論文 - 高橋　勇人

Attenuation of OX40 signaling suppression by age disrupts peripheral deletion of CD4⁺ T cells specific for the epidermal autoantigen desmoglein 3

Iriki H., Mukai M., Asahina Y., Kubo Y., Ito H., Amagai M., Takahashi H.

Immunity and Ageing （Immunity and Ageing）  20 （ 1 ） 26 2023年12月

査読有り,  ISSN  1742-4933

　概要を見る

Various autoimmune responses increase with age, but the underlying mechanism is not clear. In this study, we used CD4+ T cells expressing a transgenic T cell receptor specific for desmoglein 3 (Dsg3), which is the target antigen of the autoimmune bullous disease pemphigus vulgaris, to examine how peripheral immunological tolerance against pathogenic autoreactive CD4+ T cells changes with age. Dsg3-specific T cells were deleted within 14 days after adoptive transfer into young mice (8 weeks old), while they escaped deletion when transferred into older mice over 42 weeks old. Dsg3-specific T cells produced higher levels of the proinflammatory cytokine IFN-γ in aged mice than in young mice. In addition, the expression levels of both OX40 and Birc5, which are important for cell survival in T cell clonal proliferation, were higher in aged than in young mice. The dysfunction in suppressing proinflammatory cytokine secretion and Birc5 upregulation in Dsg3-specific autoreactive T cells may reflect an aspect of the preliminary steps in autoimmune disease development in the aged population. Understanding this mechanism may lead to better risk evaluation of autoimmune disease development and to onset prevention.

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Diverse Role of OX40 on T Cells as a Therapeutic Target for Skin Diseases

Iriki H., Takahashi H., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  143 （ 4 ） 545 - 553 2023年04月

ISSN  0022202X

　概要を見る

OX40 is an important costimulatory molecule for T-cell expansion and survival. Because OX40 is expressed on most T-cell subsets, it is an attractive therapeutic target for a variety of T-cell‒mediated diseases. Clinical trials are already underway for some skin inflammatory diseases. In this review, we present various observations that improve our understanding of how OX40-targeted therapy can be applied for skin inflammatory diseases, such as atopic dermatitis and psoriasis, T helper (Th)2- and Th17-mediated diseases, respectively. The important OX40/OX40L-mediated interaction between T cells and other immune cells is also discussed in terms of skin autoimmune diseases, such as alopecia areata and pemphigus. Regulatory T cells (Tregs) highly express OX40, and the skin harbors a large Treg population; thus, understanding how OX40-targeted treatment acts on Tregs is vital for the development of therapeutic strategies for various skin diseases.

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Rituximab therapy for intractable pemphigus: A multicenter, open-label, single-arm, prospective study of 20 Japanese patients

Yamagami J., Kurihara Y., Funakoshi T., Saito Y., Tanaka R., Takahashi H., Ujiie H., Iwata H., Hirai Y., Iwatsuki K., Ishii N., Sakurai J., Abe T., Takemura R., Mashino N., Abe M., Amagai M.

Journal of Dermatology （Journal of Dermatology）  50 （ 2 ） 175 - 182 2023年02月

ISSN  03852407

　概要を見る

This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%–91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti-desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19-positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients.

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T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

Takahashi H., Iriki H., Asahina Y.

Journal of Dermatology （Journal of Dermatology）  50 （ 2 ） 112 - 123 2023年02月

ISSN  03852407

　概要を見る

Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti-human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.

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Meeting Report: ISID2023 Tokyo Satellite Meeting. International Symposium on Autoimmunity Targeting the Skin. -Pemphigus, Pemphigoid, and Beyond-

Yamagami J., Takahashi H., Amagai M.

Journal of Dermatological Science （Journal of Dermatological Science）  2023年

査読有り,  ISSN  09231811

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Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antibiotic Use: A Case-Crossover Study

Fukasawa T., Urushihara H., Takahashi H., Okura T., Kawakami K.

Journal of Allergy and Clinical Immunology: In Practice （Journal of Allergy and Clinical Immunology: In Practice）  2023年

ISSN  22132198

　概要を見る

Background: Evidence is lacking on the association between antibiotic use and risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians. Objective: We assessed the risk of SJS/TEN associated with different antibiotic classes in Japanese. Methods: We conducted a case-crossover study using a claims database. Firth conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SJS/TEN associated with antibiotic use in a 56-day hazard period versus 3 control periods. We created 18 cohorts for each antibiotic class and calculated 56-day cumulative incidence per 100,000 new users. The association between antibiotic class and SJS/TEN was also evaluated in each case using the ALgorithm of Drug causality for Epidermal Necrolysis (ALDEN). Results: Our case-crossover study included 170 SJS/TEN cases. Increased ORs were observed for lincomycins (OR, 33.00 [95% CI, 3.74-4332.05]), trimethoprim-sulfamethoxazole (21.20 [6.73-105.98]), penicillins (14.39 [6.95-34.21]), glycopeptides (14.37 [3.17-136.10]), cephalosporins (7.06 [4.25-12.21]), aminoglycosides (6.55 [1.97-26.84]), quinolones (5.98 [3.34-11.20]), fosfomycin (5.40 [1.20-30.97]), carbapenems (5.09 [1.85-15.64]), tetracyclines (4.95 [1.78-15.27]), and macrolides (3.78 [2.13-6.83]). Cumulative incidence of SJS/TEN was 67.4 for trimethoprim-sulfamethoxazole, 86.2 for glycopeptides, and below 10.0 for the others. Despite the high incidence, only 2 cases had a probable causal relationship with glycopeptides. Conclusion: Some antibiotic classes, including lincomycins, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, were newly suggested to be associated with risk of SJS/TEN; considered together with the high incidence for trimethoprim-sulfamethoxazole and glycopeptides, these findings warrant caution in clinical practice.

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Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes

Mizukawa Y., Hama N., Miyagawa F., Takahashi H., Ogawa Y., Kurata M., Asada H., Abe R., Shiohara T.

Journal of Allergy and Clinical Immunology: In Practice （Journal of Allergy and Clinical Immunology: In Practice）  2023年

ISSN  22132198

　概要を見る

Background: We previously developed a drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity (DDS) score that may predict DIHS/DRESS-associated complications (DACs), including myocarditis, gastrointestinal bleeding, and autoimmune diseases. Objective: To externally confirm the predictive accuracy of the DDS score, clarify its ability to identify patients at high risk of DACs and fatal outcome, and determine which treatments might reduce or increase the risk. Methods: We conducted a nationwide multicenter retrospective study in which we followed 48 patients with DIHS/DRESS at 5 university hospitals in Japan for 1 year after onset. Patients were divided into mild, moderate, and severe DIHS/DRESS groups depending on their early DDS score. Results: Eight cases had DACs in the severe group (n = 17); no DACs were observed in the mild group (n = 12). Receiver-operating characteristic curve analysis showed that a cutoff DDS score of ≥4.0 and ≤2.0 could differentiate patients who would and would not develop DACs, respectively. In the moderate-to-severe disease groups, DACs occurred only in patients who received corticosteroids and not in those who received supportive care. None of the patients who received early treatment for cytomegalovirus developed DACs. Autoimmune DACs were significantly more common in patients who received pulse corticosteroid therapy. Four deaths occurred within the 1-year follow-up; all were in patients with infectious DACs who received systemic corticosteroids. Conclusion: Our scoring system allows early identification of patients at increased risk for DACs. Risk factors for DACs include systemic or pulse corticosteroid therapy.

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Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN

Hama N., Sunaga Y., Ochiai H., Kokaze A., Watanabe H., Kurosawa M., Azukizawa H., Asada H., Watanabe Y., Yamaguchi Y., Aihara M., Mizukawa Y., Ohyama M., Hashizume H., Nakajima S., Nomura T., Kabashima K., Tohyama M., Hasegawa A., Takahashi H., Mieno H., Ueta M., Sotozono C., Niihara H., Morita E., Brüggen M.C., Feingold I.M., Jeschke M.G., Dodiuk-Gad R.P., Oppel E.M., French L.E., Chen W.T., Chung W.H., Chu C.Y., Kang H.R., Ingen-Housz-Oro S., Nakamura K., Sueki H., Abe R.

Journal of Allergy and Clinical Immunology: In Practice （Journal of Allergy and Clinical Immunology: In Practice）  2023年

ISSN  22132198

　概要を見る

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. Objective: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. Methods: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. Results: The significant risk factors for death in SJS/TEN comprised 10 items, including patients’ age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. Conclusion: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

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Desmoglein-Specific B-Cell−Targeted Single-Cell Analysis Revealing Unique Gene Regulation in Patients with Pemphigus

Egami S., Watanabe T., Fukushima-Nomura A., Nomura H., Takahashi H., Yamagami J., Ohara O., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  2023年

ISSN  0022202X

　概要を見る

Autoreactive B cells are assumed to play a critical role in pemphigus; however, the characteristics of these cells are not yet fully understood. In this study, 23 pemphigus vulgaris or pemphigus foliaceus samples were used to isolate circulating desmoglein (DSG)-specific B cells. Transcriptome analysis of the samples was performed at the single-cell level to detect genes involved in disease activity. DSG1- or DSG3-specific B cells from three patients’ differentially expressed genes related to T cell costimulation (CD137L) as well as B-cell differentiation (CD9, BATF, TIMP1) and inflammation (S100A8, S100A9, CCR3), compared with nonspecific B cells from the same patients. When the DSG1-specific B cells before and after treatment transcriptomes of the patient with pemphigus foliaceus were compared, there were changes in several B-cell activation pathways not detected in non−DSG1-specific B cells. This study clarifies the transcriptomic profile of autoreactive B cells in patients with pemphigus and documents the gene expression related to disease activity. Our approach can be applied to other autoimmune diseases and has the potential for future detection of disease-specific autoimmune cells.

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Risk factors for sepsis and effects of pretreatment with systemic steroid therapy for underlying condition in SJS/TEN patients: Results of a nationwide cross-sectional survey in 489 Japanese patients

Sunaga Y., Hama N., Ochiai H., Kokaze A., Lee E.S., Watanabe H., Kurosawa M., Azukizawa H., Asada H., Watanabe Y., Yamaguchi Y., Aihara M., Mizukawa Y., Ohyama M., Abe R., Hashizume H., Nakajima S., Nomura T., Kabashima K., Tohyama M., Takahashi H., Mieno H., Ueta M., Sotozono C., Niihara H., Morita E., Sueki H.

Journal of Dermatological Science （Journal of Dermatological Science）  107 （ 2 ） 75 - 81 2022年08月

ISSN  09231811

　概要を見る

Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate. Objective: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition. Methods: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ2 test, and Fisher's exact test. Results: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate. Conclusion: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate.

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Intravenous Ig Regulates Anti-Desmoglein 3 IgG Production in B220^– Antibody-Producing Cells in Mice with Pemphigus Vulgaris

Kase Y., Takahashi H., Ito H., Kamata A., Amagai M., Yamagami J.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  142 （ 7 ） 1786 - 1792.e3 2022年07月

ISSN  0022202X

　概要を見る

Intravenous Ig (IVIG) is a treatment option for intractable cases of pemphigus vulgaris (PV), an autoimmune blistering disease caused by autoantibodies against desmoglein 3 (DSG3). To investigate the efficacy of IVIG on autoantibody secretion, we produced PV model mice by adoptive transfer of immunized Dsg3−/− splenocytes to Rag2−/− mice. We found that circulating anti-DSG3 IgG ELISA titer decreased in PV model mice after 5 days of treatment with IVIG compared with PBS-treated mice, whereas the F(ab’)2 fragment did not suppress the anti-DSG3 IgG titer. enzyme-linked immunospot assay revealed that IVIG treatment reduced the frequency of anti-DSG3 antibody–secreting cells in the spleen but not in lymph nodes and bone marrow. Moreover, this reduction was observed only in the splenic B220− fraction but not in the B220+ fraction. Furthermore, IVIG decreased the serum levels of anti-DSG3 IgG, even after a significant reduction of its titer, owing to antibody-mediated CD20+ B cell depletion. In addition, IVIG suppressed anti-DSG3 IgG production in B220−CD138+ plasma cells derived from PV model mice ex vivo. These results indicate that IVIG reduced autoantibody production in B220− cells containing plasma cells in PV model mice, and this function may indicate one of the mechanisms of action of IVIG on PV.

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Risk of Progression to Autoimmune Disease in Severe Drug Eruption: Risk Factors and the Factor-Guided Stratification

Mizukawa Y., Aoyama Y., Takahashi H., Takahashi R., Shiohara T.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  142 （ 3 ） 960 - 968.e9 2022年03月

ISSN  0022202X

　概要を見る

The identification of risk factors is key not only to uncover the pathogenesis of autoimmune disease but also to predict progression to autoimmune disease. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is likely the best prototypic example for analyzing the sequential events. We conducted a retrospective study of 55 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms followed up for the possibility of later development of autoimmune disease ∼18 years after resolution. Nine patients progressed to autoimmune sequelae regardless of treatment. The generation of autoantibodies was preceded by 8 years in eight of the nine patients. The combination of increases in lymphocyte counts, severe liver damage, a rebound increase in globulin, persistent reactivations of Epstein‒Barr virus and human herpesvirus-6, and low IL-2 and IL-4 at the acute/subacute phases were significant risk factors for the future development of autoimmune disease. On the basis of these factors, we established a scoring system that can identify high-risk patients. When stratified these patients into three risk categories (low/intermediate/high), occurrence of autoimmune disease was exclusively detected in the high group. Our data represent a scoring system to identify patients at high risk of developing autoimmune disease, although a larger study is required to validate the scoring system.

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IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3-Specific B Cell Receptor Knock-in Mouse

Nomura H., Wada N., Takahashi H., Kase Y., Yamagami J., Egami S., Iriki H., Mukai M., Kamata A., Ito H., Fujii H., Ishikura T., Koseki H., Watanabe T., Yamada T., Ohara O., Koyasu S., Amagai M.

Journal of Immunology （Journal of Immunology）  208 （ 3 ） 582 - 593 2022年02月

ISSN  00221767

　概要を見る

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2-/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b-/- and Fcgr2b1/mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.

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Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti-desmoglein IgG autoantibodies in remission: a retrospective cohort study

Zhao W.L., Ishii K., Egami S., Xu Z., Funakoshi T., Takahashi H., Tanikawa A., Ishiko A., Amagai M., Yamagami J.

Journal of the European Academy of Dermatology and Venereology （Journal of the European Academy of Dermatology and Venereology）  36 （ 2 ） 271 - 278 2022年02月

ISSN  09269959

　概要を見る

Background: The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. Objectives: To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. Methods: We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. Results: When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. Conclusions: This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

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Diagnostic utility of the basophil activation test in natto-induced hypersensitivity

Fukuda R., Ouchi T., Asahina Y., Shiiya C., Takeuchi S., Yasuda-Sekiguchi F., Iriki H., Kouno M., Takahashi S., Tanikawa A., Amagai M., Takahashi H.

Allergology International （Allergology International）  71 （ 1 ） 125 - 130 2022年01月

ISSN  13238930

　概要を見る

Background: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. Methods: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. Results: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. Conclusions: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

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Severe graft-versus-host disease-like enterocolitis accompanied with cytomegalovirus-reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Takamiyagi S., Iriki H., Asahina Y., Furuichi Y., Funakoshi T., Ichikawa M., Mikami Y., Okita H., Sakiyama T., Inazumi T., Amagai M., Takahashi H.

Journal of Dermatology （Journal of Dermatology）  49 （ 8 ） 796 - 799 2022年

ISSN  03852407

　概要を見る

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66-year-old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV-6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV-positive cells on immunohistochemical analysis, and graft-versus-host disease (GVHD)-like enterocolitis indicated by orange-peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD-like features of the gastrointestinal tract. GVHD-like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.

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Clinical severity scores as a guide for prediction of initial treatment responses in pemphigus and pemphigoid patients

Tanaka R., Kurihara Y., Egami S., Saito Y., Ouchi T., Funakoshi T., Takahashi H., Umegaki-Arao N., Kubo A., Tanikawa A., Amagai M., Yamagami J.

Journal of Dermatology （Journal of Dermatology）  50 （ 2 ） 203 - 211 2022年

ISSN  03852407

　概要を見る

Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second-line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut-off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control.

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Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus

Iriki H., Takahashi H., Wada N., Nomura H., Mukai M., Kamata A., Ito H., Yamagami J., Matsui T., Kurebayashi Y., Mise-Omata S., Nishimasu H., Nureki O., Yoshimura A., Hori S., Amagai M.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America）  118 （ 49 ）  2021年12月

ISSN  00278424

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Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg32/2 mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

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The pathogeneses of pemphigus and pemphigoid diseases

Ujiie H., Yamagami J., Takahashi H., Izumi K., Iwata H., Wang G., Sawamura D., Amagai M., Zillikens D.

Journal of Dermatological Science （Journal of Dermatological Science）  104 （ 3 ） 154 - 163 2021年12月

ISSN  09231811

　概要を見る

Autoimmune bullous diseases (AIBDs) are skin disorders which are mainly induced by autoantibodies against desmosomal or hemidesmosomal structural proteins. Previous studies using patients’ samples and animal disease models identified target antigens and elucidated the mechanisms of blister formation. Pemphigus has been the subject of more active clinical and basic research than any other AIBD. These efforts have revealed the pathogenesis of pemphigus, which in turn has led to optimal diagnostic methods and novel therapies, such as rituximab. In bullous pemphigoid (BP), studies with passive-transfer mouse models using rabbit anti-mouse BP180 antibodies and studies with passive-transfer or active mouse models using autoantigen-humanized mice elucidated the immune reactions to BP180 in vivo. Recently, dipeptidyl peptidase-4 inhibitors have attracted attention as a trigger for BP. For epidermolysis bullosa acquisita (EBA), investigations using mouse models are actively under way and several molecules have been identified as targets for novel therapies. In this review, we give an overview and discussion of the recent progress in our understanding of the pathogenesis of pemphigus, BP, and EBA. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation may expand our understanding of the etiology of AIBDs and lead to the development of novel therapeutic strategies.

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Multi-state model for predicting ocular progression in acute Stevens-Johnson syndrome/toxic epidermal necrolysis

Kinoshita F., Yokota I., Mieno H., Ueta M., Bush J., Kinoshita S., Sueki H., Asada H., Morita E., Fukushima M., Sotozono C., Teramukai S., Abe R., Hashizume H., Kurosawa M., Miyagawa F., Mushiroda T., Niihara H., Nomura T., Ohyama M., Takahashi H., Tohyama M., Watanabe H., Yamaguchi Y.

PLoS ONE （PLoS ONE）  16 （ 12 December ）  2021年12月

　概要を見る

This study aimed to clarify the etiologic factors predicting acute ocular progression in SJS/ TEN, and identify patients who require immediate and intensive ophthalmological treatment. We previously conducted two Japanese Surveys of SJS/TEN (i.e., cases arising between 2005–2007 and between 2008–2010), and obtained the medical records, including detailed dermatological and ophthalmological findings, of 230 patients. Acute ocular severity was evaluated as none, mild, severe, and very severe. A multi-state model assuming the Markov process based on the Cox proportional hazards model was used to elucidate the specific factors affecting the acute ocular progression. Our findings revealed that of the total 230 patients, 23 (24%) of 97 cases that were mild at initial presentation worsened to severe/very severe. Acute ocular progression developed within 3 weeks from disease onset. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and younger patient age were found to be statistically significant for the progression of ocular severity from mild to severe/very severe [hazard ratio (HR) 3.83; 95% confidence interval (CI) 1.48 to 9.91] and none to severe/very severe [HR 0.98; 95% CI 0.97 to 0.99], respectively. The acute ocular severity score at worst-condition was found to be significantly correlated with ocular sequelae. Thus, our detailed findings on acute ocular progression revealed that in 24% of SJS/TEN cases with ocular involvement, ocular severity progresses even after initiating intensive treatment, and that in younger-age patients with a history of exposure to NSAIDs, very strict attention must be given to their ophthalmological appearances.

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ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population

Okamori S., Ishii M., Asakura T., Suzuki S., Namkoong H., Kagawa S., Hegab A.E., Yagi K., Kamata H., Kusumoto T., Ogawa T., Takahashi H., Yoda M., Horiuchi K., Hasegawa N., Fukunaga K.

American Journal of Physiology - Lung Cellular and Molecular Physiology （American Journal of Physiology - Lung Cellular and Molecular Physiology）  321 （ 5 ） L872 - L884 2021年11月

ISSN  10400605

　概要を見る

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10DLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10DLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10DLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10DLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10DLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

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Successful treatment of a patient with adult food allergy and severe asthma using omalizumab

Nishie M., Masaki K., Okuzumi S., Mochimaru T., Kabata H., Miyata J., Takahashi H., Fukunaga K.

Asia Pacific Allergy （Asia Pacific Allergy）  11 2021年07月

ISSN  22338276

　概要を見る

Food allergy is a typical immediate-onset allergic disease in which symptoms are provoked by exposure to the sensitized antigens. Although previous reports have shown that omalizumab has helped children with egg or milk allergy achieve oral immunotherapy safely, there is still no established method for induction of remission in adult food allergy. A 51-year-old woman with oral steroid-dependent severe asthma was treated with omalizumab for 6 years. She had shellfish and wheat food allergy and oral allergy syndrome induced by kiwi and other foods associated with latex-fruit syndrome. Since omalizumab treatment, her food allergy symptoms had disappeared. After 7 years of this treatment, disseminated erythema suddenly appeared; omalizumab was discontinued because of suspected drug-induced eruption. After omalizumab interruption, she felt an itching sensation in her throat with worsened asthma control immediately after wheat ingestion. Readministration of omalizumab improved these symptoms. Thus, we raised the possibility that omalizumab not only improved asthma control but also induced pharmacological remission of the patient's food allergy. Omalizumab may be considered as a treatment option for adult patients with food allergies and severe asthma.

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Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case–control and cohort studies

Fukasawa T., Takahashi H., Takahashi K., Tanemura N., Amagai M., Urushihara H.

Allergology International （Allergology International）  70 （ 3 ） 335 - 342 2021年07月

ISSN  13238930

　概要を見る

Background: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. Methods: We conducted a matched case–control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. Results: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of “probable” or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated “unlikely” in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were “very unlikely”. Conclusions: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

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Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

Kinoshita M., Ogawa Y., Hama N., Ujiie I., Hasegawa A., Nakajima S., Nomura T., Adachi J., Sato T., Koizumi S., Shimada S., Fujita Y., Takahashi H., Mizukawa Y., Tomonaga T., Nagao K., Abe R., Kawamura T.

Science Translational Medicine （Science Translational Medicine）  13 （ 600 ）  2021年06月

ISSN  19466234

　概要を見る

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions.

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MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23

Mikami Y., Philips R.L., Sciumè G., Petermann F., Meylan F., Nagashima H., Yao C., Davis F.P., Brooks S.R., Sun H.W., Takahashi H., Poholek A.C., Shih H.Y., Afzali B., Muljo S.A., Hafner M., Kanno Y., O'Shea J.J.

Immunity （Immunity）  54 （ 3 ） 514 - 525.e6 2021年03月

ISSN  10747613

　概要を見る

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.

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Recent advancement of drug-induced hypersensitivity syndrome

Takahashi H.

Nishinihon Journal of Dermatology （Nishinihon Journal of Dermatology）  83 （ 4 ） 295 - 300 2021年

ISSN  03869784

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Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

Takahashi H., Nomura H., Iriki H., Kubo A., Isami K., Mikami Y., Mukai M., Sasaki T., Yamagami J., Kudoh J., Ito H., Kamata A., Kurebayashi Y., Yoshida H., Yoshimura A., Sun H.W., Suematsu M., O’Shea J.J., Kanno Y., Amagai M.

Science Immunology （Science Immunology）  6 （ 64 ）  2021年

　概要を見る

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

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The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018

Sunaga Y., Kurosawa M., Ochiai H., Watanabe H., Sueki H., Azukizawa H., Asada H., Watanabe Y., Yamaguchi Y., Aihara M., Mizukawa Y., Ohyama M., Hama N., Abe R., Hashizume H., Nakajima S., Nomura T., Kabashima K., Tohyama M., Takahashi H., Mieno H., Ueta M., Sotozono C., Niihara H., Morita E., Kokaze A.

Journal of Dermatological Science （Journal of Dermatological Science）  100 （ 3 ） 175 - 182 2020年12月

ISSN  09231811

　概要を見る

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey. Objective: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey). Methods: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information. Results: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52). Conclusion: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.

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Life-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report

Takise Y., Kato J., Suhara T., Yamada T., Funakoshi T., Takahashi H., Amagai M., Morisaki H.

JA Clinical Reports （JA Clinical Reports）  6 （ 1 ）  2020年12月

　概要を見る

Background: Recognition of rocuronium-induced anaphylaxis is often challenging, owing to its diverse clinical manifestations. Regarding treatment, several reports have described the efficacy of sugammadex, while conflicting reports have also been published. Case: A 71-year-old man was scheduled to undergo split-thickness skin grafting surgery on his hip. During the induction of general anesthesia, the patient developed profound circulatory collapse without any cutaneous manifestations, which required 40 min of cardiopulmonary resuscitation. Later, the patient developed circulatory collapse again during the induction of anesthesia for tracheostomy surgery, which apparently coincided with the administration of rocuronium. Rocuronium-induced anaphylactic shock was suspected, and the administration of sugammadex resulted in swift recovery of hemodynamics. The basophil activation test revealed a positive reaction to rocuronium. Conclusion: The possibility of rocuronium-induced anaphylaxis should be considered when the circulatory collapse coincides with rocuronium administration, even though cutaneous manifestation is absent. Sugammadex can be a treatment option in such atypical cases.

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Imiquimod-induced dermatitis impairs thymic tolerance of autoreactive CD4⁺ T cells to desmoglein 3

Iriki H., Mukai M., Ito H., Kurebayashi Y., Amagai M., Takahashi H.

Journal of Dermatological Science （Journal of Dermatological Science）  100 （ 3 ） 166 - 174 2020年12月

ISSN  09231811

　概要を見る

Background: The thymus plays an essential role in removing autoreactive T cells. Autoantigen-expressing thymic epithelial cells (TECs) contribute to the tolerogenic process. The thymus transiently shrinks as an acute thymic involution (ATI) under various inflammatory conditions. However, whether ATI occurs during local skin inflammation remains unclear, as does its influence on thymic immune tolerance. Objective: We investigated whether imiquimod-induced dermatitis causes ATI and impairs thymic immune tolerance against desmoglein 3 (Dsg3), an epidermal autoantigen of pemphigus vulgaris. Methods: 5% imiquimod cream was applied daily, at 62.5 mg/day (high dose group) or 31.25 mg/day (low dose group), for 1 week on the back of wild-type mice, and to wild-type mice that had undergone bone-marrow transplantation from Dsg3-specific T-cell receptor (TCR) transgenic-Rag2−/− mice. Next, thymocytes, TECs and other immune cells were analyzed by flow cytometry. TEC-associated Dsg3 expression was also analyzed by immunofluorescence staining. Results: Thymus weight and thymocyte number in all developmental stages decreased in a dose-dependent manner under imiquimod-induced dermatitis. The number of total TECs, specifically medullary, but not cortical, TECs, decreased in high and low dose groups. Accordingly, the number of Dsg3-experssing UEA-1+keratin 5+mTEC decreased in the thymus during imiquimod-induced dermatitis. Although Dsg3-sepcific transgenic thymocytes was usually deleted in the thymus under physiological condition by central tolerance, Dsg3-sepcific transgenic CD4+CD8− thymocytes significantly increased in number under imiquimod-induced dermatitis. Conclusion: These findings indicate a crosstalk between skin and thymus in adult mice and suggest that skin inflammation may impair thymic tolerance to autoantigens, such as Dsg3.

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Targeting inducible costimulator expressed on CXCR5⁺PD-1⁺ T<inf>H</inf> cells suppresses the progression of pemphigus vulgaris

Kim A.R., Han D., Choi J.Y., Seok J., Kim S.E., Seo S.H., Takahashi H., Amagai M., Park S.H., Kim S.C., Shin E.C., Kim J.H.

Journal of Allergy and Clinical Immunology （Journal of Allergy and Clinical Immunology）  146 （ 5 ） 1070 - 1079.e8 2020年11月

ISSN  00916749

　概要を見る

Background: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (TFH) cells in various autoimmune diseases, but the roles of ICOS and TFH cells in PV remain unclear. Objective: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4+ T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. Methods: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3–/– mice into Rag1–/– mice. The TFH cells and CD4+ T cells in PBMCs from PV patients were examined by flow cytometry. Results: Among CD4+ T cells from the mouse model, ICOS-positive TFH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ TFH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ TFH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Conclusions: Mouse Dsg3-specific ICOS+ TFH cells and human ICOS+CXCR5+PD-1+ TH cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ TH cells may be a therapeutic target for PV.

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Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results

Kamata A., Kurihara Y., Funakoshi T., Takahashi H., Kuroda K., Hachiya T., Amagai M., Yamagami J.

British Journal of Dermatology （British Journal of Dermatology）  182 （ 5 ） 1221 - 1227 2020年05月

共著, 査読有り,  ISSN  00070963

　概要を見る

© 2019 British Association of Dermatologists Background: A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. Objectives: To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. Methods: We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. Results: Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE− patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE− patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE− patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. Conclusions: IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic?. BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add?. Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.

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Successful treatment with secukinumab of three psoriatic patients undergoing dialysis

Mukai M, Kurihara Y, Ito Y, Shintani Y, Takahashi H, Kubo A, Amagai M, Umegaki-Arao N

（J Dermatol）  47 （ 1 ） e26 - e28 2020年01月

共著, 査読有り,  ISSN  0385-2407

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Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan

Fukasawa T., Takahashi H., Kameyama N., Fukuda R., Furuhata S., Tanemura N., Amagai M., Urushihara H.

PLoS ONE （PLoS ONE）  14 （ 8 ） e0221130 2019年08月

共著, 査読有り,  ISSN  1932-6203

　概要を見る

© 2019 Fukasawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.

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Autoimmunity and immunological tolerance in autoimmune bullous diseases

Takahashi H., Iriki H., Mukai M., Kamata A., Nomura H., Yamagami J., Amagai M.

International immunology （International immunology）  31 （ 7 ） 431 - 437 2019年07月

共著, 査読有り,  ISSN  0953-8178

　概要を見る

© The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell-cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.

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Patient voice on management of facial dermatological adverse events with targeted therapies: a qualitative study

Yagasaki K., Takahashi H., Ouchi T., Yamagami J., Hamamoto Y., Amagai M., Komatsu H.

Journal of Patient-Reported Outcomes （Journal of Patient-Reported Outcomes）  3 （ 1 ） 27 2019年05月

共著, 査読有り,  ISSN  2509-8020

　概要を見る

Background: With the increased use of targeted therapies in oncology, dermatological adverse events (dAEs) have drawn attention. Because the face is crucial for human identity and social interactions, facial dAEs have significant impact on a patient’s quality of life. This study aimed to explore patients’ experience with regard to the management of targeted oncological therapy-induced facial dAEs. Methods: In this qualitative study, 20 patients at a university hospital in Japan with advanced/metastatic cancer and targeted therapy-induced facial dAEs were individually interviewed to collect data. Thematic analysis was used to analyze the data. Results: Patients with cancer and targeted oncological therapy-induced facial dAEs who were referred to the Department of Dermatology had certain expectations from specialist services. Three key themes were identified: professional input and advice, empathetic commitment to individual management, and integrated care across specialties. Conclusions: The referred patients with cancer and facial dAEs needed more in-depth information and advice from dermatological services and were reassured by the empathetic commitment to individual management in integrated care across specialties. These findings suggest that attention to the patient’s perspective with a “sick person first” attitude and a collaborative effort across different specialties is important to minimize the effects of facial dAEs on the quality of life of patients with cancer.

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好酸球増多症と多発性単神経炎,紫斑を伴った末梢性T細胞リンパ腫非特定型の1例

柳澤絵里加, 栗原佑一, 舩越建, 高橋勇人, 加野美希, 深井達夫, 戸澤圭一, 清水隆之, 天谷雅行, 海老原全

臨床皮膚科 73 （ 6 ） 457 - 464 2019年05月

共著, 査読有り,  ISSN  0021-4973

Gamma-delta T cell large granular lymphocyte leukaemia with multiple cutaneous nodules that showed spontaneous regression

Suzuki C, Hirai I, Nomura H, Ouchi T, Okayama M, Okamoto S, Amagai M, Tanese K, Takahashi H

J Eur Acad Dermatol Venereol 33 （ 3 ） e134 - e137 2019年03月

共著, 査読有り,  ISSN  0926-9959

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Regulatory T cell deficiency and autoimmune skin disease: beyond scurfy mouse and IPEX

Hashimoto, T. Takahashi, H. Sakaguchi, S.

J Allergy Clin Immunol Epub 2018年09月

査読有り

Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis

Yamagami J., Nakamura Y., Nagao K., Funakoshi T., Takahashi H., Tanikawa A., Hachiya T., Yamamoto T., Ishida-Yamamoto A., Tanaka T., Fujimoto N., Nishigori C., Yoshida T., Ishii N., Hashimoto T., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  138 （ 7 ） 1473 - 1480 2018年07月

共著, 査読有り,  ISSN  0022202X

　概要を見る

© 2018 The Authors Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.

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Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome

Iriki H., Ouchi T., Ito H., Sawada M., Mukai M., Nomura H., Baba Y., Adachi T., Funakoshi T., Amagai M., Takahashi H.

Journal of Dermatology （Journal of Dermatology）  45 （ 6 ） 738 - 741 2018年06月

共著, 査読有り,  ISSN  03852407

　概要を見る

© 2018 Japanese Dermatological Association The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

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Unique clinical and serological features of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors

Horikawa H, Kurihara Y, Funakoshi T, Umegaki-Arao N, Takahashi H, Kubo A, Tanikawa A, Kodani N, Minami Y, Meguro S, Itoh H, Izumi K, Nishie W, Shimizu H, Amagai M, Yamagami J

Br J Dermatol 178 （ 6 ） 1462 - 1463 2018年06月

共著, 査読有り,  ISSN  0007-0963

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Azathioprine monotherapy in autoimmune blistering diseases: A feasible option for mild to moderate cases

Kakuta R., Yamagami J., Funakoshi T., Takahashi H., Ohyama M., Amagai M.

Journal of Dermatology （Journal of Dermatology）  45 （ 3 ） 334 - 339 2018年03月

査読有り,  ISSN  03852407

　概要を見る

© 2017 Japanese Dermatological Association Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1–37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 ± 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 ± 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid.

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Authors' reply: Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes

Payne, A. S. Kasperkiewicz, M. Ellebrecht, C. T. Takahashi, H. Yamagami, J. Zillikens, D. Amagai, M.

Nat Rev Dis Primers 4   18013 2018年02月

天疱瘡モデルマウスの特徴

高橋 勇人

炎症と免疫 26 （ 1 ） 80 - 85 2018年01月

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

Kitashima D., Kobayashi T., Woodring T., Idouchi K., Doebel T., Voisin B., Adachi T., Ouchi T., Takahashi H., Nishifuji K., Kaplan D., Clausen B., Amagai M., Nagao K.

EBioMedicine （EBioMedicine）  27   293 - 303 2018年01月

査読有り

　概要を見る

© 2017 Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

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Desmoglein 3-Reactive B Cells “Hiding” in Pemphigus Lesions

Takahashi H.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  137 （ 11 ） 2255 - 2257 2017年11月

査読有り,  ISSN  0022202X

　概要を見る

Pemphigus vulgaris is an autoimmune blistering disease caused by anti-desmoglein 3 IgG autoantibodies. It is accepted that interactions between autoreactive B and T cells are key to humoral autoimmunity targeting desmoglein 3. This orchestrated process usually occurs in secondary lymphoid organs, including the spleen and lymph nodes. Thus, it seems likely that autoreactive B cells reside and produce autoantibodies in these tissues. Yuan et al. analyzed lymphocytes in the lesional skin of patients with pemphigus vulgaris using several experimental techniques and concluded that desmoglein 3-reactive B cells were present. This finding expands our understanding of the pathogenesis of pemphigus and should be considered when following the clinical course of skin lesions and thinking about adjunctive therapy.

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Desmoglein 3-Reactive B cells "Hiding" in pemphigus lesions

Takahashi, H.

J Invest Dermatol 137 （ 11 ） 2255 - 2257 2017年11月

Non-pigmenting fixed drug eruption with mixed features of acute generalized exanthematous pustulosis induced by pseudoephedrine: a case report

Fukuda, R. Ouchi, T. Hirai, I. Funakoshi, T. Honda, A. Tanese, K. Tanikawa, A. Amagai, M. Takahashi, H.

Contact Dermatitis 77 （ 2 ） 123 - 126 2017年08月

査読有り

皮膚科研究における若手育成の試み

高橋 勇人

臨床皮膚科 71 （ 8 ） 574 - 575 2017年07月

Unexpected recalcitrant course of drug-induced erythema multiforme-like eruption and interstitial pneumonia sequentially occurring after nivolumab therapy

Nomura, H. Takahashi, H. Suzuki, S. Kurihara, Y. Chubachi, S. Kawada, I. Yasuda, H. Betsuyaku, T. Amagai, M. Funakoshi, T.

Journal of Dermatology 44 （ 7 ） 818 - 821 2017年07月

査読有り

Pemphigus

Kasperkiewicz, M., Ellebrecht, C.T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A.S., Amagai, M.

Nature Reviews Disease Primers 3   Article number 17026 2017年05月

Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5

Kumagai, Y. Umegaki-Arao, N. Sasaki, T. Nakamura, Y. Takahashi, H. Ashida, A. Tsunemi, Y. Kawashima, M. Shimizu, A. Ishiko, A. Nakamura, K. Tsuchihashi, H. Amagai, M. Kubo, A.

Journal of the European Academy of Dermatology and Venereology 31 （ 5 ） e241 - e243 2017年05月

査読有り,  ISSN  0926-9959

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天疱瘡―デスモグレインに対する細胞性免疫とバリア機能障害

高橋 勇人 天谷雅行

実験医学 35 （ 7 ） 1143 - 1149 2017年04月

関節リウマチ患者に生じたメトトレキサート関連リンパ増殖性疾患と考えられた1例

畠中美帆 角田梨沙 高橋勇人 谷川瑛子 竹内勤 亀山香織 天谷雅行

臨床皮膚科 70 （ 13 ） 1067 - 1071 2016年12月

ISSN  0021-4973

　概要を見る

76歳,女性.18年前に発症した関節リウマチ(rheumatoid arthritis:RA)に対し10年前よりメトトレキサート(MTX),1年前よりアバタセプト(ABT)で加療していた.初診3週間程前から両下腿に皮疹を認め,当院を受診した.四肢に一部表面に痂皮を付着した,浸潤を触れる暗赤色結節が多発散在していた.組織はCD20,bcl-2,EBER陽性の異型細胞が皮下織中心に増殖し,びまん性大細胞型B細胞リンパ腫に一致し,MTX関連リンパ増殖性疾患と診断した.ABTの投与を延期し,MTXを中止後,結節は完全に消退した.現在ABTを継続投与中だが再燃していない.過去の文献を調べえた限り,その発症には,原病の免疫異常および長期にわたる罹病期間,MTXを介したEpstein-Barrウイルスの再活性化などが複合的に関連した可能性があると推察された.(著者抄録)

天疱瘡におけるデスモグレイン3特異的T細胞の臓器を越えた病原的役割

高橋勇人 天谷雅行

医学のあゆみ 259 （ 2 ） 159 - 164 2016年10月

ISSN  0039-2359

　概要を見る

尋常性天疱瘡(PV)は、デスモグレイン(Dsg)3に対する自己抗体により生じる自己免疫性水疱症のひとつである。著者らはモデルマウスを用いて、B細胞による自己抗体産生を誘導するDsg3特異的CD4+T細胞を解析してきた。近年、樹立したDsg3特異的T細胞クローン(Dsg3H1 T細胞)を利用して、Dsg3特異的T細胞受容体トランスジェニックマウスを作成した。Dsg3H1 T細胞はB細胞による自己抗体産生を介して水疱形成を誘導するのみならず、表皮に直接浸潤し皮膚炎(interface dermatitis)を誘導することが明らかとなった。天疱瘡の亜型である腫瘍随伴性天疱瘡(PNP)においては水疱と皮膚炎がともに認められるが、その複雑な病態がDsg3特異的T細胞により誘導されることが考えられた。さらに、PNPに認められる致死的な肺障害は、肺に生じた異所性扁平上皮化生に対して表皮抗原に反応するT細胞により誘導されることが示唆された。(著者抄録)

Case of lymphoplasmacytic plaque in children: Analysis of the distribution of infiltrating immune cells

Mukai, M. Tanese, K. Umegaki-Arao, N. Kubo, A. Takahashi, H. Amagai, M.

J Dermatol 43 （ 11 ） 1368 - 1370 2016年04月

査読有り,  ISSN  0385-2407

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Condylomata lata on the ankle: an unusual location

Ikeda, E. Goto, A. Suzaki, R. Sawada, M. Dekio, I. Ishizaki, S. Fujibayashi, M. Takahashi, H. Tanaka, M.

Dermatol Pract Concept 6 （ 2 ） 49 - 51 2016年04月

査読有り,  ISSN  2160-9381

　概要を見る

A 43-year-old Japanese man presented with reddish nodules on the ankle. The nodules had a yellowish crust and eroded surface. Dermoscopy revealed red to milky-red globules at the periphery and some glomerular vessels in the center and a whitish-pink network, which corresponded to capillary dilatation in the papillary dermis and prominent acanthosis, respectively. These structures were surrounded by a yellowish peripheral structureless area and multiple white, small, round structures in the center, corresponding to the macerated horny layer and keratin plugs. Blood samples were positive for rapid plasma reagin (1:64), Treponema pallidum hemagglutination assay (1:20480), and fluorescent treponemal antibody-absorption (1:1280). A lesional skin biopsy specimen showed irregular acanthosis and papillomatosis. The Warthin-Starry and anti-Treponema pallidum antibody stains on the biopsy specimen revealed many spirochetes in the lower epidermis and the papillary dermis. A diagnosis of secondary syphilis with condylomata lata was made. After one week of treatment with oral benzylpenicillin benzathine hydrate (Bicillin((R)) G granules 400,000 units; Banyu Pharmaceutical Co., Ltd, Tokyo, Japan), 1.6 million units (U) daily, the ankle lesions had resolved with a small ulcer and pigmentation. Although syphilis is a relatively common disease, this case study reports an unusual presentation as well as dermoscopy findings.

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重症薬疹の特徴と初期診療のポイント

高橋勇人

ペインクリニック 36 （ 11 ） 1469 - 1480 2015年11月

デスモグレイン3特異的T細胞によって誘導される多彩な皮膚病理

高橋勇人 天谷雅行

実験医学 33 （ 12 ） 1948 - 1953 2015年08月

尋常性天疱瘡

高橋勇人

Visual Dermatology 14 （ 9 ） 1070 - 1074 2015年08月

Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: Survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR)

Kano, Y. Tohyama, M. Aihara, M. Matsukura, S. Watanabe, H. Sueki, H. Iijima, M. Morita, E. Niihara, H. Asada, H. Kabashima, K. Azukizawa, H. Hashizume, H. Nagao, K. Takahashi, H. Abe, R. Sotozono, C. Kurosawa, M. Aoyama, Y. Chu, C. Y. Chung, W. H. Shiohara, T.

Journal of Dermatology 42 （ 3 ） 276 - 282 2015年03月

査読有り

皮膚疾患におけるT細胞の重要な役割

高橋 勇人 天谷雅行

実験医学 32 （ 17 ） 2854 - 2860 2014年11月

共著

デスモグレイン3に対する液性および細胞性の自己免疫応答

高橋 勇人

アレルギー・免疫 21 （ 11 ） 1693 - 1700 2014年10月

単著

薬疹の重症化をもたらす要因

高橋 勇人

アレルギー・免疫 21 （ 8 ） 1208 - 1213 2014年08月

単著

アバタセプトによる乾癬様皮疹を呈した１例

伊東可寛 渡邊絵美子 高橋 勇人 谷川瑛子 亀田秀人 天谷雅行

臨床皮膚科 68 （ 6 ） 398 - 402 2014年05月

共著

　概要を見る

論文

Type I IFN induces binding of STAT1 to BCL6: Divergent roles of stat family transcription factors in the T follicular helper cell genetic program

Nakayamada, S. Poholek, A. C. Lu, K. T. Takahashi, H. Kato, M. Iwata, S. Hirahara, K. Cannons, J. L. Schwartzberg, P. L. Vahedi, G. Sun, H. W. Kanno, Y. O'Shea, J. J.

Journal of Immunology 192 （ 5 ） 2156 - 2166 2014年03月

査読有り

Immune response involving the bulge region in addition to telogen conversion contributes to hair loss in a case of atypical drug-induced hypersensitivity syndrome

Watanabe-Okada, E. Nagao, K. Takahashi, H. Amagai, M. Ohyama, M.

J Dermatol 40 （ 11 ） 928 - 929 2013年11月

研究論文（学術雑誌）, 共著, 査読有り

Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation

Nishimoto, S. Kotani, H. Tsuruta, S. Shimizu, N. Ito, M. Shichita, T. Morita, R. Takahashi, H. Amagai, M. Yoshimura, A.

Journal of Immunology 191 （ 6 ） 3065 - 3072 2013年09月

Ectopic expression of epidermal antigens renders the lung a target organ in paraneoplastic pemphigus

Hata, T. Nishimoto, S. Nagao, K. Takahashi, H. Yoshida, K. Ohyama, M. Yamada, T. Asano, K. Amagai, M.

Journal of Immunology 191 （ 1 ） 83 - 90 2013年07月

BACH2 represses effector programs to stabilize T reg-mediated immune homeostasis

Roychoudhuri R., Hirahara K., Mousavi K., Clever D., Klebanoff C.A., Bonelli M., Sciumè G., Zare H., Vahedi G., Dema B., Yu Z., Liu H., Takahashi H., Rao M., Muranski P., Crompton J.G., Punkosdy G., Bedognetti D., Wang E., Hoffmann V., Rivera J., Marincola F.M., Nakamura A., Sartorelli V., Kanno Y., Gattinoni L., Muto A., Igarashi K., O'Shea J.J., Restifo N.P.

Nature （Nature）  498 （ 7455 ） 506 - 510 2013年06月

査読有り,  ISSN  00280836

　概要を見る

Through their functional diversification, distinct lineages of CD4 + T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4+ T cells. BACH2 was required for efficient formation of regulatory (T reg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH 1, TH 2 and TH 17 cell lineages. These findings identify BACH2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. © 2013 Macmillan Publishers Limited. All rights reserved.

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BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis

Roychoudhuri, R. Hirahara, K. Mousavi, K. Clever, D. Klebanoff, C. A. Bonelli, M. Sciume, G. Zare, H. Vahedi, G. Dema, B. Yu, Z. Liu, H. Takahashi, H. Rao, M. Muranski, P. Crompton, J. G. Punkosdy, G. Bedognetti, D. Wang, E. Hoffmann, V. Rivera, J. Marincola, F. M. Nakamura, A. Sartorelli, V. Kanno, Y. Gattinoni, L. Muto, A. Igarashi, K. O'Shea, J. J. Restifo, N. P.

Nature 498 （ 7455 ） 506 - 510 2013年06月

研究論文（学術雑誌）, 共著, 査読有り

Distinct requirements for T-bet in gut innate lymphoid cells

Sciume, G. Hirahara, K. Takahashi, H. Laurence, A. Villarino, A. V. Singleton, K. L. Spencer, S. P. Wilhelm, C. Poholek, A. C. Vahedi, G. Kanno, Y. Belkaid, Y. O'Shea, J. J.

J Exp Med 209 （ 13 ） 2331 - 2338 2012年12月

研究論文（学術雑誌）, 共著, 査読有り

STATs shape the active enhancer landscape of T cell populations

Vahedi, G. Takahashi, H. Nakayamada, S. Sun, H. W. Sartorelli, V. Kanno, Y. O'Shea, J. J.

Cell 151 （ 5 ） 981 - 993 2012年11月

査読有り

TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells

Takahashi H., Kanno T., Nakayamada S., Hirahara K., Sciumè G., Muljo S.A., Kuchen S., Casellas R., Wei L., Kanno Y., O'Shea J.J.

Nature Immunology （Nature Immunology）  13 （ 6 ） 587 - 595 2012年06月

査読有り,  ISSN  15292908

　概要を見る

Distinct CD4+ T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (Treg cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-β (TGF-β) in inducible T reg cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible Treg cells into follicular helper T cells. We also found that miR-10a limited differentiation into the TH17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells. © 2012 Nature America, Inc. All rights reserved.

• Access to Document (DOI)

Helper T cell diversity and plasticity

Nakayamada, S. Takahashi, H. Kanno, Y. O'Shea, J. J.

Curr Opin Immunol 24 （ 3 ） 297 - 302 2012年06月

共著

TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells

Takahashi, H. Kanno, T. Nakayamada, S. Hirahara, K. Sciume, G. Muljo, S. A. Kuchen, S. Casellas, R. Wei, L. Kanno, Y. O'Shea, J. J.

Nature Immunology 13 （ 6 ） 587 - 595 2012年06月

研究論文（学術雑誌）, 共著, 査読有り

Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1

Hirahara, K. Ghoreschi, K. Yang, X. P. Takahashi, H. Laurence, A. Vahedi, G. Sciume, G. Hall, A. O. Dupont, C. D. Francisco, L. M. Chen, Q. Tanaka, M. Kanno, Y. Sun, H. W. Sharpe, A. H. Hunter, C. A. O'Shea, J. J.

Immunity 36 （ 6 ） 1017 - 1030 2012年06月

研究論文（学術雑誌）, 共著, 査読有り

Early Th1 Cell Differentiation Is Marked by a Tfh Cell-like Transition

Nakayamada, S., Kanno, Y., Takahashi, H., Jankovic, D., Lu, K., Johnson, T., Sun, H.-W., Vahedi, G., Hakim, O., Handon, R., Schwartzberg, P.L., Hager, G., O'Shea, J.

Immunity 35 （ 6 ） 919 - 931 2011年12月

Desmoglein 3-specific CD4⁺ T cells induce pemphigus vulgaris and interface dermatitis in mice

Takahashi H., Kouno M., Nagao K., Wada N., Hata T., Nishimoto S., Iwakura Y., Yoshimura A., Yamada T., Kuwana M., Fujii H., Koyasu S., Amagai M.

Journal of Clinical Investigation （Journal of Clinical Investigation）  121 （ 9 ） 3677 - 3688 2011年09月

査読有り,  ISSN  00219738

　概要を見る

Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4+ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3-/- mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.

• Access to Document (DOI)

Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice

Takahashi, H., Kouno, M., Nagao, K., Wada, N., Hata, T., Nishimoto, S., Iwakura, Y., Yoshimura, A., Yamada, T., Kuwana, M., Fujii, H., Koyasu, S., Amagai, M.

Journal of Clinical Investigation 121 （ 9 ） 3677 - 3688 2011年09月

Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation

Wei, L., Vahedi, G., Sun, H.-W., Watford, W.T., Takatori, H., Ramos, H.L., Takahashi, H., Liang, J., Gutierrez-Cruz, G., Zang, C., Peng, W., O'Shea, J.J., Kanno, Y.

Immunity 32 （ 6 ） 840 - 851 2010年06月

Natural killer cells control a T-helper 1 response in patients with Behçet's disease

Yamaguchi, Y., Takahashi, H., Satoh, T., Okazaki, Y., Mizuki, N., Takahashi, K., Ikezawa, Z., Kuwana, M.

Arthritis Research and Therapy 12 （ 3 ） Article number R80 2010年05月

Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis

Durant, L., Watford, W.T., Ramos, H.L., Laurence, A., Vahedi, G., Wei, L., Takahashi, H., Sun, H.-W., Kanno, Y., Powrie, F., O'Shea, J.J.

Immunity 32 （ 5 ） 605 - 615 2010年05月

A single helper T cell clone is sufficient to commit polyclonal naive B cells to produce pathogenic IgG in experimental pemphigus vulgaris

Takahashi, H., Kuwana, M., Amagai, M.

Journal of Immunology 182 （ 3 ） 1740 - 1745 2009年02月

Genetic characterization of human Dsg3-specific B cells isolated by flow cytometry from the peripheral blood of patients with pemphigus vulgaris

Yamagami, J., Takahashi, H., Ota, T., Amagai, M.

Journal of Dermatological Science 52 （ 2 ） 98 - 107 2008年11月

Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris

Takahashi, H., Amagai, M., Nishikawa, T., Fujii, Y., Kawakami, Y., Kuwana, M.

Journal of Immunology 181 （ 2 ） 1526 - 1535 2008年07月

T helper type 2-biased natural killer cell phenotype in patients with pemphigus vulgaris

Takahashi, H., Amagai, M., Tanikawa, A., Suzuki, S., Ikeda, Y., Nishikawa, T., Kawakami, Y., Kuwana, M.

Journal of Investigative Dermatology 127 （ 2 ） 324 - 330 2007年02月

A case of drug-induced hypersensitivity syndrome showing transient immunosuppression before viral reactivation during treatment for pemphigus foliaceus

Takahashi, H., Tanaka, M., Tanikawa, A., Toyohara, A., Ogo, Y., Morimoto, A., Harato, R., Kobayashi, M., Amagai, M.

Clinical and Experimental Dermatology 31 （ 1 ） 33 - 35 2006年01月

Parallel fluctuation of anti-desmoglein 3 and anti-BP180 autoantibody titres in a patient with bullous pemphigoid

Takahashi, H. Anzai, H. Suzuki, Y. Tanikawa, A. Amagai, M. Nishikawa, T.

Clinical and Experimental Dermatology 29 （ 6 ） 608-611 2004年11月

研究論文（学術雑誌）, 共著

Malignant chondroid syringoma with bone invasion: a case report and review of the literature

#HTakahashi, H.<U/> Ishiko, A. Kobayashi, M. Tanikawa, A. Takasu, H. Tanaka, M.

American Journal of Dermatopathology 26 （ 5 ） 403-406 2004年10月

研究論文（学術雑誌）, 共著

Compound heterozygosity for a point mutation and a deletion located at splice acceptor sites in the LAMB3 gene leads to generalized atrophic benign epidermolysis bullosa

Takizawa, Y., Hiraoka, Y., Takahashi, H., Ishiko, A., Yasuraoka, I., Hashimoto, I., Aiso, S., Nishikawa, T., Shimizu, H.

Journal of Investigative Dermatology 115 （ 2 ） 312 - 316 2000年