Analysis of the dynamic skin immune and physical barrier system by tight junctions and Langerhans cells

2013 Fiscal Year Final Research Report

• Project/Area Number: 22249044
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Keio University
• Principal Investigator: KUBO Akiharu 慶應義塾大学, 医学部, 講師 (70335256)
• Co-Investigator(Kenkyū-buntansha): AMAGAI Masayuki 慶應義塾大学, 医学部, 教授 (90212563) ; NAGAO Keisuke 慶應義塾大学, 医学部, 講師 (40286521) ; OOYAMA Manabu 慶應義塾大学, 医学部, 講師 (10255424)
• Project Period (FY): 2010-05-31 – 2014-03-31
• Keywords: 皮膚バリア / タイトジャンクションバリア / 角質バリア / ランゲルハンス細胞

Research Abstract

Skin barrier is constituted by the stratum corneum barrier and tight junction barrier. Insufficiency of the stratum corneum barrier predispose patients to atopic dermatitis via enhanced percutaneous allergen penetration and subsequent allergic sensitization. We discovered that epidermal Langerhans cells penetrate through the tight junction barrier from inside to outside and take up antigens that penetrate through the stratum corneum but are limited to penetrate into the body by the tight junction barrier. In the atopic dermatitis patients, the tight junction penetration of Langerhans cells are increased in number, suggesting enhanced percutaneous sensitization against external allergens.

Research Products

• [Journal Article] Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis (2013)
  • Author(s): Kubo A, Shiohama A, Sasaki T, Nakabayashi K, Kawasaki H, Atsugi T, Sato S, Shimizu A, Mikami S, Tanizaki H, Uchiyama M, Maeda T, Ito T, Sakabe J, Heike T, Okuyama T, Kosaki R, Kosaki K, Kudoh J, Hata K, Umezawa A, Tokura Y, Ishiko A, Niizeki H, Kabashima K, Mitsuhashi Y, Amagai M
  • Journal Title: Am J Hum Genet Volume: 93 Pages: 945-956
  • DOI: 10.1016/j.ajhg.2013.09.015
  • Peer Reviewed
• [Journal Article] A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis (2013)
  • Author(s): Sasaki T, Shiohama A, Kubo A, Kawasaki H, Ishida-Yamamoto A, Yamada T, Hachiya T, Shimizu A, Okano H, Kudoh J, Amagai M
  • Journal Title: J Allergy Clin Immunol Volume: 132 Pages: 1111-1120.e1114
  • DOI: 10.1016/j.jaci.2013.08.027
  • Peer Reviewed
• [Journal Article] Functional tight junction barrier localizes in the second layer of the stratum granulosum of human epidermis (2013)
  • Author(s): Yoshida K, Yokouchi M, Nagao K, Ishii K, Amagai M, Kubo A
  • Journal Title: J Dermatol Sci Volume: 71 Pages: 89-99
  • DOI: 10.1016/j.jdermsci.2013.04.021
  • Peer Reviewed
• [Journal Article] The stratum corneum comprises three layers with distinct metal-ion barrier properties (2013)
  • Author(s): Kubo A, Ishizaki I, Kubo A, Kawasaki H, Nagao K, Ohashi Y, Amagai M
  • Journal Title: Sci. Rep Volume: 3 Pages: 1731
  • DOI: 10.1038/srep01731
  • Peer Reviewed
• [Journal Article] Mutations in the SASPase Gene (ASPRV1) Are Not Associated with Atopic Eczema or Clinically Dry Skin (2012)
  • Author(s): Sandilands A, Brown SJ, Goh CS, Pohler E, Wilson NJ, Campbell LE, Miyamoto K, Kubo A, Irvine AD, Thawer-Esmail F, Munro CS, McLean WHI, Kudoh J, Amagai M, Matsui T
  • Journal Title: J Invest Dermatol Volume: 132 Pages: 1507-1510
  • DOI: 10.1038/jid.2011.479
  • Peer Reviewed
• [Journal Article] Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin (2012)
  • Author(s): Nagao K, Kobayashi T, Moro K, Ohyama M, Adachi T, Kitashima DY, Ueha S, Horiuchi K, Tanizaki H, Kabashima K, Kubo A, Cho Y-H, Clausen BE, Matsushima K, Suematsu M, Furtado GC, Lira SA, Farber JM, Udey MC, Amagai M
  • Journal Title: Nat Immunol Volume: 13 Pages: 744-752
  • DOI: 10.1038/ni.2353
  • Peer Reviewed
• [Journal Article] Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice (2012)
  • Author(s): Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H, Yamada T, Amagai M
  • Journal Title: J Allergy Clin Immunol Volume: 129 Pages: 1538-1546.e1536
  • DOI: 10.1016/j.jaci.2012.01.068
  • Peer Reviewed
• [Journal Article] Skin barrier disruption : a requirement for allergen sensitization? (2012)
  • Author(s): De Benedetto A, Kubo A, Beck LA
  • Journal Title: J Invest Dermatol Volume: 132 Pages: 949-963
  • DOI: 10.1038/jid.2011.435
  • Peer Reviewed
• [Journal Article] Epidermal barrier dysfunction and cutaneous sensitization in atopic disease (2012)
  • Author(s): Kubo A, Nagao K, Amagai M
  • Journal Title: J Clin Invest Volume: 122 Pages: 440-447
  • DOI: 10.1172/JCI57416
  • Peer Reviewed
• [Journal Article] SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing (2011)
  • Author(s): Matsui T, Miyamoto K, Kubo A, Kawasaki H, Ebihara T, Hata K, Tanahashi S, Ichinose S, Imoto I, Inazawa J, Kudoh J, Amagai M
  • Journal Title: EMBO Mol Med Volume: 3 Pages: 320-333
  • DOI: 10.1002/emmm.201100140
  • Peer Reviewed
• [Journal Article] Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome (2011)
  • Author(s): Ouchi T, Kubo A, Yokouchi M, Adachi T, Kobayashi T, Kitashima D, Fujii H, Clausen B, Koyasu S, Amagai M, Nagao K
  • Journal Title: J Exp Med Volume: 208 Pages: 2607-2613
  • DOI: 10.1084/jem.20111718
  • Peer Reviewed
• [Presentation] The stratum corneum comprises three layers with distinct barrier properties to metal ions (2013)
  • Author(s): Kubo A, Ishizaki I, Kubo A, Kawasaki H, Nagao K, Ohashi Y, Amagai M
  • Organizer: International Investigative Dermatology 2013
  • Place of Presentation: Edinburgh
  • Year and Date: 20130508-11
• [Presentation] Dendritic cells penetrate epidermal tight junction barriers to uptake external antigens : a possible involvement in atopic dermatitis (2012)
  • Author(s): Kubo A, Yoshida K, Yokouchi M, Ishii K, Kawasaki H, Ebihara T, Nagao K, Amagai M
  • Organizer: Molecular Structure and Function of the Apical Junctional Complex in Epithelia and Endothelia 2012
  • Place of Presentation: Melida, Mexico
  • Year and Date: 20121030-1107
• [Presentation] The stratum corneum comprises three layers with distinct barrier properties, as revealed by TOF-SIMS imaging (2012)
  • Author(s): Kubo A, Ishizaki I, Kubo A, Kawasaki H, Ohashi Y, Amagai M
  • Organizer: 62nd Montagna Symposium on the Biology of Skin 2012
  • Place of Presentation: Portland, Oregon
  • Year and Date: 20121011-13
• [Presentation] High-resolution TOF-SIMS Imaging reveals Multi-layered Barrier Structure of the Stratum Corneum of Skin (2012)
  • Author(s): Kubo A, Ishizaki I, Kubo A, Kawasaki H, Ohashi Y, Amagai M
  • Organizer: 19th International Mass Spectrometry Conference
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20120916-17
• [Presentation] Investigation of the tight junction barrier in hair follicles and sebaceous glands (2011)
  • Author(s): Kubo A, Yokouchi M, Atsugi T, Ohyama M, Amagai M
  • Organizer: The 36th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Kyoto
  • Year and Date: 20111209-10
• [Presentation] Langerhans cells but not Langerin-negative inflammatory dendritic epidermal cells gain access to the environment outside the tight junction barrier in atopic dermatitis skin (2011)
  • Author(s): Yoshida K, Kubo A, Kawasaki H, Nagao K, Amagai M
  • Organizer: 2011 The annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Chiba, Japan
  • Year and Date: 20111127-29
• [Presentation] Langerin-positive Langerhans cells but not Langerin-negative inflammatory dendritic epidermal cells penetrate epidermal tight junction barriers in atopic dermatitis (2011)
  • Author(s): Kubo A, Yoshida K, Yokouchi M, Ishii K, Kawasaki H, Ebihara T, Nagao K, Amagai M
  • Organizer: 12th International Workshop on Langerhans Cells
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20111004-06
• [Presentation] Langerin-positive Langerhans cells but not Langerin-negative inflammatory dendritic epidermal cells penetrate epidermal tight junction barriers in atopic dermatitis (2011)
  • Author(s): Yoshida K, Kubo A, Yokouchi M, Ishii K, Kawasaki H, Ebihara T, Nagao K, Amagai M
  • Organizer: 41st Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110908-10
• [Presentation] Langerhans cell play an essential role in inducing protective humoral immune response subsequent to antigen uptake through tight junctions (2011)
  • Author(s): Kitashima D, Fujii H, Clausen B, Koyasu S, Amagai M, Nagao K
  • Organizer: 41st Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110907-10
• [Presentation] High-resolution TOF-SIMS imaging and sequential immunofluorescent analysis of multi-layered barrier structure of the mouse skin stratum corneum (2011)
  • Author(s): Kubo A, Ishizaki I, Kubo A, Kawasaki H, Ohashi Y, Amagai M
  • Organizer: 59th ASMS Conference on Mass Spectrometry and Allied Topics
  • Place of Presentation: Denver, Colorado
  • Year and Date: 2011-06-09
• [Presentation] Human epidermal tight junctions are functional and allow penetration of activated Langerhans cell dendrites (2011)
  • Author(s): Yoshida K, Kubo A, Yokouchi M, Ishii K, Kawasaki H, Ebihara T, Ohyama M, Nagao K, Amagai M
  • Organizer: 71th Annual Meeting Society for Investigative Dermatology
  • Place of Presentation: Phoenix, Arizona
  • Year and Date: 2011-05-05
• [Presentation] Impaired stratum corneum barrier and enhanced percutaneous immune responses in filaggrin knockout mice (2011)
  • Author(s): Kawasaki H, Nagao K, Kubo A, Hata T, Mizuno H, Yamada T, Amagai M
  • Organizer: 71th Annual Meeting Society for Investigative Dermatology
  • Place of Presentation: Phoenix, Arizona
  • Year and Date: 2011-05-05
• [Presentation] Maintenance of intact epidermal tight junction barriers in filaggrin-deficient mouse models (2010)
  • Author(s): Yokouchi M, Kubo A, Kawasaki H, Amagai M
  • Organizer: The 35th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Wakayama, Japan
  • Year and Date: 2010-12-03
• [Presentation] Langerhans cell dendrites penetrate through epidermal tight junction barrier during foreign antigen uptake (2010)
  • Author(s): Kubo A, Nagao K, Yokouchi M, Yoshida K, Sasaki H, Amagai M
  • Organizer: 70th Annual Meeting Society for Investigative Dermatology
  • Place of Presentation: Atlanta, Georgia, USA
  • Year and Date: 2010-05-06
• [Book] "Molecular Dermatology : Methods and Protocols", 3D visualization of epidermal Langerhans cells. Methods Mol Biol (961) (doi:10.1007/978-1-62703-227-8_5) (2013)
  • Author(s): Kubo A, Nagao K, Amagai M
  • Total Pages: 119-127
  • Publisher: Springer