Investigation of the pathophysiologic role of inflammatory monocytes in systemic lupus erythematosus

2020 Fiscal Year Research-status Report

• Project/Area Number: 19K08797
• Research Institution: Nara Medical University
• Principal Investigator: 宮川 史 奈良県立医科大学, 医学部, 講師 (00346024)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 全身性エリテマトーデス / インターフェロン制御因子 / 炎症性単球 / I型インターフェロン / NF-kB / 自己抗体 / 臓器障害

Outline of Annual Research Achievements

我々は既にプリスタン誘発性全身性エリテマトーデス（SLE）モデルマウスを用いて、自己抗体の産生はインターフェロン制御因子（IRF）7/I型インターフェロン（IFN）経路に、臓器障害はNF-kB経路により制御されていることを報告した。I型IFNの転写に関与するIRF7を欠損したIRF7欠損マウスでは、野生型マウスと同程度に糸球体腎炎を発症するが、自己抗体の産生は認められない。一方、I型IFNとNF-kBの両者の転写に関与するIRF8を欠損したIRF8欠損マウスでは、抗体産生は起こらず、糸球体腎炎の程度も野生型マウスより軽減した。我々は野生型マウス、IRF7欠損マウスではプリスタン投与後に組織への炎症性単球の浸潤がみられるが、IRF8欠損マウスではみられないことを見出した。さらに野生型マウス由来の炎症性単球は、自己抗原（二本鎖DNA；dsDNA）に反応してI型IFNと炎症性サイトカインを産生するが、IRF7欠損マウス由来の炎症性単球は炎症性サイトカインのみ産生することも明らかにした。炎症性単球は時間とともに脾臓において樹状細胞に分化し、dsDNAに反応した。この樹状細胞への分化は、系統の異なる宿主においても生じたことより、cell-intrinsicであることも明らかにした。本研究によりプリスタン投与により生じるIRF7欠損マウスとIRF8欠損マウスの形質の差異が、炎症性単球から産生されるサイトカインに起因していることが明らかとなった。SLEはフレアを繰り返す疾患であり、単球の可塑性がSLEの病態形成やフレア時の症状に関与している可能性が考えられた。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

順調に進んでおり成果を国際誌に発表した。

Strategy for Future Research Activity

炎症性単球は感染や炎症時に骨髄より組織に動員され、局所で微生物の排除に関与すると考えられていたが、自己免疫疾患の病態に関与しているかどうかについてはあまり分かっていなかった。本研究で自己免疫疾患であるSLEにおける炎症性単球および炎症性樹状細胞の役割の一端が明らかになったことより、今後は治療に応用できるかを検討したい。具体的には、炎症性単球の組織への遊走やホーミングを阻止する化学物質や薬剤を用いることで、SLEの症状、特にフレアを抑制することができるかどうかの検討を進めていきたい。さらに他の自己免疫疾患や炎症性疾患においても炎症性単球が病態に関与している可能性があるため、他の疾患モデルマウスを用いて検討していく。

Research Products

• [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 Pages: 2147
  • DOI: 10.3390/ijms22042147.
  • Peer Reviewed / Open Access
• [Journal Article] A rare combination of holocrine poroma with follicular germinative differentiation. (2021)
  • Author(s): Ogawa K, Mitsui Y, Fukumoto T, Miyagawa F, Shinkuma S, Asada H
  • Journal Title: J Dermatol Volume: 48 Pages: e192-e193
  • DOI: 10.1111/1346-8138.15791.
  • Peer Reviewed
• [Journal Article] Case of systemic sarcoidosis involving skin lesions that exhibited histological evidence of interstitial granulomatous dermatitis accompanied by widespread thrombophlebitis. (2021)
  • Author(s): Miyagawa F, Yamaoka K, Miyamoto S, Ogawa K, Asada H
  • Journal Title: J Dermatol Volume: 48 Pages: e159-e160
  • DOI: 10.1111/1346-8138.15768.
  • Peer Reviewed
• [Journal Article] Anaplastic lymphoma kinase-negative systemic anaplastic large cell lymphoma with secondary involvement of the breast. (2021)
  • Author(s): Miyagawa F, Ogawa K, Asada H
  • Journal Title: J Dermatol Volume: 48 Pages: e90-e91
  • DOI: 10.1111/1346-8138.15678.
  • Peer Reviewed
• [Journal Article] Case of anti-laminin γ1 pemphigoid associated with ulcerative colitis and acquired perforating dermatosis. (2021)
  • Author(s): Kakehi Y, Miyagawa F, Ogawa K, Hashimoto T, Asada H
  • Journal Title: J Dermatol Volume: 48 Pages: e35-e36
  • DOI: 10.1111/1346-8138.15624.
  • Peer Reviewed
• [Journal Article] Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study. (2020)
  • Author(s): Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, Tsukasaki K; for collaborative Investigators.
  • Journal Title: Cancer Sci Volume: 111 Pages: 4567-4580
  • DOI: 10.1111/cas.14658.
  • Peer Reviewed / Open Access
• [Journal Article] Generalized morphea with extensive telangiectasia on the palms. (2020)
  • Author(s): Miyagawa F, Ogawa K, Asada H
  • Journal Title: J Dermatol Volume: 48 Pages: e22-e23
  • DOI: 10.1111/1346-8138.15609.
  • Peer Reviewed
• [Journal Article] Parallel changes in serum thymus and activation-regulated chemokine levels in response to flare-ups in drug-induced hypersensitivity syndrome. (2020)
  • Author(s): Kanatani Y, Miyagawa F, Ogawa K, Arima A, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: e417-e419
  • DOI: 10.1111/1346-8138.15548.
  • Peer Reviewed
• [Journal Article] Apocrine mixed tumor of the skin with panfollicular differentiation: A rare case report with immunohistochemical evaluation. (2020)
  • Author(s): Kurimoto T, Ogawa K, Koga K, Ishida E, Mitsui Y, Nomi K, Miyagawa F, Shinkuma S, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: e408-e410
  • DOI: 10.1111/1346-8138.15539.
  • Peer Reviewed
• [Journal Article] Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus. (2020)
  • Author(s): Miyagawa F, Tagaya Y, Ozato K, Horie K, Asada H
  • Journal Title: J Transl Autoimmun Volume: 15 Pages: 100060
  • DOI: 10.1016/j.jtauto.2020.100060.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Composite EBV-negative marginal zone lymphoma and angioimmunoblastic T-cell lymphoma presenting as multiple subcutaneous nodules. (2020)
  • Author(s): Miyagawa F, Nakajima A, Ogawa K, Takeda M, Nakamine H, Amano I, Asada H
  • Journal Title: Eur J Dermatol Volume: 30 Pages: 427-429
  • DOI: 10.1684/ejd.2020.3810.
  • Peer Reviewed
• [Journal Article] Reduced induction of human β-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies. (2020)
  • Author(s): Ommori R, Nakamura Y, Miyagawa F, Shobatake C, Ogawa K, Koyama F, Sho M, Ota I, Kitahara T, Hontsu S, Muro S, Asada H
  • Journal Title: Clin Exp Dermatol Volume: 45 Pages: 1055-1058
  • DOI: 10.1111/ced.14311.
  • Peer Reviewed
• [Journal Article] Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review. (2020)
  • Author(s): Ogawa K, Fujimoto M, Takai T, Mitsui Y, Iwasa K, Ohsita A, Komori S, Asai J, Azukizawa H, Miyagawa F, Yurugi S, Kuwahara M, Sasaki C, Ando J, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: 770-773
  • DOI: 10.1111/1346-8138.15353.
  • Peer Reviewed
• [Journal Article] Primary cutaneous follicle center lymphomas with high Ki-67 indices arising on the arm and leg. (2020)
  • Author(s): Miyagawa F, Ogawa K, Kurimoto T, Nakajima A, Himuro Y, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: e278-e280
  • DOI: 10.1111/1346-8138.15359.
  • Peer Reviewed
• [Journal Article] Case of nodal nevus with melanocytic cell aggregates in the lymphatic hilum: A potential diagnostic pitfall that requires differentiation from metastatic melanoma of the lymph node. (2020)
  • Author(s): Ogawa K, Kobayashi N, Miyagawa F, Nakai T, Fukumoto T, Mitsui Y, Arai E, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: e242-e244
  • DOI: 10.1111/1346-8138.15325.
  • Peer Reviewed
• [Journal Article] Correlation Between Expression of CD134, a Human Herpesvirus 6 Cellular Receptor, on CD4+ T cells and Th2-type Immune Responses in Drug-induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms. (2020)
  • Author(s): Miyagawa F, Nakamura-Nishimura Y, Kanatani Y, Asada H
  • Journal Title: Acta Derm Venereol Volume: 100 Pages: adv00102
  • DOI: 10.2340/00015555-3465.
  • Peer Reviewed / Open Access
• [Journal Article] Adult-onset Asymmetrical Lipomatosis. (2020)
  • Author(s): Aoki Y, Miyagawa F, Ogawa K, Yurugi S, Kuwahara M, Asada H
  • Journal Title: Acta Derm Venereol Volume: 100 Pages: adv00080
  • DOI: 10.2340/00015555-3439.
  • Peer Reviewed / Open Access
• [Journal Article] First case report of the coexistence of hydrophilic polymer embolism and cholesterol crystal embolism associated with an endovascular procedure. (2020)
  • Author(s): Mashiba K, Mitsui Y, Ogawa K, Miyagawa F, Miyata R, Kuwahara M, Asada H
  • Journal Title: J Dermatol Volume: 47 Pages: e93-e95
  • DOI: 10.1111/1346-8138.15223.
  • Peer Reviewed
• [Presentation] Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine lupus. (2020)
  • Author(s): Fumi Miyagawa, Hideo Asada
  • Organizer: The 45th annual meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Persistent HHV-6 infection has an increased risk of more severe complications in patients with DIHS (2020)
  • Author(s): Yuki Nishimura, Fumi Miyagawa, Hideaki Watanabe, Masahiro Kira, Saeko Nakajima, Yuko Higashi, Hideo Asada
  • Organizer: The 45th annual meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Reduced induction of human b-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by EGFR inhibitors (2020)
  • Author(s): Rie Ommori, Yuki Nakamura, Fumi Miyagawa, Chinatsu Shobatake, Kohei Ogawa, Fumikazu Koyama, Masayuki Sho, Ichiro Ota, Tadashi Kitahara, Shigeto Hontsu, Sigeo Muro, Hideo Asada
  • Organizer: The 45th annual meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus. (2020)
  • Author(s): Fumi Miyagawa, Hideo Asada
  • Organizer: The 78th annual meeting of Society for Investigative Dermatology
  • Int'l Joint Research