研究内容

筑波大皮膚科では、皮膚免疫・アレルギー、角化症、母斑症などの発症メカニズム、疫学、治療法の評価、新規治療法の開発などの研究に力を注いできています。また、2013年11月に着任した藤本教授は、これまで東京大学、Duke大学、国立国際医療研究センター、金沢大学などにおいて、強皮症や皮膚筋炎をはじめとする膠原病やB細胞を中心とした免疫学の研究を行ってきました。今後は、これらの双方の領域と手法を併せて新しい研究にチャレンジしていきます。

これまでの主な研究内容と成果

B細胞

CD19やCD22などの膜表面シグナル伝達分子を中心にB細胞におけるシグナル伝達メカニズムと自己免疫疾患との関連について研究を行ってきました。また、免疫反応を抑制する新しいB細胞サブセットである「制御性B細胞」の皮膚免疫疾患における役割について先駆的な成果を上げています。


  • Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K, Tedder TF, Fujimoto M. Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease. Blood. 2013;121:3274-83.
  • Jin G, Hamaguchi Y, Matsushita T, Hasegawa M, Huu DL, Ishiura N, Naka K, Hirao A, Takehara K, Fujimoto M. BLNK expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells. J Allergy Clin Immunol. 2013;131:1674-82 .
  • Nakashima H, Hamaguchi Y, Watanabe R, Ishiura N, Kuwano Y, Okochi H, Takahashi Y, Tamaki K, Sato S, Tedder TF, Fujimoto M. CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions. J Immunol. 2010;184 4637-45.
  • Watanabe R, Ishiura N, Nakashima H, Kuwano Y, Okochi H, Tamaki K, Sato S, Tedder TF, Fujimoto M. Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol. 2010;184:4801-9.
  • Haas KM*, Watanabe R*, Matsushita T, Nakashima H, Ishiura N, Okochi H, Fujimoto M, Tedder TF. Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol. 2010;184:4789-800. *, co-first authors.
  • Ishiura N, Nakashima H, Watanabe R, Kuwano Y, Adachi T, Takahashi Y, Tsubata T, Oko chi H, Tamaki K, Tedder TF, Fujimoto M. Differential phosphorylation of functional tyrosines in CD19 modulates B lymphocyte activation. Eur J Immunol. 2010; 40:1192-1204.
  • Matsushita T, Yanaba K, Bouaziz J-D, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation while other B cells promote disease progression. J Clin Invest. 2008;118:3420-30.
  • Yanaba K, Bouaziz J-D, Hass KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhighCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28:639-650.
  • Watanabe R, Fujimoto M, Ishiura N, Kuwano Y, Nakashima H, Yazawa N, Okochi H, Sato S, Tedder TF, Tamaki K. CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol. 2007;171:560-70.
  • Fujimoto M, Kuwano Y, Watanabe R, Asashima N, Nakashima H, Yoshitake S, Okochi H, Tamaki K, Poe JC, Tedder TF, Sato S. B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation. J Immunol. 2006;176:873-9.
  • Matsushita T, Fujimoto M, Hasegawa M, Komura K, Takehara K, Tedder TF, Sato S. Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response. Am J Pathol. 2006;168:812-21.
  • Poe JC, Fujimoto Y, Hasegawa M, Hass KM, Sanford I, Bock CB, Fujimoto M, Tedder TF. CD22 regulates B lymphocyte function in vivo through both ligand-dependent and -independent mechanisms. Nature Immunol. 2004; 5: 1078-87.
  • Yazawa N, Fujimoto M, Sato S, Miyake K, Asano N, Takeuchi O, Nagai, N, Okochi H, Takeda K, Akira S, Tedder TF, Tamaki K. CD19 regulates innate immunity by toll-like receptor RP105 signaling in B lymphocytes. Blood. 2003;102:1374-80.
  • Fujimoto M, Poe JC, Satterthwaite AB, Wahl MI, Witte ON, Tedder TF. Complementary roles for CD19 and Bruton’s tyrosine kinase in B lymphocyte signal transduction. J Immunol. 2002;168:5465-76.
  • Fujimoto M, Poe JC, Hasegawa M, Tedder TF. CD19 amplification of B lymphocyte antigen receptor-induced Ca2+ responses: a role for Lyn sequestration in extinguishing negative regulation. J Biol Chem. 2001;276:44820-7.
  • Fujimoto M, Fujimoto Y, Poe JC, Jansen PJ, Lowell CA, DeFranco AL, Tedder TF. CD19 regulates Src-family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity. 2000; 13:47-57.
  • Fujimoto M, Bradney A, Poe JC, Steeber DA, Tedder TF. Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop. Immunity. 1999;11:191-200.
  • Fujimoto M, Poe JC, Jansen PJ, Sato S, Tedder TF. CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation. J Immunol. 1999;162:7088-94.

強皮症

強皮症においてまだ解明されていない大きな謎である「自己免疫と線維化の関係」に主に焦点をあて、動物モデルを用いた基礎的研究から臨床的研究まで,新規治療法の開発を含めて幅広く行っています。


  • Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K, Fujimoto M. FTY720 ameliorates murine Scl-cGVHD by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin. Arthritis Rheum. 2013;65:1624-35.
  • Okamoto Y, Hasegawa M, Matsushita T, Hamaguchi Y, Le Huu D, Iwakura Y, Fujimoto M, Takehara K. Potential roles of interleukin 17A in the development of skin fibrosis. Arthritis Rheum. 2012;64:3726-35.
  • Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K, Fujimoto M. IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. J Invest Dermatol. 2012;132:2752-61.
  • Ueda-Hayakawa I, Hasegawa M, Kumada S, Tanaka C, Komura K, Hamaguchi Y, Takehara K, Fujimoto M. The usefulness of anti-cyclic citrullinated peptide antibody and rheumatoid factor to detect rheumatoid arthritis in patients with systemic sclerosis. Rheumatology. 2010;49:2135-9.
  • Tanaka C, Fujimoto M, Hamaguchi Y, Sato S, Takehara K, Hasegawa M. Inducible costimulator ligand (ICOSL) regulates bleomycin-induced lung and skin fibrosis independent of ICOS-ICOSL pathway. Arthritis Rheum. 2010;62:1723-32.
  • Komura K, Fujimoto M, Yanaba K, Matsushita T, Matsushita Y, Horikawa M, Ogawa F, Shimizu K, Hasegawa M, Takehara K, Sato S. Blockade of CD40-CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse. Ann Rheum Dis. 2008;67:867-72.
  • Matsushita T, Fujimoto M, Hasegawa M, Matsuishita Y, Komura K, Ogawa F, Watanabe R, Takehara K, Sato S. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127:2772-80.
  • Horikawa M, Fujimoto M, Hasegawa M, Matsushita T, Hamaguchi Y, Kawasuji A, Matsushita Y, Fujita T, Ogawa F, Takehara K, Steeber DA, Sato S. E- and P-selectins synergistically inhibit bleomycin-induced pulmonary fibrosis. Am J Pathol. 2006 169: 740-9.
  • Asano N, Fujimoto M, Yazawa N, Shirasawa S, Hasegawa M, Okochi H, Tamaki K, Tedder TF, Sato S. B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol. 2004;165: 641-50.
  • Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004 50:1918-27
  • Saito E, Fujimoto M, Hasegawa M, Komura K, Hamaguchi Y, Kaburagi Y, Nagaoka T, Takehara K, Tedder TF, Sato S. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the Tight Skin mice. J Clin Invest. 2002;109:1453-62.
  • Fujimoto M, Shimozuma M, Yazawa N, Kubo M, Ihn H, Sato S, Tamaki T, Kikuchi K, Tamaki K. Prevalence and clinical relevance of 52-kDa and 60-kDa Ro/SS-A autoantibodies in Japanese patients with systemic sclerosis. Ann Rheum Dis. 1997;56:667-70.
  • Fujimoto M, Kikuchi K, Tamaki T, Yazawa N, Kubo M, Ihn H, Sato S, Soma Y, Tamaki K. Distribution of anti-p80-coilin autoantibody in collagen diseases and various skin diseases. Br J Dermatol. 1997;137:916-920.
  • Fujimoto M, Sato S, Ihn H, Kikuchi K, Tamaki T, Tamaki K, Takehara K. Antiubiquitin antibody in localized scleorderma. Ann Rheum Dis. 1996;55:399-402.
  • Fujimoto M, Sato S, Takehara K, Nojima Y, Soma Y, Kikuchi K, Ihn H, Igarashi A, Tamaki K. Detection of antiribosomal P protein antibodies in patients with systemic sclerosis. Br J Rheumatol. 1995;34:908-11.
  • Fujimoto M, Sato S, Ihn H, Kikuchi K, Tamaki K, Takehara K. Autoantibodies to pyruvate dehydroghenase complex in patients with systemic sclerosis: Possible role of anti-E1a antibody as a serologic indicator for development of primary biliary cirrhosis. Arthritis Rheum. 1995;38:985-9.

皮膚筋炎

自己抗体からのアプローチを中心に皮膚筋炎の病型分類や病態の解明を目指しています。特に、悪性腫瘍合併皮膚筋炎のマーカーとなる抗155/140抗体をはじめて報告し、その対応抗原や臨床的意義を明らかにしました。


  • Oishi K, Hamaguchi Y, Matsushita T, Hasegawa M, Okiyama N, Dernedde J, Weinhart M, Haag R, Tedder TF, Takehara K, Kohsaka H, Fujimoto M. A crucial role of L-selectin in C protein-induced experimental polymyositis of mice. Arthritis Rheumatol.2014
  • Hamaguchi Y, Fujimoto M, Matsushita T, Kaji K, Komura K, Hasegawa M, Kodera M, Muroi E, Fujikawa K, Seishima M, Yamada H, Yamada R, Sato S, Takehara K, Kuwana M. Common and distinct clinical features in adult patients with anti-aminoacyl tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS ONE. 2013;8:e60442.
  • Fujimoto M, Matsushita M, Hamaguchi Y, Kaji K, Asano Y, Ogawa F, Yamaoka T, Fujikawa K, Tsukada T, Sato K, Echigo T, Hasegawa M, Takehara K. Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: Comparison with a UK Caucasian cohort. Ann Rheum Dis. 2013;72:151-3.
  • Fujimoto M, Hamaguchi Y, Kaji K, Matsushita T, Ichimura Y, Kodera M, Ishiguro N, Ueda-Hayakawa I, Asano Y, Ogawa F, Fujikawa K, Miyagi T, Mabuchi E, Hirose K, Akimoto N, Hatta N, Tsutsui K, Higashi A, Igarashi A, Seishima M, Hasegawa M, Takehara K. Myositis-specific anti-155/140 autoantibodies target transcriptional intermediary factor family proteins. Arthritis Rheum. 2012; 64:513-22.
  • Ichimura Y, Matsushita T, Hamaguchi Y, Kaji K, Hasegawa M, Tanino Y, Inokoshi Y, Kawai K, Kanekura T, Habuchi M, Igarashi A, Sogame R, Hashimoto T, Koga T, Nishino A, Ishiguro N, Sugimoto N, Aoki R, Ando N, Abe T, Kanda T, Kuwana M, Takehara K, Fujimoto M. Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis. 2012;71:710-3.
  • Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, Matsushita T, Komura K, Nakamura M, Kodera M, Suga N, Higashi A, Ogusu K, Tsutsui K, Furusaki A, Tanabe H, Sasaoka S, Muro Y, Yoshikawa M, Ishiguro N, Ayano M, Muroi E, Fujikawa K, Umeda Y, Kawase M, Mabuchi E, Asano Y, Sodemoto K, Seishima M, Yamada H, Sato S, Takehara K, Fujimoto M. Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis. Arch Dermatol. 2011;147:391-8.
  • Kaji K, Fujimoto M, Hasegawa M, Kondo M, Saito Y, Komura K, Matsushita T, Orito H, Hamaguchi Y, Yanaba K, Itoh M, Asano Y, Seishima M, Ogawa F, Sato S, Takehara K. Identification of a novel autoantibody reactive with 155- and 140-kDa nuclear proteins in patients with dermatomyositis: an association with malignancy. Rheumatology. 2007;46: 25-8.
  • Komura K, Fujimoto M, Matsushita T, Kaji K, Kondo M, Hirano T, Orito H, Horikawa M, Hamaguchi Y, Hasegawa M, Takehara K, Sato S. Prevalence and clinical characteristics of anti-Mi-2 antibodies in Japanese patients with dermatomyositis. J Dermatol Sci. 2005, 40:215-7.

その他

血管炎における新しいマウスモデルの樹立とその解析、水疱症や脱毛症におけるバイオマーカーの探索、アトピー性皮膚炎や樹状細胞マーカーCD83の研究などにも力を入れています。

血管炎

  • Jin G, Matsushita T, Hamaguch Y, Huu DL, Ishii T, Hasegawa M, Obata K, Karasuyama H, Takehara K, Fujimoto M. Basophils and mast cells play critical roles for leukocyte recruitment in IgE-mediated cutaneous reverse passive Arthus reaction. J Dermatol Sci. 2012;67:181-9.
  • Ishii T, Fujita T, Matsushita T, Yanaba K, Hasegawa M, Nakashima H, Ogawa F, Shimizu K, Takehara K, Tedder TF, Sato S, Fujimoto M. Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive Arthus reaction. Am J Pathol. 2009;174:2225-33.
  • Orito H, Fujimoto M, Ishiura N, Yanaba K. Matsushita T, Hasegawa M, Ogawa F, Takehara K, Sato S. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 cooperatively contribute to the cutaneous Arthus reaction, J Leukoc Biol. 2007; 81:1197-204.
  • Fujimoto M, Sato S, Hayashi Y, Wakugawa M, Tsuchida T, Tamaki K. Juvenile temporal arteritis with eosinophilia: a distinct clinicopathological entity. Dermatology. 1996;192:32-5.

水疱症

  • Ishiura N, Fujimoto M, Watanabe R, Nakashima H, Kuwano Y, Yazawa N, Echigo T, Okochi H, Tamaki K. Serum levels of IgE anti-BP 180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci. 2008;49:153-61.
  • Nakashima H, Fujimoto M, Asashima N, Watanabe R, Kuwano Y, Yazawa N, Maruyama N, Okochi H, Kumanogoh A, Tamaki K. Serum chemokine profile in patients with bullous pemphigioid. Br J Dermatol. 2007;156:454-9.
  • Watanabe R, Fujimoto M, Yazawa N, Nakashima H, Asashima N, Kuwano Y, Tada Y, Maruyama N, Okochi H, Tamaki K. Increased serum levels of a proliferation-inducing ligand in patients with bullous pemphigoid. J Dermatol Sci. 2007;46:53-60.
  • Asashima N, Fujimoto M, Watanabe R, Nakashima H, Yazawa N, Okochi H, Tamaki K. Serum levels of B cell activator of the TNF family (BAFF) are increased in bullous pemphigoid but not in pemphigus vulgaris. Br J Dermatol. 2006;155:330-6.

脱毛症

  • Kuwano Y, Fujimoto M, Watanabe R, Ishiura N, Nakashima H, Ohno Y, Yano S, Yazawa N, Okochi H, Tamaki K. Serum chemokine profiles in patients with alopecia areata. Br J Dermatol. 2007;157:466-73.
  • Kuwano Y, Fujimoto M, Watanabe R, Ishiura N, Nakashima H, Yano S, Yazawa N, Okochi H, Tamaki K. Serum BAFF and APRIL levels in patients with alopecia areata. J Dermatol Sci. 2008;50:236-9.

樹状細胞・皮膚免疫・アトピー性皮膚炎など

  • Matsushita T, Fujimoto M, Echigo T, Matsushita Y, Shimada Y, Hasegawa M, Takehara K, Sato S. Elevated serum levels of APRIL, but not BAFF, in patients with atopic dermatitis. Exp Dermatol. 2008;17:197-202.
  • Fujita T, Fujimoto M, Matsushita T, Shimada Y, Hasegawa M, Kuwano Y, Ogawa F, Takehara K, Sato S. Phase-dependent roles of E-selectin during chronic contact hypersensitivity responses. Am J Pathol. 2007; 170:1649-58.
  • Shirasawa S, Sugiyama S, Baba I, Inokuchi J, Sekine S, Ogino K, Kawamura Y, Dohi T, Fujimoto M, Sasazuki T. Loss of epiregulin results in dermatitis through dysregulation of immune-related responses. Proc Natl Acad Sci USA. 2004;101:13921-6.
  • Fujimoto Y, Tu L, Miller AS, Bock C, Fujimoto M, Doyle C, Steeber DA, Tedder TF. CD83 expression influences CD4+T cell development in the thymus. Cell. 2002;108:755-67.

皮膚ケラチノサイトの研究

B-Myb(Mybl2)が表皮の分化と増殖に果たす役割の解明
正常表皮におけるB-Mybの発現を検討したところ、基底層~有棘層下部の未分化角化細胞に優位に発現、表皮角化細胞が分化するに従ってB-MybのRNA、タンパク質発現ともに減少した。

表皮の分化・増殖におけるB-Mybの役割を明らかにするために、角化細胞株の三次元培養を用いてB-Mybの機能を解析した。その結果、B-Mybが表皮角化細胞の分化を抑制し、未分化な状態に維持する役割を果たしていることが明らかとなった。