOI:10.1684/ejd.2012.1858
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    ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.
    The Journal of clinical investigation 09/2012; 122(10):3781-90. DOI:10.1172/JCI64413 · 13.77 Impact Factor
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    ABSTRACT: Psoriasis greatly impacts the health-related quality of life of patients, including any dermatological conditions that are listed in the dermatology life quality index (DLQI). We investigated the relationships between DLQI and the degree of patient satisfaction using questionnaires among psoriasis patients treated only with topical corticosteroids. Patients who were dissatisfied with topical corticosteroids alone and agreed to receive cyclosporin were given low-dose oral cyclosporin. We assessed changes of the DLQI and the psoriasis area and severity index (PASI) scores in patients dissatisfied with treatment during the period of cyclosporin addition. Of 32 enrolled patients, 17 reported dissatisfaction with the current treatment of topical corticosteroids alone. There was a significantly positive correlation between the degree of patient satisfaction questionnaires and the DLQI of these 32 patients. Among the 17 dissatisfied patients, 12 patients agreed to receive additional cyclosporin therapy and five did not. The 12 patients who started on cyclosporin had a significantly lower PASI after 12 weeks than they did at baseline. The DLQI improved significantly after 12 weeks in the cyclosporin-treated patients. The 12 patients who agreed to receive cyclosporin showed a significantly lower DLQI at 12 weeks compared to the five patients who declined the addition of cyclosporin to their treatment. Assessing the degree of patient satisfaction with therapy using a questionnaire could be useful for improving clinical interventions in psoriasis patients. Low-dose oral cyclosporin could be effective in patients who are dissatisfied with topical corticosteroid treatment alone.
    Australasian Journal of Dermatology 08/2012; 53(3):202-6. DOI:10.1111/j.1440-0960.2011.00870.x · 0.98 Impact Factor

Publication Stats

275 Citations
170.42 Total Impact Points

Institutions

  • 2008–2014
    • Kurume University
      • Institute of Cutaneous Cell Biology
      Куруме, Fukuoka, Japan
  • 2010
    • Keio University
      Edo, Tōkyō, Japan
    • Shinshu University
      • Department of Dermatology
      Shonai, Nagano, Japan
  • 2009
    • Jichi Medical University
      Totigi, Tochigi, Japan