本邦ジューリング疱疹状皮膚炎の血清学的・遺伝学的研究

2014 Fiscal Year Research-status Report

• Project/Area Number: 25461678
• Research Institution: Kurume University
• Principal Investigator: 大畑 千佳 久留米大学, 医学部, 准教授 (70362712)
• Co-Investigator(Kenkyū-buntansha): 橋本 隆 久留米大学, 皮膚細胞生物学研究所, 教授 (20129597)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: ジューリング疱疹状皮膚炎 / 自己免疫性水疱症 / HLA-DQ2 / HLA-DQ8 / HLA-DR9 / グルテン

Outline of Annual Research Achievements

ジューリング疱疹状皮膚炎とグルテン過敏性腸症の合併は欧米ではほぼ必発であるが、本邦においては極めて稀である。そのため欧米と本邦のジューリング疱疹状皮膚炎は病因が異なることが予想される。
欧米のジューリング疱疹状皮膚炎患者で強く連鎖するHLAアレルは、約80％がHLA-DQ2で残りがHLA-DQ8であることが知られている。ところが、我々が1976年から2011年の35年間に報告された本邦疱疹状皮膚炎91例を検討したところ（Ohata C, et al, Clin Dev Immunol 2012）、HLA-DQ2,DQ8を有する症例は皆無であった。過去の報告ではHLA-DQB1が調べられたケースが少ないことが、過去の報告の中にこれらのHLAアレルを有する症例が見られなかった理由である可能性が考えられた。
H26年度は本邦のジューリング疱疹状皮膚炎患者16例についてHLAアレル検討した。その結果、HLA-DQ2を有する例はなかったが、6例（37.5％）がHLA-DQ8を有していることが明らかとなった。日本人コントロールにおいてもHLA-DQ2の陽性率はほぼ0%であるため、本邦のジューリング疱疹状皮膚炎患者においては、今後検討症例数が増えてもHLA-DQ2を有する症例は存在しない可能性が高いことが考えられた。
既報告91例においては、直接蛍光抗体法でIgAが顆粒状に沈着する症例群において、HLA-DR9が対象日本人コントロールと比較して優位に高頻度に見られたが、本年度検討した16例においては、コントロール群と比較してその頻度に優位差はなかった。
以上より、グルテン抗原を処理するのに必要なHLA-DQ2もしくはDQ8を有しない症例が6割強存在することが明らかとなり、本邦のジューリング疱疹状皮膚炎には欧米のジューリング疱疹状皮膚炎の発症メカニズムとは異なるメカニズムが存在することが示唆された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

ジューリング疱疹状皮膚炎は希少疾患であるため、試料の蒐集に時間がかかったが、少しずつデータを蓄積した。データをまとめて解析するのに時間を要したが、全体的な進捗状況としてはおおむね順調に進展している。

Strategy for Future Research Activity

次年度は、本邦ジューリング疱疹状皮膚炎患者のHLA解析の追加として、本邦ではあまり一般的に調べられていないHLA-DQA1を解析する予定である。また本邦患者および健常人コントロールのゲノムDNAを用いてゲノムワイド関連解析（genome-wide association study; case-control study）を行い、本症の発症に関与していることが示唆される遺伝子（疾患感受性遺伝子）および染色体上の領域（疾患感受性領域）を同定することを目指す。また、すべてのデータをまとめて論文投稿する予定である。

Research Products

• [Journal Article] Frequent office visits for injections may reduce adalimumab survival rate in patients with psoriasis. (2015)
  • Author(s): Ohata C, Shintani T, Arakawa M, Yoshimura K, Ohyama B, Ishii N, Ono F, Hamada T, Karashima T, Furumura M
  • Journal Title: J Dermatolog Treat Volume: 26 Pages: 312-313
  • DOI: 10.3109/09546634.2014.962470
  • Peer Reviewed
• [Journal Article] Loss of heterozygosity in a case of glomuvenous malformations. (2015)
  • Author(s): Ohata C, Matsuda M, Hamada T, Shintani T, Muto I, Nagata H, Furumura M, Nakama T
  • Journal Title: J Dermatol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/1346-8138.12849.
  • Peer Reviewed
• [Journal Article] Presence of autoimmune regulator and absence of desmoglein 1 in thymoma associated with a pemphigus foliaceus patient. (2015)
  • Author(s): Tsuchisaka A, Kaneko S, Imaoka K, Ota M, Kishimoto K, Tomaru U, Kasahara M, Ohata C, Furumura M, Takamori S, Morita E, Hashimoto T
  • Journal Title: Br J Dermatol Volume: 173 Pages: 268-271
  • DOI: doi: 10.1111/bjd.13617.
  • Peer Reviewed
• [Journal Article] Epidermal polymeric immunoglobulin receptors: leads from intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus. (2015)
  • Author(s): Tsuchisaka A, Ishii N, Hamada T, Teye K, Sogame R, Koga H, Tsuruta D, Ohata C, Furumura M, Hashimoto T
  • Journal Title: Exp Dermatol Volume: 24 Pages: 217-219
  • DOI: 10.1111/exd.12615.
  • Peer Reviewed
• [Journal Article] Clinical and immunological profiles of 25 patients with pemphigoid gestationis. (2015)
  • Author(s): Tani N, Kimura Y, Koga H, Kawakami T, Ohata C, Ishii N, Hashimoto T
  • Journal Title: Br J Dermatol Volume: 172 Pages: 120-129
  • DOI: 10.1111/bjd.13374.
  • Peer Reviewed
• [Journal Article] Anti-desmocollin autoantibodies in non-classical pemphigus. (2015)
  • Author(s): Ishii N, Teye K, Fukuda S, Uehara R, Hachiya T, Koga H, Tsuchisaka A, Numata S, Ohyama B, Tateishi C, Tsuruta D, Furumura M, Hattori S, Kawakami T, Ohata C, Hashimoto T
  • Journal Title: Br J Dermatol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/bjd.13711.
  • Peer Reviewed
• [Journal Article] A case of bullous pemphigoid associated with psoriasis vulgaris showing Hailey-Hailey disease-like histopathological changes in regenerated epidermis without genomic mutation in ATP2C1 or ATP2A2 gene. (2015)
  • Author(s): Iino Y, Kano T, Adachi F, Suzuki M, Nishikawa R, Ishii N, Ohata C, Furumura M, Hamada T, Hashimoto T
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 29 Pages: 1646-1648
  • DOI: 10.1111/jdv.12521.
  • Peer Reviewed
• [Journal Article] Locations of acantholysis in pemphigus vulgaris and pemphigus foliaceus. (2014)
  • Author(s): Ohata C, Ishii N, Furumura M
  • Journal Title: J Cutan Pathol Volume: 41 Pages: 880-889
  • DOI: 10.1111/cup.12384.
  • Peer Reviewed
• [Journal Article] Molluscum contagiosum with CD30+ cell infiltration in a patient with mycosis fungoides. (2014)
  • Author(s): Ohata C, Fukuda S, Hashikawa K, Ishii N, Hamada T, Nakama T, Furumura M, Tsuruta D, Ohshima K, Hashimoto T
  • Journal Title: Am J Dermatopathol Volume: 36 Pages: 685-687
  • DOI: 10.1097/DAD.0000000000000056.
  • Peer Reviewed
• [Journal Article] Hailey-Hailey disease. (2014)
  • Author(s): Ohata C
  • Journal Title: Cutis Volume: 94 Pages: 8, 33-34
  • Peer Reviewed
• [Journal Article] Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University. (2014)
  • Author(s): Yoshimura K, Ishii N, Hamada T, Abe T, Ono F, Hashikawa K, Fukuda S, Ohyama B, Koga H, Sogame R, Teye K, Ochiai T, Nakajima H, Nakajima K, Iijima S, Kanzaki M, Kojima K, Nagatani T, Fujimoto W, Karashima T, Nakama T, Ohata C, Furumura M, Tsuruta D, Hashimoto T
  • Journal Title: Br J Dermatol Volume: 171 Pages: 544-553
  • DOI: 10.1111/bjd.12925.
  • Peer Reviewed
• [Journal Article] Immunological and statistical studies of anti-BP180 antibodies in paraneoplastic pemphigus. (2014)
  • Author(s): Tsuchisaka A, Kawano H, Yasukochi A, Teye K, Ishii N, Koga H, Sogame R, Ohzono A, Krol RP, Kawakami T, Furumura M, Ohata C, Li X, Hashimoto T
  • Journal Title: J Invest Dermatol Volume: 134 Pages: 2283-2287
  • DOI: 10.1038/jid.2014.151.
  • Peer Reviewed
• [Journal Article] Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease. (2014)
  • Author(s): Teye K, Hamada T, Krol RP, Numata S, Ishii N, Matsuda M, Ohata C, Furumura M, Hashimoto T
  • Journal Title: J Dermatol Sci Volume: 75 Pages: 36-42
  • DOI: 10.1016/j.jdermsci.2014.04.003.
  • Peer Reviewed
• [Journal Article] Characterization of two cases of bullous pemphigoid reactive only with BP230 on Japanese enzyme-linked immunosorbent assays. (2014)
  • Author(s): Sasai S, Nishikawa R, Ohzono A, Hayakawa T, Tsuruta D, Kudoh K, Kikuchi T, Hashiguchi M, Ohata C, Furumura M, Koga H, Ishii N, Hashimoto T
  • Journal Title: Acta Derm Venereol Volume: 94 Pages: 734-736
  • DOI: 10.2340/00015555-1848.
  • Peer Reviewed
• [Journal Article] Adenocarcinoma of Moll's gland with multiple metastases. (2014)
  • Author(s): Saruta H, Ohata C, Muto I, Yoshimura K, Inoue Y, Hamada T, Furumura M, Hashimoto T
  • Journal Title: Eur J Dermatol Volume: 24 Pages: 269-271
  • DOI: 10.1684/ejd.2014.2296.
  • Peer Reviewed
• [Journal Article] B-cell activating factor detected on both naive and memory B cells in bullous pemphigoid. (2014)
  • Author(s): Qian H, Kusuhara M, Li X, Tsuruta D, Tsuchisaka A, Ishii N, Koga H, Hayakawa T, Ohara K, Karashima T, Ohyama B, Ohata C, Furumura M, Hashimoto T
  • Journal Title: Exp Dermatol Volume: 23 Pages: 596-605
  • DOI: 10.1111/exd.12421.
  • Peer Reviewed
• [Journal Article] Late-onset Brooke-Spiegler syndrome with family histories of various cancers. (2014)
  • Author(s): Matsuda M, Ohata C, Hamada T, Oiso N, Tsuruta D, Furumura M, Hashimoto T
  • Journal Title: J Dermatol Volume: 41 Pages: 454-456
  • DOI: 10.1111/1346-8138.12451.
  • Peer Reviewed
• [Journal Article] Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease. (2014)
  • Author(s): Matsuda M, Hamada T, Numata S, Teye K, Okazawa H, Imafuku S, Ohata C, Furumura M, Hashimoto T
  • Journal Title: Exp Dermatol Volume: 23 Pages: 514-516
  • DOI: 10.1111/exd.12410.
  • Peer Reviewed
• [Journal Article] Human dermal fibroblast migration induced by fibronectin in autocrine and paracrine manners. (2014)
  • Author(s): Li X, Qian H, Ono F, Tsuchisaka A, Krol RP, Ohara K, Hayakawa T, Matsueda S, Sasada T, Ohata C, Furumura M, Hamada T, Hashimoto T
  • Journal Title: Exp Dermatol Volume: 23 Pages: 682-684
  • DOI: 10.1111/exd.12447.
  • Peer Reviewed
• [Journal Article] Mouse bone marrow-derived dendritic cells can phagocytize the Sporothrix schenckii, and mature and activate the immune response by secreting interleukin-12 and presenting antigens to T lymphocytes. (2014)
  • Author(s): Kusuhara M, Qian H, Li X, Tsuruta D, Tsuchisaka A, Ishii N, Ohata C, Furumura M, Hashimoto T
  • Journal Title: J Dermatol Volume: 41 Pages: 386-392
  • DOI: 10.1111/1346-8138.12472.
  • Peer Reviewed
• [Journal Article] Distinct protein expression and activity of transglutaminases found in different epidermal tumors. (2014)
  • Author(s): Karashima T, Furumura M, Ishii N, Ohyama B, Saruta H, Natsuaki Y, Nakama T, Ohata C, Tsuruta D, Hitomi K, Hashimoto T
  • Journal Title: Exp Dermatol Volume: 23 Pages: 433-435
  • DOI: 10.1111/exd.12418.
  • Peer Reviewed
• [Journal Article] Diagnosis of oral mucous membrane pemphigoid by means of combined serologic testing. (2014)
  • Author(s): Hayakawa T, Furumura M, Fukano H, Li X, Ishii N, Hamada T, Ohata C, Tsuruta D, Shimozato K, Hashimoto T
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol Volume: 117 Pages: 483-496
  • DOI: 10.1016/j.oooo.2013.12.402.
  • Peer Reviewed
• [Journal Article] Antibodies to the amino-terminal domain of desmoglein 1 are retained during transition from pemphigus vulgaris to pemphigus foliaceus. (2014)
  • Author(s): Espana A, Koga H, Suarez-Fernandez R, Ohata C, Ishii N, Irarrazaval I, Teye K, Ohyama B, Hashimoto T
  • Journal Title: Eur J Dermatol Volume: 24 Pages: 174-179
  • DOI: 10.1684/ejd.2014.2277.
  • Peer Reviewed
• [Journal Article] Detection of autoantibodies to precursor proteins of desmogleins in sera of a patient with Bowen carcinoma. (2014)
  • Author(s): Demitsu T, Yamada T, Nakamura S, Kakurai M, Dohmoto T, Kamiya K, Aoyama Y, Iwatsuki K, Yamagami J, Ohyama B, Ohata C, Koga H, Hashimoto T
  • Journal Title: Acta Derm Venereol Volume: 94 Pages: 601-603
  • DOI: 10.2340/00015555-1776.
  • Peer Reviewed
• [Presentation] Loss of heterozygosity in a case of glomuvenous malformations. (2015)
  • Author(s): Chika Ohata, Mitsuhiro Matsuda, Takahiro Hamada, Kwesi Teye, Sanae Numata, Takako Shintani, Ikko Muto, Minao Furumura, Takekuni Nakama.
  • Organizer: 73rd Annual Meeting of American Academy of Dermatology.
  • Place of Presentation: San Francisco, CA. USA
  • Year and Date: 2015-03-20 – 2015-03-24
• [Presentation] Reappraisal of the histopathological features of bullous pemphigoid. (2015)
  • Author(s): Chika Ohata, Norito Ishii, Minao Furumura, Takekuni Nakama.
  • Organizer: 18th Joint Meeting of The International Society of Dermatopathology.
  • Place of Presentation: San Francisco, CA. USA
  • Year and Date: 2015-03-18 – 2015-03-19
• [Presentation] 久留米大学皮膚科における乾癬患者実態調査2014 (2014)
  • Author(s): 大畑千佳、大山文悟、小野文武、辛島正志、濱田尚宏、石井文人、夏秋洋平、猿田寛、合原みち、谷直実、古村南夫、名嘉眞武国
  • Organizer: 第29回日本乾癬学会
  • Place of Presentation: 高知
  • Year and Date: 2014-09-19 – 2014-09-20