1996 年度実績報告書

ヒトT細胞白血病ウイルスI型のシェ-グレン症候群発症機序解明と治療法に関する研究

研究課題

研究課題/領域番号	07670534
研究機関	長崎大学
研究代表者	江口勝美長崎大学, 医学部, 助教授 (30128160)
研究分担者	河部庸次郎長崎大学, 医学部附属病院, 助手 (50244059)
キーワード	ヒトT細胞白血病ウイルスI型 / シェ-グレン症候群 / Tax遺伝子 / 抗HTLV-I抗体 / 自己抗体 / アポトーシス / HTLV-I関連脊髄症 / T細胞レセプター
研究概要	リウマチ疾患におけるT細胞白血病ウイルスI型(HTLV-I)の病因論的関与について研究した。疫学的検討では先に、一次性シェ-グレン症候群(SS)52例中12例(23.1%)に抗HTLV-I抗体陽性で、献血者(3.4%)と比較して有意に高いことを報告した。今回、さらに症例を増やし、169例中42例(24.9%)が陽性であり、前回とほぼ同じで高率であった。臨床的検討ではHTLV-I感染SSと非感染SS患者群で血清γ-グロブリン量、抗核抗体、抗SS-A/Ro抗体と抗SS-B/La抗体の陽性率において差を認めなかった。しかし、抗セントロメア抗体陽性SS患者(21例,12.7%)では抗HTLV-I抗体は1例も検出されず、HTLV-I感染は抗セントロメア抗体陽性SSの病因ではないことが示唆された。 HTLV-I関連脊髄症(HAM)はHTLV-I感染が原因と考えられる。そこで、当科に入院してきたHAM患者すべてを小唾液腺生検を行い、全例(14例)にリンパ球の浸潤を検出した。European Communityの診断基準に照らし合わせて見ると確実例8例、疑い例4例、陰性例2例であり、HAM患者はSSを高率に合併することが明らかになった。確実例8例のHAM患者群では血清中リウマトイド因子、抗核抗体、抗SS-A/Ro抗体、抗SS-B/La抗体も非感染SS患者群と同程度に検出された。次に、小唾液腺浸潤リンパ球のphenotypeを検討した。HTLV-I感染SSの小唾液腺組織は主としてCD4′T細胞が浸潤し、一部CD8′T細胞やCD20′B細胞の浸潤が見られ、非感染SSの浸潤リンパ球のphenotypeと差を認めなかった。小唾液腺組織のFas抗原やFasリガンドの発現とアポトーシスを検出した。HTLV-I感染SSの小唾液腺組織にはFas抗原が腺細胞、導管細胞と浸潤リンパ球に、Fasリガンドは浸潤リンパ球に発現し、アポトーシス像は腺細胞と導管細胞に検出された。しかし、非感染SSと差異を認めなかった。 HTLV-I感染SSの小唾液腺組織ではPCR法でHTLV-I genomeのLTR,gag,pol,pXの4領域とも検出された。pX領域で半定量的にウイルス量を測定しHAMを合併していない抗HTLV-I抗体陽性SS4例中3例で末梢血単核球より小唾液腺組織の方がウイルス量が多かった。血清中抗HTLV-I抗体陰性SSの17例中3例に、HTLV-I provieus DNA taxが検出された。しかし、これらの患者のウイルス量は少なく、SSの原因となっていないと判断した。 HAM患者の小唾液腺組織へリンパ球浸潤が見られたことから、HAM患者末梢T細胞の性質について検討した。基底膜再構成基質の通過性についてはHAM患者の末梢血T細胞は亢進しており、特にCD4′細胞は著明であった。HAM患者末梢血T細胞のアミノペプチダーゼN活性は対照者に比較して有意に高く、これが基質通過性亢進の一原因と考えられた。興味深いことに、基底膜再構成基質を通過したCD4′T細胞は非通過細胞に比較してHTLV-I provirusのコピー数は2-8倍多く、HTLV-I感染CD4′細胞がより基底膜を通過しやすいことが示唆された。さらに、HAM患者の末梢血T細胞の中で臍帯由来血管内皮細胞に接着する細胞群は無刺激でもTNF-α,INF-γ,GM-CSFを培養上清中に多量に産生し、またspontaneous proliferationも高値を示した。以上より、SSの一原因としてHTLV-I感染が強く示唆された。病態ではHTLV-I感染CD4′細胞が末梢血より唾液腺組織へ浸潤し、この感染CD4′細胞が炎症性サイトカインを産生し、炎症を増幅・進展すると同時に、HTLV-Iや自己抗原に対する反応性T細胞や抗体産生を誘導し、アポトーシスや細胞傷害性T細胞により腺管が破壊されることが示唆された。

研究成果
(34件)

すべてその他

すべて文献書誌 (34件)

[文献書誌] Tomoki Origuchi,et al: "Increased levels of serum IgM antibody to staphylococcal enterotoxin B in patients with rheumatoid arthritis" Ann Rheum Dis. 54. 744-747 (1995)
[文献書誌] Hiroyuki Uno,et al: "Removal of LDL from plasma by adsorption reduces adhesion molecules on mononuclear cells in patients with arteriosclerotic obliterance" Atherosclerosis. 116. 93-102 (1995)
[文献書誌] Kiyoshi Migita,et al: "The role of protein kinase in human synovial fibroblast growth" Biochem Biophs Res Commun. 210(3). 1066-1075 (1995)
[文献書誌] Toshiaki Tsukada,et al: "Transforming growth factor β1 induces apoptotic cell-death in cultured human umbilical vein endothelial cells with down-regulated expression on bcl-2" Biochem Biophs Res Commun. 210(3). 1076-1082 (1995)
[文献書誌] Tomoki Origuchi,et al: "Synovial cells are potent antigen-presenting cells for superantigens,staphylococcal enterotoxin B" Clinical and Experimental Immunology. 99(3). 345-351 (1995)
[文献書誌] Kiyoshi Migita,et al: "Thyrosine phosphorylation participates in peripheral T-cell activation and programmed cell death in vivo" Immunology. 85(4). 550-555 (1995)
[文献書誌] Kiyoshi Migita,et al: "FK506 augments activation-induced programmed cell death of T lymphocytes in vivo" J Clin Invest. 96(2). 727-732 (1995)
[文献書誌] Kiyoshi Migita,et al: "Defects of T cell receptor-mediated signaling in anergic T cells" J Immunol. 155. 5083-5087 (1995)
[文献書誌] Souko Sakito,et al: "Serum cytokines in patients with rheumatoid arthritis : correlation of interferon γ and tumor necrosis factor α with the characteristics of peripheral blood mononuclear cells" Rheumatol Intl. 53(1). 31-37 (1995)
[文献書誌] Masako Kita,et al: "Abnormal liver function in patients with Sjogren′s syndrome" Acta Med Nagasaki. 41(3-4). 31-37 (1996)
[文献書誌] Yoshiko Arichi,et al: "Texture analysis of sonographic features of the parotid gland in Sjogren′s syndrome" Am J Roentgenol. 166(4). 935-941 (1996)
[文献書誌] Masahiro Izumi,et al: "MR imaging of the paroid gland in Sjogren′s syndrome : a proposal for new diagnostic criteria" Am J Roentgenol. 166(6). 1483-1487 (1996)
[文献書誌] Hiroyuki Takashima,et al: "Cytokine Production by endothelial cells infected with human T cell lymphotropic virus type I" Ann Rheum Dis. 55(9). 632-637 (1996)
[文献書誌] Katsumi Eguchi,et al: "High seroprevalence of anti-HTLV-I antibody in rheumatoid arthritis" Arthritis Rheum. 39(3). 463-466 (1996)
[文献書誌] Atsushi Kawakami,et al: "Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor β1" Arthritis Rheum. 39(8). 1267-1276 (1996)
[文献書誌] Masahiko Tsuboi,et al: "Fas antigen expression on synovial cells was down-regukated by interleukin 1β" Biochem Biophs Res Commun. 218(1). 280-285 (1996)
[文献書誌] Kiyoshi Migita,et al: "The effects of the immunosuppressant rapamycin on the growth of rheumatoid arthritis (RA) synovial fibroblast" Clin Exp Immunol. 104(1). 86-91 (1996)
[文献書誌] Naoki Matsuoka,et al: "Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells" Clin Exp Immunol. 104(3). 501-508 (1996)
[文献書誌] Koji Yano,et al: "Behcet′s disease complicated with myeledysplastic syndrome : a report of two caes and review of the literature" Clin Rheumatol. 15(1). 91-93 (1996)
[文献書誌] Satoshi Yamasaki,et al: "Wegener′s granulomatosis overlapped with Takayasu arteritis" Clin Rheumatol. 15(3). 303-306 (1996)
[文献書誌] Atsushi Kawakami,et al: "Thyroid-stimulating hormone inhibits Fas antigen-mediated apoptosis human thyrocytes in nitro" Endocrinology. 137(8). 3163-3169 (1996)
[文献書誌] Masako Kita,et al: "Staphylococcal enterotoxin B-specific adhesion of murine splenic T cells to a human endothelis cell line" Immunology. 88. 441-446 (1996)
[文献書誌] Naofumi Ishikawa,et al: "Defective organification of iodide causing congenital goitrous hypothyroidism" J Clin Endocrinol Metab. 81(1). 376-383 (1996)
[文献書誌] Naoki Matsuoka,et al: "Lack of B7-1/BB1 and B7-2/B70 expression on thyrocytes from patients with Graves′disease : deliver of the costimulatory signals from bystander professional antigen-presenting cells" J Clin Endocrinol Metab. 81(11). 4137-4143 (1996)
[文献書誌] Yukitaka Ueki,et al: "Incresed nitric oxide levels inpatients with rheumatoid arthritis" J Rheumatol. 23(2). 230-236 (1996)
[文献書誌] Akinari Mizokami,et al: "Increased popukation of higt fluorescence 1F7 (CD26) antigen on T cells in synovial fluid of patients with rheumatoid arthritis" J Rheumatol. 23(12). 2022-2026 (1996)
[文献書誌] Kiyoshi Migita,et al: "Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients with secondary amyloidosis" Lab Invest. 75(3). 371-375 (1996)
[文献書誌] Akira Tsujino,et al: "Pentoxifylline down-regulates adhesion molecule expression and inflammatory cytokine production in cultired peripheral blood mononuclear cells from patients with HTLV-I-associated myelopathy" J Neuroimmunol. (in press). (1997)
[文献書誌] Masahiro Izumi,et al: "Premature fat deposition salivary glands effected by Sjogren′s syndrome : evidence by MR and CT" Am J Neuroradiol. (in accepted). (1997)
[文献書誌] Hideki Nakamura,et al: "High prevalence of Sjogren′s syndrome in patients with HTLV-I-associated myelopathy" Ann Rheum Dis. (in accepted). (1997)
[文献書誌] Kiyoshi Migita,et al: "Superantigen-induced stromelysin production from rheumatoid synovial cells" Biochem Biophs Commun. (in accepted). (1997)
[文献書誌] Kiyoshi Migita,et al: "Induction of human T lymphocyte apoptosis in vivo by methylprednisolone pulse therapy" Transplantation. (in accepted). (1997)
[文献書誌] Hiroaki Ida,et al: "Proceeding of 5th International Conference on Human Differentiation Antigens" Oxford University Press, 2 (1995)
[文献書誌] Katsumi Eguchi,et al: "Bailliere′s Clinical Endocrinology and Metabolism" Bailliere Tindall Press, 24 (1995)

1996 年度 実績報告書

ヒトT細胞白血病ウイルスI型のシェ-グレン症候群発症機序解明と治療法に関する研究

研究代表者

江口 勝美 長崎大学, 医学部, 助教授 (30128160)

研究成果

[文献書誌] Tomoki Origuchi,et al: "Increased levels of serum IgM antibody to staphylococcal enterotoxin B in patients with rheumatoid arthritis" Ann Rheum Dis. 54. 744-747 (1995)

[文献書誌] Hiroyuki Uno,et al: "Removal of LDL from plasma by adsorption reduces adhesion molecules on mononuclear cells in patients with arteriosclerotic obliterance" Atherosclerosis. 116. 93-102 (1995)

[文献書誌] Kiyoshi Migita,et al: "The role of protein kinase in human synovial fibroblast growth" Biochem Biophs Res Commun. 210(3). 1066-1075 (1995)

[文献書誌] Toshiaki Tsukada,et al: "Transforming growth factor β1 induces apoptotic cell-death in cultured human umbilical vein endothelial cells with down-regulated expression on bcl-2" Biochem Biophs Res Commun. 210(3). 1076-1082 (1995)

[文献書誌] Tomoki Origuchi,et al: "Synovial cells are potent antigen-presenting cells for superantigens,staphylococcal enterotoxin B" Clinical and Experimental Immunology. 99(3). 345-351 (1995)

[文献書誌] Kiyoshi Migita,et al: "Thyrosine phosphorylation participates in peripheral T-cell activation and programmed cell death in vivo" Immunology. 85(4). 550-555 (1995)

[文献書誌] Kiyoshi Migita,et al: "FK506 augments activation-induced programmed cell death of T lymphocytes in vivo" J Clin Invest. 96(2). 727-732 (1995)

[文献書誌] Kiyoshi Migita,et al: "Defects of T cell receptor-mediated signaling in anergic T cells" J Immunol. 155. 5083-5087 (1995)

[文献書誌] Souko Sakito,et al: "Serum cytokines in patients with rheumatoid arthritis : correlation of interferon γ and tumor necrosis factor α with the characteristics of peripheral blood mononuclear cells" Rheumatol Intl. 53(1). 31-37 (1995)

[文献書誌] Masako Kita,et al: "Abnormal liver function in patients with Sjogren′s syndrome" Acta Med Nagasaki. 41(3-4). 31-37 (1996)

[文献書誌] Yoshiko Arichi,et al: "Texture analysis of sonographic features of the parotid gland in Sjogren′s syndrome" Am J Roentgenol. 166(4). 935-941 (1996)

[文献書誌] Masahiro Izumi,et al: "MR imaging of the paroid gland in Sjogren′s syndrome : a proposal for new diagnostic criteria" Am J Roentgenol. 166(6). 1483-1487 (1996)

[文献書誌] Hiroyuki Takashima,et al: "Cytokine Production by endothelial cells infected with human T cell lymphotropic virus type I" Ann Rheum Dis. 55(9). 632-637 (1996)

[文献書誌] Katsumi Eguchi,et al: "High seroprevalence of anti-HTLV-I antibody in rheumatoid arthritis" Arthritis Rheum. 39(3). 463-466 (1996)

[文献書誌] Atsushi Kawakami,et al: "Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor β1" Arthritis Rheum. 39(8). 1267-1276 (1996)

[文献書誌] Masahiko Tsuboi,et al: "Fas antigen expression on synovial cells was down-regukated by interleukin 1β" Biochem Biophs Res Commun. 218(1). 280-285 (1996)

[文献書誌] Kiyoshi Migita,et al: "The effects of the immunosuppressant rapamycin on the growth of rheumatoid arthritis (RA) synovial fibroblast" Clin Exp Immunol. 104(1). 86-91 (1996)

[文献書誌] Naoki Matsuoka,et al: "Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells" Clin Exp Immunol. 104(3). 501-508 (1996)

[文献書誌] Koji Yano,et al: "Behcet′s disease complicated with myeledysplastic syndrome : a report of two caes and review of the literature" Clin Rheumatol. 15(1). 91-93 (1996)

[文献書誌] Satoshi Yamasaki,et al: "Wegener′s granulomatosis overlapped with Takayasu arteritis" Clin Rheumatol. 15(3). 303-306 (1996)

[文献書誌] Atsushi Kawakami,et al: "Thyroid-stimulating hormone inhibits Fas antigen-mediated apoptosis human thyrocytes in nitro" Endocrinology. 137(8). 3163-3169 (1996)

[文献書誌] Masako Kita,et al: "Staphylococcal enterotoxin B-specific adhesion of murine splenic T cells to a human endothelis cell line" Immunology. 88. 441-446 (1996)

[文献書誌] Naofumi Ishikawa,et al: "Defective organification of iodide causing congenital goitrous hypothyroidism" J Clin Endocrinol Metab. 81(1). 376-383 (1996)

[文献書誌] Naoki Matsuoka,et al: "Lack of B7-1/BB1 and B7-2/B70 expression on thyrocytes from patients with Graves′disease : deliver of the costimulatory signals from bystander professional antigen-presenting cells" J Clin Endocrinol Metab. 81(11). 4137-4143 (1996)

[文献書誌] Yukitaka Ueki,et al: "Incresed nitric oxide levels inpatients with rheumatoid arthritis" J Rheumatol. 23(2). 230-236 (1996)

[文献書誌] Akinari Mizokami,et al: "Increased popukation of higt fluorescence 1F7 (CD26) antigen on T cells in synovial fluid of patients with rheumatoid arthritis" J Rheumatol. 23(12). 2022-2026 (1996)

[文献書誌] Kiyoshi Migita,et al: "Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients with secondary amyloidosis" Lab Invest. 75(3). 371-375 (1996)

[文献書誌] Akira Tsujino,et al: "Pentoxifylline down-regulates adhesion molecule expression and inflammatory cytokine production in cultired peripheral blood mononuclear cells from patients with HTLV-I-associated myelopathy" J Neuroimmunol. (in press). (1997)

[文献書誌] Masahiro Izumi,et al: "Premature fat deposition salivary glands effected by Sjogren′s syndrome : evidence by MR and CT" Am J Neuroradiol. (in accepted). (1997)

[文献書誌] Hideki Nakamura,et al: "High prevalence of Sjogren′s syndrome in patients with HTLV-I-associated myelopathy" Ann Rheum Dis. (in accepted). (1997)

[文献書誌] Kiyoshi Migita,et al: "Superantigen-induced stromelysin production from rheumatoid synovial cells" Biochem Biophs Commun. (in accepted). (1997)

[文献書誌] Kiyoshi Migita,et al: "Induction of human T lymphocyte apoptosis in vivo by methylprednisolone pulse therapy" Transplantation. (in accepted). (1997)

[文献書誌] Hiroaki Ida,et al: "Proceeding of 5th International Conference on Human Differentiation Antigens" Oxford University Press, 2 (1995)

[文献書誌] Katsumi Eguchi,et al: "Bailliere′s Clinical Endocrinology and Metabolism" Bailliere Tindall Press, 24 (1995)

1996 年度実績報告書

江口勝美長崎大学, 医学部, 助教授 (30128160)