1997 Fiscal Year Annual Research Report

レトロウイルス感染によるシェ-グレン症候群発症とその分子機構の解明

Research Project

Project/Area Number	09670482
Research Category	Grant-in-Aid for Scientific Research (C)
Research Institution	Nagasaki University
Principal Investigator	江口勝美長崎大学, 医学部, 教授 (30128160)
Co-Investigator(Kenkyū-buntansha)	河部庸次郎長崎大学, 医学部附属病院, 助手 (50244059) 中村龍文長崎大学, 医学部附属病院, 講師 (00198219)
Keywords	ヒトT細胞白血病ウイルス / シェ-グレン症候群 / Tax蛋白 / NF-kB / カスペース / アポトーシス / HTLV-I関連脊髄症 / マトリックスメタロプロテアーゼ
Research Abstract	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、HTLV-I高浸淫地区である長崎市の女性SSの患者の約17%がHTLV-I感染に関与していることが明らかになった。マトリックスメタロプロテアーゼ(MMP)は、細胞外マトリックスの分解活性に加え、TNF-αやFasリガンドなどの分泌を促す。HTLV-I感染SS及び非感染SSにおける口唇小唾液腺でのMMPの発現を検討した。HTLV-I感染SSの唾液腺においてのみMMP-2が検出されたことにより、組織破壊にMMP-2が関与していることが示唆された。 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 provirus DNA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の病因となっていないと判断した。 HTLV-I genomeのpX領域が検出されることから、pX領域から産生されるTax蛋白の役割について検討した。Tax蛋白は転写因子NF-kBを活性化し、サイトカイン産生を亢進させることを既に報告した。今回、pX遺伝子導入細胞を用いて、Tax蛋白がNF-kB活性化を介して抗アポトーシス作用を惹起することを明らかにした。NF-kBの活性化を阻害するとカスペース3活性化を介して細胞にアポトーシスが惹起された。すなわち、HTLV-IはTax蛋白を介して、NF-kB活性化を強く誘導することで、抗アポトーシス作用を現し、ひいてはHTLV-I感染細胞の増殖やサイトカイン産生を介して、自己免疫疾患の発展・進展に関与すると考えられた。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障害性T細胞により線管が破壊されることが示唆された。

Research Products

(40 results)

All Other

All Publications (40 results)

[Publications] Y.Arizi,M.Ohki,K.Eguchi,et al.: "Texture analysis of sonographic features ofthe parotid gland in Sjogren′s syndrome." Am J Roentgenol. 166(4). 935-941 (1996)
[Publications] M.Izumi,K.Eguchi,et al.: "MR imaging of the parotid glands inSjogren′s syndrome : a proposal for newdiagnostic criteria." Am J Roentgenol. 166(6). 1483-1487 (1996)
[Publications] K.Eguchi,et al.: "High seroprevalence of anti-HTLV-Iantibody in rheumatoid arthritis." Arthritis Rheum. 39(3). 463-466 (1996)
[Publications] A.Kawakami,K.Eguchi: "Inhibition of Fas antigen-mediated apoptosisof rheumatoid synovial cells in vitro bytransforming growth factor β1." Arthritis Rheum. 39(8). 1267-1276 (1996)
[Publications] M.Tsuboi,K.Eguchi,et al.: "Fas anitgen expression on synovial cells wasdown-regulated by interleukin 1 β." Biochem Biophs Res Commun. 218. 280-285 (1996)
[Publications] K.Migita,K.Eguchi,et al.: "The effects of immunosuppressantrepamycin on the growth of rheumatoidarthritis (RA) synovial fibroblast." Clin Exp Immunol. 104(1). 86-91 (1996)
[Publications] N.Matsuoka,K.Eguchi,et al.: "Inhibitory effects of clarithromycin oncostimulatory molecules expression andcytokine production by synovial fibroblast-like cells." Clin Exp Immunol. 104(3). 501-508 (1996)
[Publications] K.Yano,K.Eguchi,et al.: "Behcet′s disease complicated withmyelodysplastic syndrome : a report of twocases and review of literature." Clin Rheumatol. 15(1). 91-93 (1996)
[Publications] M.Yamamichi,N.Matsuoka,K.Eguchi,et al.: "Shared TCRr V β gene expression by thepancresa and salivary gland inimmunodeficient alymphoplasic mice" J Immunol. 159(1). 427-432 (1997)
[Publications] H.Goto,T.Nakamura,K.Eguchi,et al.: "Up-regulation of iNOS mRNA expressionand increased production of NO in a cellline of macrophage lineage. transfectedby HTLV-I tax gene." Immunobiol. 197. 513-521 (1997)
[Publications] S.Urayama,A.Kawakami,K.Eguchi,et al.: "Fas/Fas ligand interaction regulatescytotoxicity of CD4_+ T cells againststaphylococcal enterotoxin B-pulsedendothelial cells" Biochem Biophs Res Commun. 239. 782-788 (1997)
[Publications] A.Kawakami,K.Eguchi,et al.: "Expression and function of both Fasand Fas ligand on peripheral bloodlymphocytes from healty donors" J Lab Clin Med. (accepted). (1998)
[Publications] Y.Ichinose,K.Eguchi,et al.: "Apoptotic induction of synovial fibroblastsby ceramide : in vitro and in vivo effects" J Lab Clin Med. (accepted). (1998)
[Publications] K.Migita,K.Eguchi,et al.: "FK506 potentiates steroid-induced T cellapoptosis" Transplantation. (accepted). (1998)
[Publications] T.Nakashima,K.Eguchi,et al.: "Inhibitory effect of glucocorticoidfor osteoblast apoptosis inducedby activated peripheral bloodmononuclear cells" Endocrinology. (in press). (1998)
[Publications] T.Furuya,T.Nakamura,et al.: "HTLV-I-Associated myelopathyassociated with multi-organinflammatory disease" J Neurol Sci. (in press). (1998)
[Publications] T.Furuya,T.Nakamura,K.Eguchi,et al.: "Up-regulated transmigrating activity of CD4positive T cells through reconstitutedbasement membrane in patients with human T lymphotropic virus type-l associatedmyelopathy." Proc Association Am Physicians,. 109. 228-236 (1997)
[Publications] K.Migita,K.Eguchi,et al.: "Apoptosis Induction in human peripheral blood T lymphocytes by high-dose steroid therapy." Transplantation. 63. 583-587 (1997)
[Publications] S.Nakane,Y.Kawabe,K.Eguchi,et al.: "A case of cytophagic histiocytic panniculitis : successful treatment of recurrent attack withsteroid pulse therapy and oral cyclosporin A" Clin Rheumatoll. 16(3). 417-42 (1997)
[Publications] T.Tsukada,K.Eguchi,et al.: "Granulocyte macrophage-colony stimulatingfactor induced growth and activation ofJAK2 in HUVEC cell line" Tohoku J Exp Med. 183. 185-195 (1997)
[Publications] K.Migita,K.Eguchi,et al.: "Effects of rapamycin on apoptosis ofrheumatoid synovial cells" Clin Exp Immunol. 108. 199-203 (1997)
[Publications] A.Kawakami,K.Eguchi,et al.: "Immunoglobulin G from patients withGraves′ disease inhibits Fas-mediatedapoptosis of human thyrocytes" Clin Exp Immunol. 110(3). 434-439 (1997)
[Publications] K.Migita,K.Eguchi,et al.: "β2-microglobulin induces stromelysinproduction by human synovialfibroblasts" Biochem Biophs Res Commun,. 239. 612-625 (1997)
[Publications] A.Kawakami,K.Eguchi,et al.: "Fas and Fas ligand interaction is necessaryfor human osteoblast apoptosis" J Bone Miner Res.12(11). 1637-1646 (1997)
[Publications] S.Yamasaki,K.Eguchi,et al.: "Wegeners granulomatosis overlapped with Takayasu arteritis." Clin Rheumatol. 15(3)6. 303-30 (1996)
[Publications] A.Kawakami,K.Eguchi,et al.: "Thyroid-stimulating hormone inhibits Fasantigen-mediated apoptosis of humanthyrocytes in vitro." Endocrinology. 137. 3163-3169 (1996)
[Publications] N.Ishikawa,K.Eguchi,et al.: "Defective organification of iodide causingcongenital goitrous hypothyroidism." J Clin Endocrinol Metab. 81(1). 376-383 (1996)
[Publications] N.Matsuoka,K.Eguchi,et al.: "Lack of B7-1/BB1 and B7-2/B70 expressionon thyrocytes of patients with Graves′disease. Delivery of costimulatory signalsfrom bystander professional antigen-presenting cells." J Clin Endocrinol Metab. 81(11). 4137-4143 (1996)
[Publications] Y.Ueki,S.Miyake,Y.Tominaga,K.Eguchi: "Increased nitric oxide levels in patients withrheumatoid arthritis." J Rheumatol. 23(2). 230-236 (1996)
[Publications] M.Kita,K.Eguchi,et al.: "Staphylococcal enterotoxin B-specificadhesion of murine splenic T cells to ahuman endothelial cell line." Immunology. 88. 441-446 (1996)
[Publications] K.Migita,K.Eguchi,et al.: "Increased circulating serum amyloid Aprotein derivatives in rheumatoid arthritispatients with secondary amyloidosis." Lab Invest. 75(3)5. 371-37 (1996)
[Publications] K.Migita,K.Eguchi: "TNF-α-mediated expression of membranetype matrix-metalloproteinase in rheumatoidsynovial fibroblasts." Immunology. 89:8. 553-55 (1996)
[Publications] M.Kita,K.Eguchi,et al.: "Abnormal liver function in patients withSjogren′s syndrome." Acta Med Nagasaki. 41(3-4). 31-37 (1996)
[Publications] A.Mizokami,K.Eguchi,et al.: "Increased high-fluorescence population ofCD26 antigen on T cell in synovial fluid impatients with rheumatoid arthritis." J Rheumatol. 23(12). 2022-2026 (1996)
[Publications] K.Eguchi,et al.: "HTLV-I infection in the pathogenesis ofSjogren′s syndrome." Proceeding of 200 years anniversary ofDr. Philipp Franz von Sieblod,Sep,Nagasaki. 26-29 (1996)
[Publications] M.Izumi,K.Eguchi,et al.: "Premature fat deposition in salivary glandseffected by Sjogren′s syndrome : evidenceby MR and CT." Am J Neuroradiol. 18(5). 951-958 (1997)
[Publications] H.Nakamura,K.Eguchi,et al.: "High prevalence of Sjogren′s syndrome inpatients with HTLV-I-associatedmyelopathy." Ann Rheum Dis,. 56(3). 167-172 (1997)
[Publications] K.MigitaK.Eguchi,et al.: "Superantigen-induced stromelysinproduction from rheumatoid synovial cells." Biochem Biophs Res Commun. 231. 222-226 (1997)
[Publications] A.Kawakami,K.Eguchi,et al.: "Inhibition effect of IL-10 on humansynovial cells in vitro." Immunology. 91(2). 252-259 (1997)
[Publications] A.Tsujino,T.Nishiura,S.Shirabe,T.Furuya,H.Goto,A.Kawakami,K.Eguchi,S.Nagataki: "Pentoxifymne down-regulates adhesionmolecule expression and inflammatorycytokine production in cultured peripheralblood mononuclear cells from patients withHTLV-I-associated myelopathy." J Neuroimmunol. 73. 191-196 (1997)

1997 Fiscal Year Annual Research Report

レトロウイルス感染によるシェ-グレン症候群発症とその分子機構の解明

Principal Investigator

江口 勝美 長崎大学, 医学部, 教授 (30128160)

Research Products

[Publications] Y.Arizi,M.Ohki,K.Eguchi,et al.: "Texture analysis of sonographic features ofthe parotid gland in Sjogren′s syndrome." Am J Roentgenol. 166(4). 935-941 (1996)

[Publications] M.Izumi,K.Eguchi,et al.: "MR imaging of the parotid glands inSjogren′s syndrome : a proposal for newdiagnostic criteria." Am J Roentgenol. 166(6). 1483-1487 (1996)

[Publications] K.Eguchi,et al.: "High seroprevalence of anti-HTLV-Iantibody in rheumatoid arthritis." Arthritis Rheum. 39(3). 463-466 (1996)

[Publications] A.Kawakami,K.Eguchi: "Inhibition of Fas antigen-mediated apoptosisof rheumatoid synovial cells in vitro bytransforming growth factor β1." Arthritis Rheum. 39(8). 1267-1276 (1996)

[Publications] M.Tsuboi,K.Eguchi,et al.: "Fas anitgen expression on synovial cells wasdown-regulated by interleukin 1 β." Biochem Biophs Res Commun. 218. 280-285 (1996)

[Publications] K.Migita,K.Eguchi,et al.: "The effects of immunosuppressantrepamycin on the growth of rheumatoidarthritis (RA) synovial fibroblast." Clin Exp Immunol. 104(1). 86-91 (1996)

[Publications] N.Matsuoka,K.Eguchi,et al.: "Inhibitory effects of clarithromycin oncostimulatory molecules expression andcytokine production by synovial fibroblast-like cells." Clin Exp Immunol. 104(3). 501-508 (1996)

[Publications] K.Yano,K.Eguchi,et al.: "Behcet′s disease complicated withmyelodysplastic syndrome : a report of twocases and review of literature." Clin Rheumatol. 15(1). 91-93 (1996)

[Publications] M.Yamamichi,N.Matsuoka,K.Eguchi,et al.: "Shared TCRr V β gene expression by thepancresa and salivary gland inimmunodeficient alymphoplasic mice" J Immunol. 159(1). 427-432 (1997)

[Publications] H.Goto,T.Nakamura,K.Eguchi,et al.: "Up-regulation of iNOS mRNA expressionand increased production of NO in a cellline of macrophage lineage. transfectedby HTLV-I tax gene." Immunobiol. 197. 513-521 (1997)

[Publications] S.Urayama,A.Kawakami,K.Eguchi,et al.: "Fas/Fas ligand interaction regulatescytotoxicity of CD4_+ T cells againststaphylococcal enterotoxin B-pulsedendothelial cells" Biochem Biophs Res Commun. 239. 782-788 (1997)

[Publications] A.Kawakami,K.Eguchi,et al.: "Expression and function of both Fasand Fas ligand on peripheral bloodlymphocytes from healty donors" J Lab Clin Med. (accepted). (1998)

[Publications] Y.Ichinose,K.Eguchi,et al.: "Apoptotic induction of synovial fibroblastsby ceramide : in vitro and in vivo effects" J Lab Clin Med. (accepted). (1998)

[Publications] K.Migita,K.Eguchi,et al.: "FK506 potentiates steroid-induced T cellapoptosis" Transplantation. (accepted). (1998)

[Publications] T.Nakashima,K.Eguchi,et al.: "Inhibitory effect of glucocorticoidfor osteoblast apoptosis inducedby activated peripheral bloodmononuclear cells" Endocrinology. (in press). (1998)

[Publications] T.Furuya,T.Nakamura,et al.: "HTLV-I-Associated myelopathyassociated with multi-organinflammatory disease" J Neurol Sci. (in press). (1998)

[Publications] T.Furuya,T.Nakamura,K.Eguchi,et al.: "Up-regulated transmigrating activity of CD4positive T cells through reconstitutedbasement membrane in patients with human T lymphotropic virus type-l associatedmyelopathy." Proc Association Am Physicians,. 109. 228-236 (1997)

[Publications] K.Migita,K.Eguchi,et al.: "Apoptosis Induction in human peripheral blood T lymphocytes by high-dose steroid therapy." Transplantation. 63. 583-587 (1997)

[Publications] S.Nakane,Y.Kawabe,K.Eguchi,et al.: "A case of cytophagic histiocytic panniculitis : successful treatment of recurrent attack withsteroid pulse therapy and oral cyclosporin A" Clin Rheumatoll. 16(3). 417-42 (1997)

[Publications] T.Tsukada,K.Eguchi,et al.: "Granulocyte macrophage-colony stimulatingfactor induced growth and activation ofJAK2 in HUVEC cell line" Tohoku J Exp Med. 183. 185-195 (1997)

[Publications] K.Migita,K.Eguchi,et al.: "Effects of rapamycin on apoptosis ofrheumatoid synovial cells" Clin Exp Immunol. 108. 199-203 (1997)

[Publications] A.Kawakami,K.Eguchi,et al.: "Immunoglobulin G from patients withGraves′ disease inhibits Fas-mediatedapoptosis of human thyrocytes" Clin Exp Immunol. 110(3). 434-439 (1997)

[Publications] K.Migita,K.Eguchi,et al.: "β2-microglobulin induces stromelysinproduction by human synovialfibroblasts" Biochem Biophs Res Commun,. 239. 612-625 (1997)

[Publications] A.Kawakami,K.Eguchi,et al.: "Fas and Fas ligand interaction is necessaryfor human osteoblast apoptosis" J Bone Miner Res.12(11). 1637-1646 (1997)

[Publications] S.Yamasaki,K.Eguchi,et al.: "Wegeners granulomatosis overlapped with Takayasu arteritis." Clin Rheumatol. 15(3)6. 303-30 (1996)

[Publications] A.Kawakami,K.Eguchi,et al.: "Thyroid-stimulating hormone inhibits Fasantigen-mediated apoptosis of humanthyrocytes in vitro." Endocrinology. 137. 3163-3169 (1996)

[Publications] N.Ishikawa,K.Eguchi,et al.: "Defective organification of iodide causingcongenital goitrous hypothyroidism." J Clin Endocrinol Metab. 81(1). 376-383 (1996)

[Publications] N.Matsuoka,K.Eguchi,et al.: "Lack of B7-1/BB1 and B7-2/B70 expressionon thyrocytes of patients with Graves′disease. Delivery of costimulatory signalsfrom bystander professional antigen-presenting cells." J Clin Endocrinol Metab. 81(11). 4137-4143 (1996)

[Publications] Y.Ueki,S.Miyake,Y.Tominaga,K.Eguchi: "Increased nitric oxide levels in patients withrheumatoid arthritis." J Rheumatol. 23(2). 230-236 (1996)

[Publications] M.Kita,K.Eguchi,et al.: "Staphylococcal enterotoxin B-specificadhesion of murine splenic T cells to ahuman endothelial cell line." Immunology. 88. 441-446 (1996)

[Publications] K.Migita,K.Eguchi,et al.: "Increased circulating serum amyloid Aprotein derivatives in rheumatoid arthritispatients with secondary amyloidosis." Lab Invest. 75(3)5. 371-37 (1996)

[Publications] K.Migita,K.Eguchi: "TNF-α-mediated expression of membranetype matrix-metalloproteinase in rheumatoidsynovial fibroblasts." Immunology. 89:8. 553-55 (1996)

[Publications] M.Kita,K.Eguchi,et al.: "Abnormal liver function in patients withSjogren′s syndrome." Acta Med Nagasaki. 41(3-4). 31-37 (1996)

[Publications] A.Mizokami,K.Eguchi,et al.: "Increased high-fluorescence population ofCD26 antigen on T cell in synovial fluid impatients with rheumatoid arthritis." J Rheumatol. 23(12). 2022-2026 (1996)

[Publications] K.Eguchi,et al.: "HTLV-I infection in the pathogenesis ofSjogren′s syndrome." Proceeding of 200 years anniversary ofDr. Philipp Franz von Sieblod,Sep,Nagasaki. 26-29 (1996)

[Publications] M.Izumi,K.Eguchi,et al.: "Premature fat deposition in salivary glandseffected by Sjogren′s syndrome : evidenceby MR and CT." Am J Neuroradiol. 18(5). 951-958 (1997)

[Publications] H.Nakamura,K.Eguchi,et al.: "High prevalence of Sjogren′s syndrome inpatients with HTLV-I-associatedmyelopathy." Ann Rheum Dis,. 56(3). 167-172 (1997)

[Publications] K.MigitaK.Eguchi,et al.: "Superantigen-induced stromelysinproduction from rheumatoid synovial cells." Biochem Biophs Res Commun. 231. 222-226 (1997)

[Publications] A.Kawakami,K.Eguchi,et al.: "Inhibition effect of IL-10 on humansynovial cells in vitro." Immunology. 91(2). 252-259 (1997)

江口勝美長崎大学, 医学部, 教授 (30128160)