Elucidation of the pathogenic mechanism of autoimmune diseases focusing on HHV-6 persistent infection in DIHS

• Project/Area Number: 21K08306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nara Medical University
• Principal Investigator: 浅田 秀夫 奈良県立医科大学, 医学部, 教授 (60252681)
• Co-Investigator(Kenkyū-buntansha): 新熊 悟 奈良県立医科大学, 医学部, 准教授 (00613788) ; 森 康子 神戸大学, 医学研究科, 教授 (50343257)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 薬剤性過敏症症候群 / DIHS / ヒトヘルペスウイルス / HHV-6 / 再活性化 / 持続感染 / 自己免疫疾患 / シングルセルRNA-seq解析

Outline of Research at the Start

われわれはこれまでにDIHS後の自己免疫疾患の発症にHHV-6持続感染が密接に関与している可能性を見出した。そこで、本研究ではDIHSにおけるHHV-6持続感染が患者の免疫状態にいかなる影響をおよぼすのかを明らかにして、DIHS後の自己免疫疾患の発症機序を解明する。本研究により、薬剤アレルギーとHHV-6感染が複雑に絡み合ったDIHSの病態におけるHHV-6の役割の一端を明らかにできるとともに、DIHSに対する新たな治療戦略の基盤となる情報を得ることが期待できる。

Outline of Annual Research Achievements

薬剤性過敏症症候群（DIHS）は多臓器障害を伴う重症薬疹の一つである。経過中にHHV-6の再活性化を生じ、症状の遷延化、重症化に関わっている。本疾患では回復期にⅠ型糖尿病、慢性甲状腺炎などの自己免疫疾患をしばしば発症するが、その機序は不明である。
我々はこれまでにDIHSにおけるHHV-6持続感染患者では、回復期に高率に自己免疫疾患を発症することを見出した。そこで本研究では、DIHS後自己免疫疾患の発症機序の解明を目指して、HHV-6持続感染と宿主の免疫状態との関係を解析した。
初年度および2年目は、DIHS後にHHV-6持続感染をきたした患者では、HHV-6が主にCD4 central memory T細胞に持続感染していることが判明した。また、持続感染群では一過性群と比較して、急性期における皮膚粘膜症状が重症、DIHSの予後予測スコアが高値、HHV-6およびCMVの再活性化時の血中ウイルスDNAピーク値が高値、血清中IL-4、IL-5、sIL-2受容体が高値を示すことも明らかになった。さらに、自己免疫疾患を発症した持続感染群と、合併症をみとめなかった一過性群について、急性期と回復期のPBMCを用いたシングルセルRNAシーケンス解析を行った結果、一過性群の急性期では単球系細胞の増加および活性化がみられたのに対して、持続感染群では、その現象はみられなかった。最終年度は、持続感染群の急性期のCD14陽性単球系細胞において、貪食・抗原提示に関連する遺伝子の発現低下が判明し、DIHS発症早期の単球系細胞の機能低下がその後のHHV-6持続感染、さらに自己免疫疾患の発症に関わっているものと推測された。また、持続感染群では一過性群と比べて、NK細胞の減少、NK細胞およびCD8陽性T細胞におけるNKG7の発現低下を認め、ウイルス感染細胞の排除に関わる細胞傷害活性の減弱が推測された。

Research Products

• [Journal Article] Clinical Profiles of Japanese Patients with Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023 (2024)
  • Author(s): Tsukagoshi E, Nakamura R, Kaniwa N, Sai K, Kikura-Hanajiri R, Matsunaga K, Abe R, Asada H, Saito Y
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 47 Issue: 1 Pages: 88-97
  • DOI: 10.1248/bpb.b23-00595
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2024-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Differential Effects of HLA-B8727;15:11 and HLA-A8727;31:01 on Carbamazepine-Induced Cutaneous Adverse Reactions. (2023)
  • Author(s): Fukunaga K, Tsukagoshi E, Kurata M, Mizukawa Y, Niihara H, Morita E, Watanabe Y, Yamaguchi Y, Watanabe H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Azukizawa H, Asada H, Hasegawa A, Hama N, Ozeki T, Mashimo Y, Sekine A, Matsunaga K, Tanaka Y, Nakamura R, Abe R, Mushiroda T, Saito Y.
  • Journal Title: J Invest Dermatol. Volume: 144（４） Issue: 4 Pages: 908-911
  • DOI: 10.1016/j.jid.2023.09.282
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes. (2023)
  • Author(s): Mizukawa Y, Hama N, Miyagawa F, Takahashi H, Ogawa Y, Kurata M, Asada H, Abe R, Shiohara T.
  • Journal Title: J Allergy Clin Immunol Pract. Volume: 11（10） Issue: 10 Pages: 3169-3178
  • DOI: 10.1016/j.jaip.2023.06.065
  • Peer Reviewed / Open Access
• [Journal Article] Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN. (2023)
  • Author(s): Hama N, Sunaga Y, French LE, Chen WT, Chung WH, Chu CY, Abe R. et al
  • Journal Title: J Allergy Clin Immunol Pract. Volume: 11（10） Issue: 10 Pages: 3161-3168
  • DOI: 10.1016/j.jaip.2023.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a new HISCL automated CXCL9 immunoassay. (2023)
  • Author(s): Hasegawa T, Yoshida M, Watanabe S, Kondo T, Asada H, Nakagawa A, Tomii K, Kameda M, Otsuka M, Kuronuma K, Chiba H, Katayanagi S, Miyazaki Y, Mori A.
  • Journal Title: Sci Rep. Volume: 13 Issue: 1 Pages: 5342-5342
  • DOI: 10.1038/s41598-023-32513-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Validation of a genotyping technique for a surrogate marker of HLA-B*58:01 for allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in the Japanese population. (2023)
  • Author(s): Tsukagoshi E, Nakamura R, Tanaka Y, Maekawa K, Hiratsuka M, Asada H, Saito Y
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 49 Pages: 100495-100495
  • DOI: 10.1016/j.dmpk.2023.100495
  • Peer Reviewed
• [Journal Article] 薬剤性過敏症症候群診療ガイドライン2023 (2023)
  • Author(s): 水川良子、濱 菜摘、新原寛之、宮川 史、橋爪秀夫、藤山幹子、高橋勇人、渡辺秀晃、大山 学、山口由衣、川村龍吉、野村尚史、椛島健治、末木博彦、森田栄伸、阿部理一郎、浅田秀夫
  • Journal Title: 日皮会誌 Volume: 134 Pages: 559-580
  • Open Access
• [Journal Article] Purpura as an indicator of severity in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: evidence from a 49-case series (2022)
  • Author(s): Takei S, Hama N, Mizukawa Y, Takahashi H, Miyagawa F, Asada H, Abe R
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 36 Issue: 4
  • DOI: 10.1111/jdv.17838
  • Peer Reviewed
• [Journal Article] Serum Soluble OX40 as a Diagnostic and Prognostic Biomarker for Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (2022)
  • Author(s): Mitsui Y, Shinkuma S, Nakamura-Nishimura Y, Ommori R, Ogawa K, Miyagawa F, Mori Y, Tohyama M, Asada H
  • Journal Title: J Allergy Clin Immunol Pract Volume: 10 Issue: 2 Pages: 585-565
  • DOI: 10.1016/j.jaip.2021.10.042
  • Peer Reviewed
• [Journal Article] 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. (2022)
  • Author(s): Sunaga Y, Hama N, Ochiai H, Kokaze A, Lee ES, Watanabe H, Kurosawa M, Azukizawa H, Asada H, Watanabe Y, Yamaguchi Y, Aihara M, Mizukawa Y, Ohyamag M, Abe R, Hashizume H, Nakajima S, Nomurai T, Kabashima K, Tohyama M, Takahashi H, Mieno H, Ueta M, Sotozono C, Niiharam H, Morita E, Sueki H.
  • Journal Title: J Dermatol Sci. Volume: 107(2) Issue: 2 Pages: 75-81
  • DOI: 10.1016/j.jdermsci.2022.07.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Psoriatic Skin Lesions after Apalutamide Treatment (2022)
  • Author(s): Miyagawa F, Akioka N, Yoshida N, Ogawa K, Asada H
  • Journal Title: Acta Derm Venereol Volume: 102 Pages: adv00659-adv00659
  • DOI: 10.2340/actadv.v102.858
  • Peer Reviewed / Open Access
• [Journal Article] DIHS とヘルペスウイルス (2022)
  • Author(s): 浅田秀夫
  • Journal Title: 皮膚科 Volume: 1 Pages: 789-795
• [Journal Article] 【ウイルスと皮膚疾患-新しい考え方】知っておきたいウイルスの話題 DIHS 最近の話題. (2022)
  • Author(s): 浅田秀夫
  • Journal Title: Visual Dermatology. Volume: 21 Pages: 1017-1019
• [Journal Article] Japanese Research Committee on Severe Cutaneous Adverse Reaction. Multi-state model for predicting ocular progression in acute Stevens-Johnson syndrome/toxic epidermal necrolysis. (2021)
  • Author(s): Kinoshita F, Yokota I, Mieno H, Ueta M, Bush J, Kinoshita S, Sueki H, Asada H, Morita E, Fukushima M, Sotozono C, Teramukai S
  • Journal Title: PLoS One. Volume: 16 Issue: 12 Pages: e0260730-e0260730
  • DOI: 10.1371/journal.pone.0260730
  • Peer Reviewed / Open Access
• [Journal Article] Chemokines in Severe Cutaneous Adverse Reactions (SCARs) (2021)
  • Author(s): Miyagawa F, Asada H
  • Journal Title: Biomolecules Volume: 11 Issue: 6 Pages: 847-847
  • DOI: 10.3390/biom11060847
  • Peer Reviewed / Open Access
• [Journal Article] Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS). (2021)
  • Author(s): Miyagawa F, Asada H
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 4 Pages: 2147-2147
  • DOI: 10.3390/ijms22042147
  • Peer Reviewed / Open Access
• [Presentation] Pathological implications of persistent HHV-6 infection in DIHS/DRESS (2023)
  • Author(s): H Asada
  • Organizer: iSCAR2023 Meeting
  • Int'l Joint Research
• [Presentation] Biomarkers of DIHS/DRESS. (2022)
  • Author(s): Asada H
  • Organizer: 9th Drug Hypersensitivity Meeting
  • Int'l Joint Research / Invited
• [Presentation] Early Diagnostic and Prognostic Biomarkers for DIHS/DRESS. (2022)
  • Author(s): Asada H
  • Organizer: DRESS Syndrome Global Conference 2022
  • Int'l Joint Research / Invited
• [Presentation] Combination of TARC and soluble OX40 in the diagnosis of DIHS/DRESS. (2022)
  • Author(s): Mitsui Y, Shinkuma S, Nakamura-Nishimura Y, Ommori R, Ogawa K, Miyagawa F, Asada H
  • Organizer: 日本研究皮膚科学会
• [Presentation] 薬剤性過敏症症候群におけるHHV-6の病的意義 (2021)
  • Author(s): 浅田秀夫
  • Organizer: 第120回日本皮膚科学会総会
  • Invited
• [Presentation] 重症薬疹の最新の知見－薬剤性過敏症症候群の病態と診断－ (2021)
  • Author(s): 浅田秀夫
  • Organizer: 第7回総合アレルギー講習会
  • Invited
• [Presentation] Persistent HHV-6 infection has an increased risk of autoimmune disorders in patients with DIHS. (2021)
  • Author(s): Nishimura Y, Shobatake C, Miyagawa F, Shinkuma S, Watanabe H, Kira M, Nakajima S, Higashi Y, Asada H
  • Organizer: The 46th annual meeting of the Japanese Society for Investigative Dermatology
• [Presentation] Cutaneous adverse events caused by EGFR inhibitors may result from reduced expression of human β-defensins induced by staphylococci. (2021)
  • Author(s): Ommori R, Nishimura Y, Miyagawa F, Shobatake C, Ogawa K, Shinkuma S, Asada H
  • Organizer: The 46th annual meeting of the Japanese Society for Investigative Dermatology