Can we explain the varying pathologic processes of rheumatoid arthritis by CaMKII delta abnormality?

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591173
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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 Nagasaki University, 医歯薬学総合研究科, 教授 (90325639)
• Co-Investigator(Kenkyū-buntansha): ABIRU Norio 長崎大学, 病院, 講師 (00380981) ; TAMAI Mami 長崎大学, 保健・医療推進センター, 助教 (60380862) ; IDA Hiroaki 長崎大学, 病院, 講師 (60363496) ; FUJIKAWA Keita 長崎大学, 病院, 医員 (90404285) ; KAWASHIRI Shinya 長崎大学, 病院, 医員 (20457576)
• Project Period (FY): 2008 – 2010
• Keywords: 関節リウマチ / 滑膜細胞 / 免疫担当細胞 / CaMKII / シトルリン化

Research Abstract

We have examined the relationship between the pathogenesis of rheumatoid arthritis (RA) and CaMKII/PADIs/peptide citrullination/cellular abnormality of synovial cells and immune competent cells. Expression of PADIs in the rheumatoid synovial tissues remains to be clarified at present. According to our data, the expression of PADIs was weak whereas that of PADIs substrates were present in rheumatoid synovial cells. PADIs substrates in rheumatoid synovial cells could be citrullinated by interaction with neighboring immune competent cells, resulting in stimulation of anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) in patients with RA. Our present data also suggested that the function of regulatory T cells (Treg cells), a major immune competent cell population, is down-regulated in patients with RA that may associate with perpetuation of the disease's process. However, further investigation is necessary to identify whether these phenomena are primary events or secondary results. In addition, the investigations regarding to the association of Treg cells with CaMKII/PADIs are also be necessary. In clinical study, we have identified a close association of MRI-proven bone edema with anti-CCP antibodies. At present, a detection of peptide citrullination is very difficult. Therefore, we are also going to solve this problem by immune complexsome analysis.

Research Products

• [Journal Article] Switching to the anti-interleukin-6 receptor antibody tocilizumab in rheumatoid arthritis patients refractory to antitumor necrosis factor biologics. (2010)
  • Author(s): Kawashiri SY, Kawakami A, Iwamoto N, Fujikawa K, Aramaki T, Tamai M, Arima K, Ichinose K, Kamachi M, Yamasaki S, Nakamura H, Origuchi T, Ida H, Eguchi K
  • Journal Title: Mod Rheumatol 20(1): Pages: 40-45
• [Journal Article] Regulation of disease susceptibility and mononuclear cell infiltration into the labial salivary glands of Sjogren fs syndrome by monocyte chemotactic protein-1. (2010)
  • Author(s): Iwamoto N, Kawakami A, Arima K, Nakamura H, Kawashiri S, Tamai M, Kita J, Okada A, Koga T, Kamachi M, Yamasaki S, Ichinose K, Ida H, Origuchi T, Eguchi K
  • Journal Title: Rheumatology (Oxford) 49(8) Pages: 1472-1478
• [Journal Article] Decrement of serum cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis (RA) patients achieving remission after 6 months of etanercept treatment : comparison with CRP, IgM-RF, MMP-3 and anti-CCP Ab. (2010)
  • Author(s): Kawashiri S, Kawakami A, Imazato T, Ueki Y, Iwamoto N, Fujikawa K, Aramaki T, Tamai M, Arima K, Kamachi M, Nakamura H, Origuchi T, Ida H, Eguchi K
  • Journal Title: Joint Bone Spine 77(5) Pages: 418-420
• [Journal Article] Contribution of anti-CCP antibodies, proximal interphalangeal joint involvement, HLA-DRB 1 shared epitope and PADI4 as risk factors for the development of rheumatoid arthritis in palindromic rheumatism. (2010)
  • Author(s): Tamai M, Kawakami A, Iwamoto N, Arima K, Aoyagi H, Eguchi K
  • Journal Title: Scand J Rheumatol 39(4) Pages: 287-291
• [Journal Article] Monitoring of therapeutic efficacy in a patient with RS3PE syndrome by serologic variables and radiographic methods. (2010)
  • Author(s): Kawashiri S, Nakano M, Kawakami A, Eguchi K
  • Journal Title: Rheumatol Int 30 Pages: 1677-1680
• [Journal Article] Anti-cyclic citrullinated peptide antibody (anti-CCP antibody) is present in the sera of patients with dementia of Alzheimer's type in Asian. (2010)
  • Author(s): Satoh K, Kawakami A, Shirabe S, Tamai M, Sato A, Tsujihata M, Nagasato K, Eguchi K
  • Journal Title: Acta Neurol Scand 121(5) Pages: 338-341
• [Journal Article] 【III.関節リウマチの成因と病態生理】概論的事項病態形成とアポトーシス (2010)
  • Author(s): 岩本直樹, 川上純, 江口勝美
  • Journal Title: 日本臨床関節リウマチ(第2版)-寛解を目指す治療の新時代- 68(増刊号5) Pages: 71-75
• [Journal Article] A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. (2009)
  • Author(s): Aramaki T, Ida H, Izumi Y, Fujikawa K, Huang M, Arima K, Tamai M, Kamachi M, Nakamura H, Kawakami A, Origuchi T, Matsuoka N, Eguchi K
  • Journal Title: Mod Rheumatol 19(3) Pages: 245-252
• [Journal Article] High serum cartilage oligomeric matrix protein determines the subset of patients with early-stage rheumatoid arthritis with high serum C-reactive protein, matrix metalloproteinase-3, and MRI-proven bone erosion. (2009)
  • Author(s): Fujikawa K, Kawakami A, Tamai M, Uetani M, Takao S, Arima K, Iwamoto N, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K
  • Journal Title: J Rheumatol 36(6) Pages: 1126-1129
• [Journal Article] Proinflammatory cytokines synergistically enhance the production of chemokine ligand 20 (CCL20) from rheumatoid fibroblast-like synovial cells in vitro and serum CCL20 is reduced in vivo by biologic disease-modifying antirheumatic drugs. (2009)
  • Author(s): Kawashiri S, Kawakami A, Iwamoto N, Fujikawa K, Aramaki T, Tamai M, Arima K, Kamachi M, Yamasaki S, Nakamura H, Tsurumoto T, Kono M, Shindo H, Ida H, Origuchi T, Eguchi K
  • Journal Title: J Rheumato 136(11) Pages: 2397-2402
• [Journal Article] A prediction rule for disease outcome in patients with undifferentiated arthritis using magnetic resonance imaging of the wrists and finger joints and serologic autoantibodies. (2009)
  • Author(s): Tamai M, Kawakami A, Uetani M, Takao S, Arima K, Iwamoto N, Fujikawa K, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K
  • Journal Title: Arthritis Rheum 61(6) Pages: 772-778
• [Journal Article] Different expression levels of TNF receptors on the rheumatoid synovial macrophages derived from surgery and a synovectomy as detected by a new flow cytometric analysis. (2009)
  • Author(s): Ida H, Aramaki T, Nakamura H, Fujikawa K, Arima K, Tamai M, Kamachi M, Satoh K, Origuchi T, Kawakami A, Furuichi I, Kawabe Y, Eguchi K
  • Journal Title: Cytotechnology 60(1-3) Pages: 161-164
• [Journal Article] Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt. (2009)
  • Author(s): Fujikawa K, Kawakami A, Tanaka F, Iwamoto N, Tamai M, Eguchi K
  • Journal Title: Clin Exp Rheumato 127(6) Pages: 952-957
• [Journal Article] 【関節リウマチ治癒を目指す治療の新時代へ】治療に直結する病因・病態研究最前線 治療反応性と関連する予後因子 (2009)
  • Author(s): 川上純, 玉井慎美, 岩本直樹, 川尻真也, 藤川敬太, 江口勝美
  • Journal Title: 最新医学 64(5) Pages: 974-980
• [Journal Article] 特集膠原病・リウマチ性疾患診察のより深い理解を目指してトピックス I.診断を的確に下すために 1.診断不明の関節炎を如何に診断するか (2009)
  • Author(s): 川上純, 玉井慎美, 喜多潤子, 川尻真也, 岩本直樹, 江口勝美
  • Journal Title: 日本内科学会雑誌 98(10) Pages: 2414-2420
• [Journal Article] 関節リウマチ滑膜組織のTNF-α産生とTLR (2009)
  • Author(s): 古賀智裕, 川上純, 江口勝美
  • Journal Title: リウマチ科 42(4) Pages: 434-439
• [Journal Article] Rapid and significant induction of TRAIL-mediated type II cells in apoptosis of primary salivary epithelial cells in primary Sjogren's syndrome. Apoptosis : an international journal on programmed cell death. (2008)
  • Author(s): Nakamura H, Kawakami A, Iwamoto N, Ida H, Koji T, Eguchi K
  • Journal Title: Apoptosis 13(11) Pages: 1322-1330
• [Journal Article] 関節リウマチと抗CCP抗体:早期診断および予後予測マーカーとしての重要性 (2008)
  • Author(s): 玉井慎美、川上純
  • Journal Title: リウマチ科 40(3) Pages: 215-219
• [Presentation] 早期関節リウマチの経過における手指関節MRI骨髄浮腫と抗CCP抗体価変動の検討 (2010)
  • Author(s): 玉井慎美, 川上純, 上谷雅孝, 有馬和彦, 岩本直樹, 中村英樹, 折口智樹, 井田弘明, 江口勝美
  • Organizer: 第25回日本臨床リウマチ学会
  • Place of Presentation: 東京
  • Year and Date: 20101127-20101128
• [Presentation] Post-Transcriptional Regulation of IL-6 Production by Zc3h12a in Fibroblast-Like Synovial Cells. (2010)
  • Author(s): 古賀智裕, 山崎聡士, 岡田覚丈, 川尻真也, 中村英樹, 川上純, 江口勝美
  • Organizer: ACR/ARHP 2010.
  • Place of Presentation: アトランタ/米国
  • Year and Date: 20101107-20101111
• [Presentation] The Power Doppler Ultrasonography Score from 24 Synovial Sites or 6 Simplified Synovial Sites, Including the Metacarpophalangeal (MCP) Joints, Reflects Well the Clinical Disease Activity and Serum Biomarkers in atients with Rheumatoid Arthritis. (2010)
  • Author(s): 川上純, 川尻真也, 岩本直樹, 玉井慎美, 中村英樹, 喜多潤子, 岡田覚丈, 古賀智裕, 山崎聡士, 折口智樹, 江口勝美
  • Organizer: ACR/ARHP 2010.
  • Place of Presentation: アトランタ/米国
  • Year and Date: 20101107-20101111
• [Presentation] MRI-Proven Bone Edema of Wrist and Finger Joints at Entry Is the Strongest Predictor toward Further Radiografic Progression in Patients with Undifferentiated Arthritis : Results from the Prospective Cohart at Nagasaki university. (2010)
  • Author(s): 喜多潤子, 川上純, 玉井慎美, 岩本直樹, 川尻真也, 有馬和彦, 岡田覚丈, 古賀智裕, 山崎聡士, 中村英樹, 折口智樹, 青柳潔, 上谷雅孝, 江口勝美
  • Organizer: ACR/ARHP 2010.
  • Place of Presentation: アトランタ/米国
  • Year and Date: 20101107-20101111
• [Presentation] 早期関節炎に対するTNF阻害剤の有効性の検討 (2010)
  • Author(s): 川上純, 喜多潤子, 玉井慎美, 岩本直樹, 川尻真也, 岡田覚丈, 古賀智裕, 山崎聡士, 中村英樹, 折口智樹, 荒牧俊幸, 中島宗敏, 青柳潔, 上谷雅孝, 江口勝美
  • Organizer: 第40回九州リウマチ学会
  • Place of Presentation: 鹿児島
  • Year and Date: 20100904-20100905
• [Presentation] Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells. (2010)
  • Author(s): 古賀智裕, 山崎聡士, 岡田覚丈, 川尻真也, 岩本直樹, 井田弘明, 折口智樹, 川上純, 江口勝美
  • Organizer: Annual European Congress of Rheumatology (EULAR 2010).
  • Place of Presentation: Rome, Italy.
  • Year and Date: 20100616-20100619
• [Presentation] RS3PE syndrome is associated with VEGF derived from platelets. (2010)
  • Author(s): 有馬和彦, 玉井慎美, 岡田覚丈, 岩本直樹, 川上純, 江口勝美, 折口智樹
  • Organizer: Annual European Congress of Rheumatology (EULAR 2010).
  • Place of Presentation: Rome, Italy.
  • Year and Date: 20100616-20100619
• [Presentation] 関節リウマチにおける関節超音波によるスコアリングとバイオマーカーとの関連 (2010)
  • Author(s): 川尻真也, 岩本直樹, 古賀智裕, 岡田覚丈, 有馬和彦, 川上純, 折口智樹, 江口勝美
  • Organizer: 第54回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20100422-20100425
• [Presentation] 関節リウマチにおける末梢血CD4+cD25highcDl27low/-T細胞の検討 (2010)
  • Author(s): 川尻真也, 川上純, 江口勝美
  • Organizer: 第54回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20100422-20100425
• [Presentation] 関節リウマチ滑膜細胞におけるRNA結合蛋白を介したIL-6の転写後制御の可能性 (2010)
  • Author(s): 古賀智裕, 山崎聡士, 川上純, 江口勝美
  • Organizer: 第54回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20100422-20100425
• [Presentation] 抗体アレイ法を用いた関節リウマチに対するアダリムマブの治療効果の検討 (2010)
  • Author(s): 古賀智裕, 岡田覚丈, 川尻真也, 岩本直樹, 山崎聡士, 中村英樹, 有馬和彦, 折口智樹, 井田弘明, 川上純, 江口勝美
  • Organizer: 第54回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20100422-20100425
• [Presentation] 骨髄浮腫の細胞生物学的検討 (2010)
  • Author(s): 岡田覚丈, 山崎聡士, 中村英樹, 井田弘明, 折口智樹, 川上純, 江口勝美
  • Organizer: 第54回日本リウマチ学会総会・学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20100422-20100425
• [Presentation] 関節リウマチにおける末梢血CD4+CD25+CDl27low/-制御性T細胞の検討 (2009)
  • Author(s): 川尻真也, 川上純, 江口勝美
  • Organizer: 第37回日本臨床免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 20091113-20091115
• [Presentation] A Prediction Rule far Disease Outcome in Patients with Undifferentiated Arthritis by MRI of the Wrists and Finger Joints and Serologic (2009)
  • Author(s): 玉井慎美, 川上純, 上谷雅孝, 有馬和彦, 藤川敬太, 岩本直樹, 川尻真也, 喜多潤子, 岡田覚丈,古賀智裕, 荒牧俊幸, 蒲池誠, 山崎聡士, 中村英樹, 井田弘明, 折口智樹, 青柳潔, 江口勝美
  • Organizer: Autoantibodies : Second Report Regarding to the Utility of Plain MRL ACR/ARHP Scientific Meeting 2009.
  • Place of Presentation: Philadelphia.
  • Year and Date: 20091016-20091021
• [Presentation] Serum Amyloid A Protein Stimulates Th17-Related Cytokines Production in Rheumatoid Synoviocytes. (2009)
  • Author(s): Koga T, Migita K, Yamasaki S, Tamai M, Kawashiri S, Iwamoto N, Nakamura H, Origuchi T, Ida1 H, Kawakami A, Eguchi K
  • Organizer: ACR/ARHP Scientific Meeting 2009.
  • Place of Presentation: Philadelphia.
  • Year and Date: 20091016-20091021
• [Presentation] A prediction rule for disease outcome in patients with undifferentiated arthritis using mri of wrists and finger joints and serologic autoantibodies. (2009)
  • Author(s): Tamai M, Kawakami A, Uetani M, Takao S, Arima K, Iwamoto N, Fujikawa K, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K
  • Organizer: Annual European Congress of Rheumatology EULAR 2009.
  • Place of Presentation: Copenhagen, Dennmark.
  • Year and Date: 20090610-20090613
• [Presentation] Early classification and therapeutic intervention toward patients in undifferentiated arthritis with MRI-proven bone changes and autoantibodies by disease modifying anti-rheumatic drugs (DMARDs) : NAGASAKI Early Arthritis Intervention Trial. (2009)
  • Author(s): 川上純, 玉井慎美, 岩本直樹, 川尻真也, 折口智樹, 江口勝美
  • Organizer: 18^<th> lnternational Rheumatology Symposium.
  • Place of Presentation: Tokyo.
  • Year and Date: 20090423-20090426
• [Presentation] 関節リウマチを早期に予測するには? (2009)
  • Author(s): 川上純, 玉井慎美, 岩本直樹, 川尻真也, 藤川敬太, 荒牧俊幸, 一瀬邦弘, 有馬和彦, 蒲池誠, 中村英樹, 井田弘明, 折口智樹, 上谷雅孝, 青柳潔, 江口勝美
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20090423-20090426
• [Presentation] MRI骨変化と自己抗体が陽性のUAに対するDMARDs治療の評価 (2009)
  • Author(s): 川上純, 玉井慎美, 岩本直樹, 川尻真也, 藤川敬太, 荒牧俊幸, 一瀬邦弘, 蒲池誠, 中村英樹, 井田弘明, 折口智樹, 有馬和彦, 山崎聡士, 上谷雅孝, 青柳潔, 江口勝美
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20090423-20090426
• [Presentation] 関節リウマチにおける末梢血CD4+CD25+CDI27lo/-制御性T細胞の検討 (2009)
  • Author(s): 川尻真也, 川上純, 岩本直樹, 藤川敬太, 荒牧俊幸, 江口勝美
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20090423-20090426
• [Presentation] 抗CCP抗体と関節リウマチの診断・病態 (2008)
  • Author(s): 川上純, 玉井慎美, 藤川敬太, 岩本直樹, 川尻真也, 江口勝美
  • Organizer: 第52回日本リウマチ学会総会・学術集会
  • Place of Presentation: 札幌
  • Year and Date: 20080420-20080423
• [Presentation] 関節リウマチにおけるケモカインCCL20と生物学的製剤 (2008)
  • Author(s): 川尻真也, 川上純, 岩本直樹, 藤川敬太, 荒牧俊幸, 一瀬邦弘, 蒲池誠, 玉井慎美, 中村英樹, 井田弘明, 折口智樹, 江口勝美
  • Organizer: 第52回本リウマチ学会総会・学術集会
  • Place of Presentation: 札幌
  • Year and Date: 20080420-20080423
• [Presentation] 関節リウマチ(RA)に対する生物学的製剤による悪性腫瘍発生リスクの検討;ナチュラルキラー(NK)細胞への影響(第三報) (2008)
  • Author(s): 荒牧俊幸, 井田弘明, 川尻真也, 岩本直樹, 藤川敬太, 一瀬邦弘, 玉井慎美, 蒲池誠, 中村英樹, 川上純, 折口智樹, 松岡直樹, 江口勝美
  • Organizer: 第52回日本リウマチ学会総会・学術集会
  • Place of Presentation: 札幌
  • Year and Date: 20080420-20080423