Analysis of mechanisms for blister formation via autoantibodies-mediated interference of adhesion system of laminins and integrins

• Project/Area Number: 24659534
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: Kurume University
• Principal Investigator: HASHIMOTO Takashi 久留米大学, 医学部, 教授 (20129597)
• Co-Investigator(Kenkyū-buntansha): HAMADA Takahiro 久留米大学, 医学部, 講師 (40320204) ; ISHII Norito 久留米大学, 医学部, 講師 (80330827) ; TSUCHISAKA Atsunari 久留米大学, 医学部, 研究員 (50599313) ; TEYE Kwesi 久留米大学, 医学部, 研究員 (30599303)
• Project Period (FY): 2012-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 眼型粘膜類天疱瘡 / インテグリンベータ4 / ヘミデスモソーム

Research Abstract

By novel immunoblotting using newly established hemidesmosome-rich fraction, in which BP230, BP180, laminin 332, integrin alpha 6, integrin beta 4 are concentrated, IgG antibodies in the sera from patients with pure ocular mucous membrane pemphigoid (MMP) reacted specifically with integrin beta 4, as well as recombinant protein of integrin beta 4. IgG antibodies in the sera from patients with anti-laminin 332 MMP reacted with 3 laminin 332 subunits in various patterns. These results indicated that major autoantigen for pure ocular MMP is integrin beta 4. In addition, the novel immunoblotting using newly established hemidesmosome-rich fraction should be a useful tool to detect various autoantigen present at epidermal basement membrane zone, including integrin beta 4 and laminin 332.

Research Products

• [Journal Article] Zillikens D : From epidemiology and genetics to diagnostics, outcome measures and novel treatments in autoimmune bullous diseases (2014)
  • Author(s): Ludwig RJ, Borradori L, Diaz LA, Hashimoto T, Hertl M, Ibrahim SM, Jonkman MF, Kitajima Y, Murrell DF, Schmidt E, Shimizu H, Stanley JR, Woodley D
  • Journal Title: J Invest Dermatol Volume: (in press)
  • 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 Issue: 8 Pages: 2283-2287
  • DOI: 10.1038/jid.2014.151
  • Peer Reviewed
• [Journal Article] Ex Vivo Pathogenicity of Anti-Laminin gamma1 Autoantibodies (2014)
  • Author(s): Florea F, Bernards C, Caproni M, Kleindienst J, Hashimoto T, Koch M, Sitaru C
  • Journal Title: Am J Pathol Volume: 184(2) Issue: 2 Pages: 494-506
  • DOI: 10.1016/j.ajpath.2013.10.019
  • Peer Reviewed
• [Journal Article] From epidemiology and genetics to diagnostics, outcome measures and novel treatments in autoimmune bullous diseases (2014)
  • Author(s): Ludwig RJ, Borradori L, Diaz LA, Hashimoto T, Hertl M, Ibrahim SM, Jonkman MF, Kitajima Y, Murrell DF, Schmidt E, Shimizu H, Stanley JR, Woodley D, Zillikens D
  • Journal Title: J Invest Dermatol Volume: in press
  • Peer Reviewed
• [Journal Article] Molecular diagnosis of autoimmune blistering diseases (2013)
  • Author(s): Tsuruta D, Dainichi T, Hamada T, Ishii N, Hashimoto T
  • Journal Title: Methods Mol Biol Volume: 961 Pages: 17-32
  • DOI: 10.1007/978-1-62703-227-8_2
  • ISBN: 9781627032261, 9781627032278
  • Peer Reviewed
• [Journal Article] Three Cases of Linear IgA/IgG Bullous Dermatosis Showing IgA and IgG Reactivity With Multiple Antigens, Particularly Laminin-332 (2013)
  • Author(s): Sakaguchi M, Bito T, Oda Y, Kikusawa A, Nishigori C, Munetsugu T, Yokozeki H, Itotani Y, Niguma T, Tsuruta D, Tateishi C, Ishii N, Koga H, Hashimoto T
  • Journal Title: JAMA Dermatol Volume: 149(11) Issue: 11 Pages: 1308-1313
  • DOI: 10.1001/jamadermatol.2013.5691
  • Peer Reviewed
• [Journal Article] An attempt to develop mouse model for anti-laminin gamma1 pemphigoid (2013)
  • Author(s): Koga H, Ishii N, Dainichi T, Tsuruta D, Hamada T, Ohata C, Karashima T, Furumura M, Hashimoto T
  • Journal Title: J Dermatol Sci Volume: 70(2) Issue: 2 Pages: 108-115
  • DOI: 10.1016/j.jdermsci.2013.01.001
  • Peer Reviewed
• [Journal Article] Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway (2013)
  • Author(s): Hiroyasu S, Ozawa T, Kobayashi H, Ishii M, Aoyama Y, Kitajima Y, Hashimoto T, Jones JC, Tsuruta D
  • Journal Title: Am J Pathol Volume: 182(3) Issue: 3 Pages: 828-840
  • DOI: 10.1016/j.ajpath.2012.11.029
  • Peer Reviewed
• [Journal Article] How do keratinizing disorders and blistering disorders overlap (2013)
  • Author(s): Hamada T, Tsuruta D, Fukuda S, Ishii N, Teye K, Numata S, Dainichi T, Karashima T, Ohata C, Furumura M,Hashimoto T.
  • Journal Title: Exp Dermatol Volume: 22 Issue: 2 Pages: 83-87
  • DOI: 10.1111/exd.12021
  • Peer Reviewed
• [Journal Article] Efficacy and safety of rituximab treatment in Indian pemphigus patients. (2013)
  • Author(s): Kanwar AJ, Tsuruta D, Vinay K, Koga H, Ishii N, Dainichi T, Hashimoto T.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 27(1) Issue: 1
  • DOI: 10.1111/j.1468-3083.2011.04391.x
  • Peer Reviewed
• [Journal Article] 眼型粘膜類天疱瘡 (2013)
  • Author(s): 十亀良介
  • Journal Title: Visual Dermatology Volume: 第2巻 Pages: 168-169
• [Journal Article] Bullous Pemphigoid IgG Induces BP180 Internalization via a Macropinocytic Pathway (2013)
  • Author(s): Hiroyasu S, Ozawa T, Kobayashi H, Ishii M, Aoyama Y, Kitajima Y, Hashimoto T, Jones JC, Tsuruta D.
  • Journal Title: Am J Pathol Volume: 182(3) Pages: 828-40
  • Peer Reviewed
• [Journal Article] Anti-alpha-2-macroglobulin-like-1 Autoantibodies are Detected Frequently and may be Pathogenic in Paraneoplastic Pemphigus. (2013)
  • Author(s): Numata S, Teye K, Tsuruta D, Sogame R, Ishii N, Koga H, Natsuaki Y, Tsuchisaka A, Hamada T, Karashima T,Nakama T, Furumura M, Ohata C, Kawakami T, Schepens I, Borradori L, Hashimoto T.
  • Journal Title: J Invest Dermatol Volume: Epub ahead of print Issue: 7 Pages: 1785-1793
  • DOI: 10.1038/jid.2013.65
  • Peer Reviewed
• [Journal Article] Pathogenicity of autoantibodies in anti-p200 pemphigoid (2012)
  • Author(s): Vafia K, Groth S, Beckmann T, Hirose M, Dworschak J, Recke A, Ludwig RJ, Hashimoto T, Zillikens D, Schmidt E
  • Journal Title: PLoS One Volume: 7(7) Issue: 7 Pages: e41769-e41769
  • DOI: 10.1371/journal.pone.0041769
  • Peer Reviewed
• [Journal Article] Pathogenesis of epidermolysis bullosa acquisita, an autoimmune subepidermal bullous disease (2012)
  • Author(s): Hashimoto T, Ishii N, Ohata C, Furumura M
  • Journal Title: J Pathol Volume: 228(1) Issue: 1 Pages: 1-7
  • DOI: 10.1002/path.4062
  • Peer Reviewed
• [Journal Article] Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface (2012)
  • Author(s): Di Zenzo G, Di Lullo G, Corti D, Calabresi V, Sinistro A, Vanzetta F, Didona B, Cianchini G, Hertl M, Eming R, Amagai M, Ohyama B, Hashimoto T, Sloostra J, Sallusto F, Zambruno G, Lanzavecchia A
  • Journal Title: J Clin Invest Volume: 122(10) Issue: 10 Pages: 3781-3790
  • DOI: 10.1172/jci64413
  • Peer Reviewed
• [Journal Article] Five Japanese cases of anti-Dsg1 antibody positive and anti-Dsg3 antibody negative pemphigus with oral lesions. (2012)
  • Author(s): Koga H, Ohyama B, Tsuruta D, Ishii N, Hamada T, Dainichi T, Natsuaki Y, Sogame R, Fukuda S, Karashima T, Tada J, Yamashiro M, Uezato H, Chan PT, Hashimoto T.
  • Journal Title: Br J Dermatol Volume: 166(5) Issue: 5 Pages: 976-980
  • DOI: 10.1111/j.1365-2133.2012.10827.x
  • Peer Reviewed
• [Journal Article] Interaction of plectin and intermediate filaments. (2012)
  • Author(s): Karashima T, Tsuruta D, Hamada T, Ishii N, Ono F, Hashikawa K, Ohyama B, Natsuaki Y, Fukuda S, Koga H,Sogame R, Nakama T, Dainichi T, Hashimoto T.
  • Journal Title: J Dermatol Sci Volume: 66 Issue: 1 Pages: 44-50
  • DOI: 10.1016/j.jdermsci.2012.01.008
  • Peer Reviewed
• [Journal Article] Non-scarring skin blistering disease and mucosal lesions with IgA autoantibodies reactive with collagen VII and IgG reactivity with laminin γ2. (2012)
  • Author(s): Florea F, Torio-Padron N, Hashimoto T, Sitaru C.
  • Journal Title: Br J Dermatol Volume: 167(4) Issue: 4 Pages: 938-41
  • DOI: 10.1111/j.1365-2133.2012.10946.x
  • Peer Reviewed
• [Journal Article] Prevalence of collagen VII-specific autoantibodies in patients with autoimmune and inflammatory diseases. (2012)
  • Author(s): Licarete E, Ganz S, Recknagel M, Di Zenzo G, Hashimoto T, Hertl M, Zambruno G, Hundorfean G, Mudter J, Neurath M, Bruckner-Tuderman L, Sitaru C.
  • Journal Title: BMC Immunol Volume: 13(1) Issue: 1 Pages: 16-16
  • DOI: 10.1186/1471-2172-13-16
  • Peer Reviewed
• [Journal Article] Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient. (2012)
  • Author(s): Tsuruta D, Nishikawa T, Yamagami J, Hashimoto T.
  • Journal Title: J Dermatol Volume: 39(9) Issue: 9 Pages: 787-789
  • DOI: 10.1111/j.1346-8138.2012.01562.x
  • Peer Reviewed
• [Journal Article] Decline of disease activity and autoantibodies to desmoglein 3 and envoplakin by oral prednisolone in paraneoplastic pemphigus with benign thymoma. (2012)
  • Author(s): Ishii N, Hamada T, Koga H, Sogame R, Ohyama B, Fukuda S, Natsuaki Y, Dainichi T, Karashima T, Nakama T, Tsuruta D, Hashimoto T.
  • Journal Title: Eur J Dermatol Volume: 22(4) Issue: 4 Pages: 547-549
  • DOI: 10.1684/ejd.2012.1742
  • Peer Reviewed
• [Journal Article] Mucous membrane pemphigoid with antibodies againt ß3 subunit of laminin-332: First report from India. (2012)
  • Author(s): Kanwar AJ, Vinay K, Koga H, Hashimoto T.
  • Journal Title: Indian J Dermatol Venereol Leprol Volume: 78(4) Issue: 4 Pages: 475-479
  • DOI: 10.4103/0378-6323.98079
  • Peer Reviewed
• [Journal Article] Distinct Characteristics in Japanese Dermatitis Herpetiformis: A Review of All 91 Japanese Patients over the Last 35 Years. (2012)
  • Author(s): Ohata C, Ishii N, Hamada T, Shimomura Y, Niizeki H, Dainichi T, Furumura M, Tsuruta D, Hashimoto T.
  • Journal Title: Clin Dev Immunol Volume: 2012 Pages: 562168-562168
  • DOI: 10.1155/2012/562168
  • Peer Reviewed
• [Journal Article] Diagnosis and treatment of pemphigus. (2012)
  • Author(s): Tsuruta D, Ishii N, Hashimoto T.
  • Journal Title: Immunotherapy Volume: 4(7) Issue: 7 Pages: 735-745
  • DOI: 10.2217/imt.12.67
  • Peer Reviewed
• [Journal Article] Concurrence of bullous pemphigoid and herpetiform pemphigus with igg antibodies to desmogleins 1/3 and desmocollins 1-3. (2012)
  • Author(s): Ohata C, Koga H, Teye K, Ishii N, Hamada T, Dainichi T, Furumura M, Sato M, Sueki H, Hashimoto T.
  • Journal Title: Br J Dermatol Volume: 168(4) Issue: 4 Pages: 879-81
  • DOI: 10.1111/bjd.12019
  • Peer Reviewed
• [Journal Article] Fluorescence overlay antigen mapping using laser scanning confocal microscopy differentiates linear IgA bullous dermatosis from epidermolysis bullosa acquisita mediated by IgA. (2012)
  • Author(s): Wozniak K, Hashimoto T, Ishii N, Koga H, Huczek M, Kowalewski C.
  • Journal Title: Br J Dermatol Volume: 168(3) Issue: 3 Pages: 634-8
  • DOI: 10.1111/bjd.12017
  • Peer Reviewed
• [Journal Article] Retrospective analysis of 12 Korean patients with paraneoplastic pemphigus. (2012)
  • Author(s): Choi Y, Nam KH, Lee JB, Lee JY, Ihm CW, Lee SE, Oh SH, Hashimoto T, Kim SC.
  • Journal Title: J Dermatol Volume: 39(12) Issue: 12 Pages: 973-981
  • DOI: 10.1111/j.1346-8138.2012.01655.x
  • Peer Reviewed
• [Journal Article] Mizoribine treatment for antihistamine-resistant chronic autoimmune urticaria. (2012)
  • Author(s): Hashimoto T, Kawakami T, Ishii N, Ishii K, Karashima T, Nakama T, Tsuruta D, Dainichi T, Hide M, Hamada T.
  • Journal Title: Dermatol Ther Volume: 25(4) Issue: 4 Pages: 379-381
  • DOI: 10.1111/j.1529-8019.2012.01468.x
  • Peer Reviewed
• [Journal Article] Therapeutic effect of mizoribine on pemphigus vulgaris and pemphigus foliaceus. (2012)
  • Author(s): Hashimoto T, Kawakami T, Koga H, Ohyama B, Hamada T, Dainichi T, Nakama T, Yasumoto S, Tsuruta D, Ishii N.
  • Journal Title: Dermatol Ther Volume: 25(4) Issue: 4 Pages: 382-385
  • DOI: 10.1111/j.1529-8019.2012.01469.x
  • Peer Reviewed
• [Journal Article] Childhood pemphigus vulgaris successfully treated with rituximab. (2012)
  • Author(s): Kanwar AJ, Sawatkar GU, Vinay K, Hashimoto T.
  • Journal Title: Indian J Dermatol Venereol Leprol Volume: 78(5) Issue: 5 Pages: 632-634
  • DOI: 10.4103/0378-6323.100587
  • Peer Reviewed
• [Journal Article] Pemphigoid with autoantibodies to all laminin 332 subunits and BP230 developing vesicles within psoriatic plaques. (2012)
  • Author(s): Ohata C, Mori Y, Tokita T, Koga H, Ohyama B, Sogame R, Hamada T, Ishii N, Furumura M, Hashimoto T.
  • Journal Title: Eur J Dermatol Volume: 22(6) Issue: 6 Pages: 812-3
  • DOI: 10.1684/ejd.2012.1858
  • Peer Reviewed
• [Journal Article] 水疱症に対する使い方，予期せぬ結果とその対策 (2012)
  • Author(s): 石井文人，橋本 隆
  • Journal Title: Visual Dermatol Volume: 11(6) Pages: 600-604
• [Journal Article] 類天疱瘡：高齢者の非ステロイド療法 (2012)
  • Author(s): 名嘉眞武国，橋本 隆
  • Journal Title: デルマ Volume: 190 Pages: 94-99
• [Journal Article] Premmune抗Dsg1抗体ELISA「コスミック」およびPremmune抗Dsg3抗体ELISA「コスミック」の基礎的・臨床的検討 (2012)
  • Author(s): 橋本 隆，石井文人
  • Journal Title: 医学と薬学 Volume: 68(1) Pages: 143-148
• [Journal Article] Premmune抗BP180抗体ELISA「コスミック」の基礎的・臨床的検討 (2012)
  • Author(s): 橋本 隆，石井文人
  • Journal Title: 医学と薬学 Volume: 68(1) Pages: 143-148
• [Journal Article] Immunoglobulin G deposition to nonhemidesmosomal lamina lucida and early neutrophil involvement are characteristic features in a case of anti-p200 pemphigoid (2012)
  • Author(s): Shimizu A, Funakoshi T, Ishibashi M, Yoshida T, Koga H, Hashimoto T, Amagai M, Ishiko A.
  • Journal Title: Br J Dermatol Volume: 168(3) Issue: 3 Pages: 647-55
  • DOI: 10.1111/bjd.12033
  • Peer Reviewed
• [Journal Article] Epitope spreading is rarely found in pemphigus vulgaris by large-scale longitudinal study using desmoglein 2-based swapped molecules (2012)
  • Author(s): Ohyama, B.
  • Journal Title: J Invest Dermatol Volume: 132 Issue: 4 Pages: 1158-1168
  • DOI: 10.1038/jid.2011.448
  • Peer Reviewed
• [Presentation] Identification of novel autoantigens and new classification in autoimmune bullous diseases (2013)
  • Author(s): Hashimoto T
  • Organizer: The 30-year Anniversary Symposium of Department of Dermatology, Gangnam Severance Hospital
  • Place of Presentation: Korea
• [Presentation] Identification of autoantigens and development of modern serological diagnostics for various autoimmune blistering skin diseases (poster) (2013)
  • Author(s): Hashimoto T
  • Organizer: 78^<th> Cold Spring Harbor Symposium on Quantitative Biology Immunity & Tolerance
  • Place of Presentation: NY
• [Presentation] New classification of autoimmune bullous diseases (2013)
  • Author(s): Hashimoto T, Ishii N, Tsuchisaka A, Natsuaki Y, Teye K, Numata S
  • Organizer: Takashi Hashimoto (Japan) International preIID 2013 Satellite Meeting on Autoimmune Bullous Diseases (AIBD)
  • Place of Presentation: Lubeck
• [Presentation] New classification of autoimmune bullous diseases (2013)
  • Author(s): Takashi Hashimoto, Norito Ishii, Atsunari Tsuchisaka, Yohei Natsuaki, Teye Kwesi, Sanae Numata
  • Organizer: International preIID 2013 Satellite Meeting on Autoimmune Bullous Diseases (AIBD)
  • Place of Presentation: リューベック、ドイツ
• [Presentation] Identification of autoantigens and development of modern serological diagnostics for various autoimmune blistering skin diseases (2013)
  • Author(s): Takashi Hashimoto
  • Organizer: 78th Cold Spring Harbor Symposium on Quantitative Biology Immunity & Tolerance
  • Place of Presentation: ニューヨーク、アメリカ
• [Presentation] Identification of novel autoantigens and new classification in autoimmune bullous diseases (2013)
  • Author(s): Takashi Hashimoto
  • Organizer: The 30-year Anniversary Symposium of Department of Dermatology, Gangnam Severance Hospital
  • Place of Presentation: ソウル、韓国
• [Presentation] Isolation of mouse monoclonal aitibodies reactive with maturation-related unique epitope(s) on human type VII collagen (2012)
  • Author(s): Hayakawa T, Hirako Y, Teye K, Hamada T, Ishii N, Furumura M, Tsuruta D, Tateishi C, Shinkuma S, Shimizu H, Fukano H, Shimozato K, Owaribe K, Hashimoto T
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okinawa
• [Presentation] An attempt to identify antigen for IgA pemphigus accidentally showed the presence of transmembrane secretory component in keratinocytes (2012)
  • Author(s): Tsuchisaka A, Ishii N, Koga H, Hamada T, Ohata C, Furumura M, Hashimoto T
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okinawa
• [Presentation] Newly developed IgA ELISAs of eukaryotic recombinant proteins of desmocollins 1-3 are more sensitive and specific than baculoprotein ELISAs (2012)
  • Author(s): Teye K, Ishii N, Koga H, Hamada T, Karashima T, Numata S, Ohata C, Furumura, M, Hashimoto T
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okinawa
• [Presentation] Molecular studies of six pemphigus vulgaris cases in remission stage showed paradoxical changes of high titer antiーdesmoglein 3 antibodies (2012)
  • Author(s): Ohata C, Koga H, Ohyama B, Ishii N, Hamada T, Furumura M, Hashimoto T
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okinawa
• [Presentation] Large scale study using novel antigen detection system defined human β4 integrin as the major autoantigen for pure ocular mucous membrane pemphigoid
  • Author(s): 十亀良介、平子善章、鶴田大輔、石井文人、古賀浩嗣、濱田尚宏、辛島正志、大畑千佳、古村南夫、坪田一男、木下茂、橋本隆
  • Organizer: 第34回水疱症研究会
  • Place of Presentation: 弘前市（青森）
• [Presentation] Large scale study using novel antigen detection system defined human β4 integrin as the major autoantigen for pure ocular mucous membrane pemphigoid
  • Author(s): 十亀良介
  • Organizer: 第34回水疱症研究会
  • Place of Presentation: 弘前市(青森）