Investigation of autoantigens in patients with rheumatoid arthritis through protemic analysis: exploration from diagnosis, pathogenesis to therapy

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591439
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Nagasaki University
• Principal Investigator: KAWAKAMI Atsushi 長崎大学, 医歯(薬)学総合研究科, 教授 (90325639)
• Co-Investigator(Kenkyū-buntansha): ORIGUCHI Tomoki 長崎大学, 大学院医歯薬学総合研究科, 教授 (90295105) ; ABIRU Norio 長崎大学, 大学院医歯薬学総合研究科, 准教授 (00380981) ; OHYAMA Kaname 長崎大学, 大学院医歯薬学総合研究科, 准教授 (50437860) ; TAMAI Mami 長崎大学, 大学院医歯薬学総合研究科, 講師 (60380862) ; ARIMA Kazuhiko 長崎大学, 大学院医歯薬学総合研究科, 講師 (30423635) ; YAMASAKI Satoshi 広島大学, 大学病院, 助教 (30367388)
• Project Period (FY): 2011 – 2013
• Keywords: リウマチ学

Research Abstract

Serum immune complexome analysis has found that TSP-1 and PF-4 are candidate autoantigens in RA. Especially, TSP-1 was considered as more useful than PF-4 in terms of detection sensitivity. In fact, prominent expression of TSP-1 was found in RA synovial tissues. TSP-1 was spontaneously produced in RA synovial cells and TGF- beta1 significantly stimulated the synthesis of TSP-1 at transcriptional level. A clear reduction of plasma TSP-1 and TGF- beta1 was found in RA patients successfully treated by disease-modifying anti-rheumatic drugs (DMARDs), however, the above change was not determined in RA patients DMARDs did not improve the clinical disease activity. It has been reported that the inflammatory niche of rheumatoid synovial tissues contain high TGF- beta1. We suspect that TGF- beta1 acts on synovial cells to produce TSP-1, and furthermore, the augmented production of TSP-1 may stimulate the autoantibody production toward TSP-1 in patients with RA.

Research Products

• [Journal Article] Synovial inflammation assessed by ultrasonography correlates with MRI-proven osteitis in patients with rheumatoid arthritis (2014)
  • Author(s): Kawashiri SY, Suzuki T, Nakashima Y, Horai Y, Okada A, Nishino A, Iwamoto N, Ichinose K, Arima K, Tamai M, Nakamura H, Origuchi T, Uetani M, Aoyagi K, Eguchi K, Kawakami A
  • Journal Title: Rheumatology (Oxford)
  • Peer Reviewed
• [Journal Article] Ultrasonographic examination of rheumatoid arthritis patients who are free of physical synovitis : power Doppler subclinical synovitis is associated with bone erosion (2014)
  • Author(s): Kawashiri SY, Suzuki T, Nakashima Y, Horai Y, Okada A, Iwamoto N, Ichinose K, Tamai M, Arima K, Nakamura H, Origuchi T, Uetani M, Aoyagi K, Eguchi K, Kawakami A
  • Journal Title: Rheumatology (Oxford) Volume: 53(3) Pages: 562-9
  • Peer Reviewed
• [Journal Article] Musculoskeletal ultrasonography assists the diagnostic performance of the 2010 classification criteria for rheumatoid arthritis (2013)
  • Author(s): Kawashiri SY, Suzuki T, Okada A, Yamasaki S, Tamai M, Nakamura H, Origuchi T, Mizokami A, Uetani M, Aoyagi K, Eguchi K, Kawakami A
  • Journal Title: Mod Rheumatol Volume: 23(1) Pages: 36-43
  • Peer Reviewed
• [Journal Article] 【リウマチ・膠原病における重要臓器障害と難治性病態-病態と治療の進歩】トピックス重要な臓器障害骨・関節病態と治療の進歩 (2013)
  • Author(s): 玉井慎美,川上純
  • Journal Title: 日本内科学会雑誌 Volume: 102 (10) Pages: 2600-2606
• [Journal Article] 関節リウマチ患者における抗リウマチ薬治療による関節超音波パワードプラスコアと血管新生因子血清濃度の改善 (2013)
  • Author(s): 川尻真也,鈴木貴久,中島好一,寶來吉朗,岩本直樹,一瀬邦弘,中村英樹,川上純,玉井慎美,折口智樹,有馬和彦,青柳潔
  • Journal Title: 九州リウマチ Volume: 33 (2) Pages: 74-80
  • Peer Reviewed
• [Journal Article] 関節リウマチ患者におけるエタネルセプト治療による関節超音波所見の改善 (2013)
  • Author(s): 川尻真也,鈴木貴久,中島好一,寶來吉朗,岩本直樹,一瀬邦弘,中村英樹,川上純,玉井慎美,折口智樹,有馬和彦,青柳潔
  • Journal Title: 九州リウマチ Volume: 33(1) Pages: 15-21
  • Peer Reviewed
• [Journal Article] 【早期関節リウマチ治療を考える】血清学的因子、炎症・バイオマーカーによる早期診断の可能性 (2013)
  • Author(s): 岩本直樹,川上純
  • Journal Title: Progress in Medicine Volume: 33 (9) Pages: 1905-1908
• [Journal Article] Magnetic resonance imaging (MRI)detection of synovitis and bone lesions of the wrists and finger joints in early-stage rheumatoid arthritis : comparison of the accuracy of plain MRI-based findings and gadolinium-diethylenetriamine pentaacetic acid-enhanced MRI-based findings (2012)
  • Author(s): Tamai M, Kawakami A, Uetani M, Fukushima A, Arima K, Fujikawa K, Iwamoto N, Aramaki T, Kamachi M, Nakamura H, Ida H, Origuchi T, Aoyagi K, Eguchi K
  • Journal Title: Modern Rheumatology Volume: 22 Pages: 654-658
  • Peer Reviewed
• [Journal Article] Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis (2012)
  • Author(s): Okada A, Yamasaki S, Koga T, Kawashiri SY, Tamai M, Origuchi T, Nakamura H, Eguchi K, Kawakami A
  • Journal Title: Clin Exp Rheumatol Volume: 30(3) Pages: 332-7
  • Peer Reviewed
• [Journal Article] Serum immune complex containing thrombospondin-1: a novel biomarker for early rheumatoid arthritis (2012)
  • Author(s): Ohyama K, Kawakami A, Tamai M, Baba M, Kishikawa N, Kuroda N
  • Journal Title: Ann Rheum Dis Volume: 71(11) Pages: 1916-7
  • Peer Reviewed
• [Journal Article] Treatment discontinuation in patients with very early rheumatoid arthritis in sustained simplified disease activity index remission after synthetic disease-modifying anti-rheumatic drug administration (2012)
  • Author(s): Kita J, Tamai M, Arima K, Nakashima Y, Suzuki T, Kawashiri SY, Iwamoto N, Okada A, Koga T, Yamasaki S, Nakamura H, Origuchi T, Ida H, Aoyagi K, Uetani M, Eguchi K, Kawakami A
  • Journal Title: Mod Rheumatol Volume: 22(3) Pages: 346-52
  • Peer Reviewed
• [Journal Article] Delayed treatment with tumor necrosis factor inhibitors in incomplete responders to synthetic disease-modifying anti-rheumatic drugs shows an excellent effect in patients with very early rheumatoid arthritis with poor prognosis factors (2012)
  • Author(s): Kita J, Tamai M, Arima K, Nakashima Y, Suzuki T, Kawashiri SY, Okada A, Koga T, Yamasaki S, Nakamura H, Origuchi T, Aramaki T, Nakashima M, Fujikawa K, Tsukada T, Ida H, Aoyagi K, Uetani M, Eguchi K, Kawakami A
  • Journal Title: Mod Rheumatol Volume: 22(2) Pages: 195-201
  • Peer Reviewed
• [Journal Article] Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells (2011)
  • Author(s): Koga T, Yamasaki S, Migita K, Kita J, Okada A, Kawashiri S, Iwamoto N, Tamai M, Arima K, Origuchi T, Nakamura H, Osaki M, Tsurumoto T, Shindo H, Eguchi K, Kawakami A
  • Journal Title: Clin Exp Rheumatol Volume: 29(6) Pages: 906-12
  • Peer Reviewed
• [Journal Article] Soluble urokinase plasminogen activator receptor as a useful biomarker to predict the response to adalimumab in patients with rheumatoid arthritis in a Japanese population (2011)
  • Author(s): Koga T, Okada A, Kawashiri SY, Kita J, Suzuki T, Nakashima Y, Tamai M, Satoh K, Origuchi T, Iwamoto N, Yamasaki S, Nakamura H, Migita K, Ida H, Ueki Y, Eguchi K, Kawakami A
  • Journal Title: Clin Exp Rheumatol Volume: 29(5) Pages: 811-5
  • Peer Reviewed
• [Journal Article] CD4+CD25(high)CD127(low/-) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis (2011)
  • Author(s): Kawashiri SY, Kawakami A, Okada A, Koga T, Tamai M, Yamasaki S, Nakamura H, Origuchi T, Ida H, Eguchi K
  • Journal Title: J Rheumatol Volume: 38(12) Pages: 2517-21
  • Peer Reviewed
• [Journal Article] Immune complexome analysis of serum and its application in screening for immune complex antigens in rheumatoid arthritis (2011)
  • Author(s): Ohyama K, Ueki Y, Kawakami A, Kishikawa N, Tamai M, Osaki M, Kamihira S, Nakashima K, Kuroda N
  • Journal Title: Clin Chem Volume: 57(6) Pages: 905-9
  • Peer Reviewed
• [Presentation] 関節リウマチ(RA)患者におけるメトトレキサート(MTX)投与による関節超音波画像の検討 (2013)
  • Author(s): 鈴木貴久,川尻真也,西野文子,高谷亜由子,中島好一,寳來吉朗,岡田覚丈,岩本直樹,一瀬邦弘,玉井慎美,有馬和彦,中村英樹,折口智樹,江口勝美,川上純
  • Organizer: 第28回日本臨床リウマチ学会
  • Place of Presentation: 埼玉県入間郡
  • Year and Date: 20131130-1201
• [Presentation] イムノコンプレキソーム解析による自己抗原プロファイリングに基づく自己免疫疾患へのアプローチ (2013)
  • Author(s): 馬場雅子,大山要、一瀬邦弘、玉井慎美、岸川直哉、川上純、黒田直敬
  • Organizer: 第7回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 20131123-24
• [Presentation] Immune complexome analysis for identifying immune complex antigens (2013)
  • Author(s): Baba M, Ohyama K, Tamai M, Kishikawa N, Kawakami A, Kuroda N
  • Organizer: 12^<th> HUPO World Congress
  • Place of Presentation: Yokohama
  • Year and Date: 20130914-18
• [Presentation] 関節リウマチ滑膜組織におけるThrombospondin-1(TSP-1)の重要性と調節機能の検討 (2013)
  • Author(s): 鈴木貴久,山崎聡士,中島好一,寳來吉朗,岡田覚丈,川尻真也,岩本直樹,一瀬邦弘,玉井慎美,有馬和彦,中村英樹,折口智樹,尾崎誠,大山要,黒田直敬,植木幸孝,江口勝美,川上純
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 京都市
  • Year and Date: 20130702-03
• [Presentation] 関節リウマチ(RA)患者の滑膜におけるtransforming growth factorβ1(TGF-β1)によるthrombospondin-1(TSP-1)産生機構の検討:TSP-1を含む血清免疫複合体がなぜRA患者で認められるのか (2013)
  • Author(s): 鈴木貴久,山崎聡士,中島好一,寳來吉朗,岡田覚丈,川尻真也,岩本直樹,一瀬邦弘,玉井慎美,有馬和彦,中村英樹,折口智樹,植木幸孝,川上純
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都市
  • Year and Date: 20130418-20
• [Presentation] 脂肪分化誘導による滑膜細胞からのマトリックスメタロプロテアーゼ産生抑制 (2013)
  • Author(s): 山崎聡士,岡田覚丈,遠藤功二,大岩寛,野島崇樹,熊谷和彦,川上純,杉山英
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都市
  • Year and Date: 20130418-20
• [Presentation] MRIからみた寛解基準の意義 (2013)
  • Author(s): 川上純,玉井慎美,川尻真也,中村英樹,折口智樹,上谷雅孝,青柳潔,江口勝美
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都市
  • Year and Date: 20130418-20
• [Presentation] イムノコンプレキソーム解析による自己免疫疾患患者の抗原プロファイリング (2013)
  • Author(s): 大山要,馬場雅子,玉井慎美,一瀬邦弘,岸川直哉,川上純,黒田直敬
  • Organizer: 第24回日本臨床化学会九州支部総会
  • Place of Presentation: 沖縄
  • Year and Date: 2013-12-09
• [Presentation] 関節リウマチ予後における関節MRI (2012)
  • Author(s): 玉井慎美,有馬和彦,上谷雅孝,岩本直樹,岡田覚丈,喜多潤子,川尻真也,一瀬邦弘,中村英樹,折口智樹,青柳潔,江口勝美,川上純
  • Organizer: 第40回日本臨床免疫学会
  • Place of Presentation: 東京都
  • Year and Date: 20120927-29
• [Presentation] LC-MS/MSによる関節リウマチ患者血清のイムコンプレキソーム解析 (2012)
  • Author(s): 川上純,鈴木貴久,玉井慎美,中村英樹,植木幸孝,江口勝美
  • Organizer: 第56回日本リウマチ学会総会・学術総会
  • Place of Presentation: 東京
  • Year and Date: 20120426-28
• [Presentation] 血清アミロイドA蛋白(SAA)によるRA滑膜細胞へのPTX3の誘導 (2012)
  • Author(s): 里村健志,鳥越雄史,泉政寛,宮下賜一郎,和泉元衛,古賀智裕,川上純,本川哲,右田清志
  • Organizer: 第56回日本リウマチ学会総会・学術総会
  • Place of Presentation: 東京
  • Year and Date: 20120426-28
• [Presentation] 滑膜細胞におけるKruppel like factor4の機能解析 (2012)
  • Author(s): 山崎聡士,岡田覚丈,一瀬邦弘,中村英樹,川㞍真也,玉井慎美,鈴木貴久,折口智樹,川上純
  • Organizer: 第56回日本リウマチ学会総会・学術総会
  • Place of Presentation: 東京
  • Year and Date: 20120426-28
• [Presentation] 臨床的寛解に到達した関節リウマチ患者における関節エコー所見の意義の検討 (2012)
  • Author(s): 川尻真也,西野文子,鈴木貴久,中島好一,寳來吉朗,岡田覚丈,一瀬邦弘,玉井慎美,中村英樹,折口智樹,江口勝美,川上純
  • Organizer: 第56回日本リウマチ学会総会・学術総会
  • Place of Presentation: 東京
  • Year and Date: 20120426-28
• [Presentation] 免疫疾患に関連する免疫複合体抗原のスクリーニングへのイムノコンプレキソーム解析法の応用 (2012)
  • Author(s): 大山要,川上純,玉井慎美,馬場雅子,岸川直哉,黒田直敬
  • Organizer: 第6回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2012-11-24
• [Presentation] 関節リウマチ患者血清のLC-MS/MSによるイムノコンプレキソーム解析 (2011)
  • Author(s): 川上純,大山要,植木幸孝,玉井慎美,中村英樹,岸川直哉,上平憲,中島憲一郎,黒田直敬
  • Organizer: 第26回日本臨床リウマチ学会
  • Place of Presentation: 神奈川(横浜)
  • Year and Date: 20111203-04
• [Presentation] Functional changes of bone marrow derived mesenchymal stem cell through adipogenesis. A possible in vitro model of bone edema in rheumatoid arthritis (2011)
  • Author(s): Yamasaki S, Okada A, Koga T, Kawashiri SY, Tamai M, Nakamura H, Origuchi T, Kawakami A
  • Organizer: ACR/ARHP Annual Scientific Meeting 2011
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 20111104-09
• [Presentation] 骨髄浮腫形成における間葉系幹細胞の役割 (2011)
  • Author(s): 岡田覚丈,山崎聡士,玉井慎美,中村英樹,折口智樹,川上純
  • Organizer: 第55回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 20110717-20
• [Presentation] Angiogenin-induced tiRNA represses translation under stress (2011)
  • Author(s): Yamasaki S, Ivanov P, Hu GF, Kawakami A, Anderson P
  • Organizer: Annual Meeting of the RNA Society and 13th Annual Meeting of the RNA Society of Japan (RNA 2011)
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20110614-18
• [Presentation] 炎症性サイトカインによる骨髄間葉系幹細胞の脂肪分化抑制 (2011)
  • Author(s): 岡田覚丈,山崎聡士,中村英樹,折口智樹,川上純
  • Organizer: 第32回日本炎症・再生医学会
  • Place of Presentation: 京都市
  • Year and Date: 20110602-03