全身性エリテマトーデスにおけるリンパ球のテロメラーゼ活性およびテロメア長の異常
全身性エリテマトーデス（SLE）においてT細胞のテロメラーゼ活性は活動期，非活動期どちらにおいても高い．一方，B細胞のテロメラーゼ活性は活動期においてのみ異常に高い．また，正常群と比べてT細胞のテロメア長は短く，B細胞のテロメア長は変わらない．このことからSLEのT細胞は常時活性化しているが，疾患の顕在化にはそれだけでは不十分で，B細胞の活性化が重要であると考えられた．SLEの臨床症状を抑えるだけならば，B細胞の抑制だけで十分かもしれない．しかしながら，本質的な治療を行う為にはT細胞をもターゲットに入れた治療が必要であると考えられた．近年SLEの治療に各種生物製剤が用いられ始めている．今後，こ...
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| Published in | 日本臨床免疫学会会誌 Vol. 30; no. 1; pp. 29 - 36 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本臨床免疫学会
2007
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| Online Access | Get full text |
| ISSN | 0911-4300 1349-7413 |
| DOI | 10.2177/jsci.30.29 |
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| Abstract | 全身性エリテマトーデス（SLE）においてT細胞のテロメラーゼ活性は活動期，非活動期どちらにおいても高い．一方，B細胞のテロメラーゼ活性は活動期においてのみ異常に高い．また，正常群と比べてT細胞のテロメア長は短く，B細胞のテロメア長は変わらない．このことからSLEのT細胞は常時活性化しているが，疾患の顕在化にはそれだけでは不十分で，B細胞の活性化が重要であると考えられた．SLEの臨床症状を抑えるだけならば，B細胞の抑制だけで十分かもしれない．しかしながら，本質的な治療を行う為にはT細胞をもターゲットに入れた治療が必要であると考えられた．近年SLEの治療に各種生物製剤が用いられ始めている．今後，このような生物製剤を用いた場合の各リンパ球におけるテロメラーゼ活性の動向は興味深い．SLEに対する生物製剤を用いた治療戦略を組み立てる際に，各リンパ球におけるテロメラーゼ活性の測定は，適切なターゲット細胞の設定，治療薬の選択，治療効果の判定などに有用となると考えられた． |
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| AbstractList | 全身性エリテマトーデス（SLE）においてT細胞のテロメラーゼ活性は活動期，非活動期どちらにおいても高い．一方，B細胞のテロメラーゼ活性は活動期においてのみ異常に高い．また，正常群と比べてT細胞のテロメア長は短く，B細胞のテロメア長は変わらない．このことからSLEのT細胞は常時活性化しているが，疾患の顕在化にはそれだけでは不十分で，B細胞の活性化が重要であると考えられた．SLEの臨床症状を抑えるだけならば，B細胞の抑制だけで十分かもしれない．しかしながら，本質的な治療を行う為にはT細胞をもターゲットに入れた治療が必要であると考えられた．近年SLEの治療に各種生物製剤が用いられ始めている．今後，このような生物製剤を用いた場合の各リンパ球におけるテロメラーゼ活性の動向は興味深い．SLEに対する生物製剤を用いた治療戦略を組み立てる際に，各リンパ球におけるテロメラーゼ活性の測定は，適切なターゲット細胞の設定，治療薬の選択，治療効果の判定などに有用となると考えられた． 「抄録」全身性エリテマトーデス(SLE)においてT細胞のテロメラーゼ活性は活動期, 非活動期どちらにおいても高い. 一方, B細胞のテロメラーゼ活性は活動期においてのみ異常に高い. また, 正常群と比べてT細胞のテロメア長は短く, B細胞のテロメア長は変わらない. このことからSLEのT細胞は常時活性化しているが, 疾患の顕在化にはそれだけでは不十分で, B細胞の活性化が重要であると考えられた. SLEの臨床症状を抑えるだけならば, B細胞の抑制だけで十分かもしれない. しかしながら, 本質的な治療を行う為にはT細胞をもターゲットに入れた治療が必要であると考えられた. 近年SLEの治療に各種生物製剤が用いられ始めている. 今後, このような生物製剤を用いた場合の各リンパ球におけるテロメラーゼ活性の動向は興味深い. SLEに対する生物製剤を用いた治療戦略を組み立てる際に, 各リンパ球におけるテロメラーゼ活性の測定は, 適切なターゲット細胞の設定, 治療薬の選択, 治療効果の判定などに有用となると考えられた. 「はじめに」テロメアは真核生物の染色体末端に存在するDNA蛋白質複合体であり, 染色体の安定化には必須の構造であると考えられている1). |
| Author | 黒坂, 大太郎 |
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| References | 5) Hiyama K, Hirai Y, Kyoizumi S, et al. : Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155 : 3711-3715, 1995. 8) Honda M, Mengesha E, Albano S,et al. : Telomere shortening and decreased replicative potential, contrasted by continued proliferation of telomerase-positive CD8+ CD28lo T cells in patients with systemic lupus erythematosus. Clin Immunol 99(2) : 211-221, 2001. 27) Gmelig-Meyling F, Dawisha S, Steinberg AD. : Assessment of in vivo frequency of mutated T cells in patients with systemic lupus erythematosus. J Exp Med 175(1) : 297-300, 1992. 2) Counter CM. : The roles of telomeres and telomerase in cell life span. Mutat Res 366 : 45-63, 1996. 16) Weng N, Levine BL, June CH, et al. : Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183 : 2471-2479, 1996. 22) Igarashi H, Sakaguchi N. : Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 89 (4) : 1299-1307, 1997. 15) Igarashi H, Sakaguchi N. : Telomerase activity is induced by the stimulation to antigen receptor in human peripheral lymphocytes. Biochem Biophys Res Commun 219 : 649-655, 1996. 28) Desai-Mehta A, Lu L, Ramsey-Goldman R, et al. : Hyper-expression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97(9) : 2063-2073, 1996. 30) ter Borg EJ, Horst G, Limburg PC, Kallenberg CG. : Changes in plasma levels of interleukin-2 receptor in relation to disease exacerbations and levels of anti-dsDNA and complement in systemic lupus erythematosus. Clin Exp Immunol 82(1) : 21-26, 1990. 23) Koetz K, Bryl E, Spickchen K, et al. : T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 97(16) : 9203-9208, 2000. 24) Artlett CM, Black CM, Bliggs DC, et al. : Telomere reduction in scleroderma patients : a possible cause for chromosomal instability. Br J Rheumatol 35 : 732-737, 1996. 3) Weinrich SL, Pruzan R, Ma L, et al. : Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 17(4) : 498-502, 1997. 9) Kurosaka D, Ysuada J, Kingetsu I, et al. : Two cases of adult Still's disease with abnormally high level of telomerase activity in peripheral blood mononuclear cells. Mod Rheumatol 14 : 394-398, 2004. 25) Sakane T, Suzuki N, Takada S, et al. : B cell hyperactivity and its relation to distinct clinical features and the degree of disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 31(1) : 80-87, 1988. 21) Hu BT, Lee SC, Marin E, et al. : Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J Immunol 159 : 1068-1071, 1997. 18) Buchkovich KJ, Greider CW. : Telomerase regulation during entry into the cell cycle in normal human T cells. Mol Biol Cell 7 : 1443-1454, 1996. 12) Kurosaka D, Ozawa Y, Yasuda J, et al. : Telomerase activity in peripheral blood mononuclear cells from patients with SLE. Ann Rheum Dis 60 : 1158-1159, 2001. 7) Katayama Y, Kohriyama K. : Telomerase activity in peripheral blood mononuclear cells of systemic connective tissue diseases. J Rheumatol 28(2) : 288-291, 2001. 13) Kurosaka D, Yasuda J, Yoshida K, et al. : Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients. Lupus 12 : 591-599, 2003. 1) Zakian VA. : Telomeres : beginning to understand the end. Science 270 : 1601-1607, 1995. 10) Klapper W, Moosig F, Sotmikova A, et al. : Telomerase activity in B and T lymphocytes of patients with systemic lupus erythematosus. Ann Rheum Dis 63 : 1681-1683, 2004. 4) Shay JW, Bacchetti S. : A survey of telomerase activity in human cancer. Eur J Cancer 33(5) : 787-791, 1997. 29) Koshy M, Berger D, Crow MK. : Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98(3) : 826-837, 1996. 11) Wu K, Higashi N, Hansen ER, et al. : Telomerase activity is increased and telomere length shortened in T cells from blood of patients with atopic dermatitis and psoriasis. J Immunol 165 : 4742-4747, 2000. 6) Yudoh K, Matsuno H, Nezuka T, and Kimura T. : Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis. The role of telomerase activity in synovial proliferation. Arthritis Rheum 42(4) : 669-677, 1999. 20) Yamada O, Motoji T, Mizoguchi H. : Up-regulation of telomerase activity in human lymphocytes. Biochim Biophys Acta 1314 : 260-266, 1996. 14) Kurosaka D, Yasuda J, Yoshida K, et al. : Abnormal telomerase activity and telomere length in T and B cells from patients with systemic lupus erythematosus. J Rheumatol 33(6) : 1102-1107, 2006. 17) Weng N, Levine BL, June CH, et al. : Regulation of telomerase RNA template expression in human T lymphocyte development and activation. J Immunol 158 : 3215-3220, 1997. 19) Bodnar AG, Kim NW, Effros RB, et al. : Mechanism of telomerase induction during T cell activation. Exp Cell Res 228 : 58-64, 1996. 26) Eisenberg RA, Cohen PL. : Class II major histocompatibility antigens and the etiology of systemic lupus erythematosus. Clin Immunol Iummnopathol 29(1) : 1-6, 1983. 31) Looney RJ, Anolik J, Sanz I. : B lymphocytes in systemic lupus erythematosus : lessons from therapy targeting B cells. Lupus 13(5) : 381-390, 2004. |
| References_xml | – reference: 2) Counter CM. : The roles of telomeres and telomerase in cell life span. Mutat Res 366 : 45-63, 1996. – reference: 31) Looney RJ, Anolik J, Sanz I. : B lymphocytes in systemic lupus erythematosus : lessons from therapy targeting B cells. Lupus 13(5) : 381-390, 2004. – reference: 11) Wu K, Higashi N, Hansen ER, et al. : Telomerase activity is increased and telomere length shortened in T cells from blood of patients with atopic dermatitis and psoriasis. J Immunol 165 : 4742-4747, 2000. – reference: 20) Yamada O, Motoji T, Mizoguchi H. : Up-regulation of telomerase activity in human lymphocytes. Biochim Biophys Acta 1314 : 260-266, 1996. – reference: 25) Sakane T, Suzuki N, Takada S, et al. : B cell hyperactivity and its relation to distinct clinical features and the degree of disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 31(1) : 80-87, 1988. – reference: 3) Weinrich SL, Pruzan R, Ma L, et al. : Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 17(4) : 498-502, 1997. – reference: 28) Desai-Mehta A, Lu L, Ramsey-Goldman R, et al. : Hyper-expression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97(9) : 2063-2073, 1996. – reference: 1) Zakian VA. : Telomeres : beginning to understand the end. Science 270 : 1601-1607, 1995. – reference: 27) Gmelig-Meyling F, Dawisha S, Steinberg AD. : Assessment of in vivo frequency of mutated T cells in patients with systemic lupus erythematosus. J Exp Med 175(1) : 297-300, 1992. – reference: 16) Weng N, Levine BL, June CH, et al. : Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183 : 2471-2479, 1996. – reference: 24) Artlett CM, Black CM, Bliggs DC, et al. : Telomere reduction in scleroderma patients : a possible cause for chromosomal instability. Br J Rheumatol 35 : 732-737, 1996. – reference: 30) ter Borg EJ, Horst G, Limburg PC, Kallenberg CG. : Changes in plasma levels of interleukin-2 receptor in relation to disease exacerbations and levels of anti-dsDNA and complement in systemic lupus erythematosus. Clin Exp Immunol 82(1) : 21-26, 1990. – reference: 13) Kurosaka D, Yasuda J, Yoshida K, et al. : Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients. Lupus 12 : 591-599, 2003. – reference: 10) Klapper W, Moosig F, Sotmikova A, et al. : Telomerase activity in B and T lymphocytes of patients with systemic lupus erythematosus. Ann Rheum Dis 63 : 1681-1683, 2004. – reference: 12) Kurosaka D, Ozawa Y, Yasuda J, et al. : Telomerase activity in peripheral blood mononuclear cells from patients with SLE. Ann Rheum Dis 60 : 1158-1159, 2001. – reference: 22) Igarashi H, Sakaguchi N. : Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 89 (4) : 1299-1307, 1997. – reference: 17) Weng N, Levine BL, June CH, et al. : Regulation of telomerase RNA template expression in human T lymphocyte development and activation. J Immunol 158 : 3215-3220, 1997. – reference: 29) Koshy M, Berger D, Crow MK. : Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98(3) : 826-837, 1996. – reference: 4) Shay JW, Bacchetti S. : A survey of telomerase activity in human cancer. Eur J Cancer 33(5) : 787-791, 1997. – reference: 26) Eisenberg RA, Cohen PL. : Class II major histocompatibility antigens and the etiology of systemic lupus erythematosus. Clin Immunol Iummnopathol 29(1) : 1-6, 1983. – reference: 9) Kurosaka D, Ysuada J, Kingetsu I, et al. : Two cases of adult Still's disease with abnormally high level of telomerase activity in peripheral blood mononuclear cells. Mod Rheumatol 14 : 394-398, 2004. – reference: 15) Igarashi H, Sakaguchi N. : Telomerase activity is induced by the stimulation to antigen receptor in human peripheral lymphocytes. Biochem Biophys Res Commun 219 : 649-655, 1996. – reference: 21) Hu BT, Lee SC, Marin E, et al. : Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J Immunol 159 : 1068-1071, 1997. – reference: 6) Yudoh K, Matsuno H, Nezuka T, and Kimura T. : Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis. The role of telomerase activity in synovial proliferation. Arthritis Rheum 42(4) : 669-677, 1999. – reference: 7) Katayama Y, Kohriyama K. : Telomerase activity in peripheral blood mononuclear cells of systemic connective tissue diseases. J Rheumatol 28(2) : 288-291, 2001. – reference: 23) Koetz K, Bryl E, Spickchen K, et al. : T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 97(16) : 9203-9208, 2000. – reference: 19) Bodnar AG, Kim NW, Effros RB, et al. : Mechanism of telomerase induction during T cell activation. Exp Cell Res 228 : 58-64, 1996. – reference: 18) Buchkovich KJ, Greider CW. : Telomerase regulation during entry into the cell cycle in normal human T cells. Mol Biol Cell 7 : 1443-1454, 1996. – reference: 14) Kurosaka D, Yasuda J, Yoshida K, et al. : Abnormal telomerase activity and telomere length in T and B cells from patients with systemic lupus erythematosus. J Rheumatol 33(6) : 1102-1107, 2006. – reference: 5) Hiyama K, Hirai Y, Kyoizumi S, et al. : Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155 : 3711-3715, 1995. – reference: 8) Honda M, Mengesha E, Albano S,et al. : Telomere shortening and decreased replicative potential, contrasted by continued proliferation of telomerase-positive CD8+ CD28lo T cells in patients with systemic lupus erythematosus. Clin Immunol 99(2) : 211-221, 2001. |
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| Snippet | 全身性エリテマトーデス（SLE）においてT細胞のテロメラーゼ活性は活動期，非活動期どちらにおいても高い．一方，B細胞のテロメラーゼ活性は活動期においてのみ異常に... 「抄録」全身性エリテマトーデス(SLE)においてT細胞のテロメラーゼ活性は活動期, 非活動期どちらにおいても高い. 一方, B細胞のテロメラーゼ活性は活動期においてのみ異常に... |
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| Title | 全身性エリテマトーデスにおけるリンパ球のテロメラーゼ活性およびテロメア長の異常 |
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