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Clinical and pathological significance of autoantibodies to calpastatin in rheumatoid arthritis

Research Project

Project/Area Number 07670540
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionKeio University School of Medicine

Principal Investigator

MIMORI Tsuneyo  Keio University School of Medicine Assistant Professor, 医学部, 講師 (10157589)

Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1996: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
Keywordsautoantibody / calpastatin / calpain / autoimmune disease / rheumatoid arthritis / proteinase / proteinase inhibitor / antigenic epitope
Research Abstract

We found novel autoantibodies to calpastatin, natural inhibitor for calcium-dependent neutral proteinase (calpain), in patients with rheumatoid arthritis (RA). Since calpain is thought to be one of neutral proteinases that may be involved in joint destruction and inflammation process, the production of autoantibodies to its inhibitor protein, calpastatin, might be associated with pathogenic mechanisms of RA.In this study, we intended to elucidate 1) the clinical significance of autoantibodies ot calpastatin, 2) analysis of autoantigenic epitopes recognized by patient autoantibodies, and 3) the pathogenic role of anti-clpastatin antibodies.
Autoantibodies to calpastatin in various rheumatic diseases were screened by immunoblotting using the fusion protein expressed from E.coli with a partial cDNA (RA-6) encoding the C-terminal 178 amino acids of human calpastatin. Anti-calpastatin antibodies were detected in 57% of patients with RA and were significantly more frequent than in SLE (27%), … More scleroderma (38%) and myositis (24%).
Antigenic epitopes were analyzed by using an epitope library constructed by restriction enzyme-digested RA-6 cDNA that was subcloned into an expression vector. Autoantibodies from patient sera recognized a C-terminal region (C1 ; aa. 152-178) and a N-terminal region (C2 ; aa. 1-76), whereas a mouse monoclonal antibody (CSF3-3) recognized an entirely different region containing the calpain-binding site (B2 ; aa. 77-130) RA patients whose sera reacted with the Cl epitope represented a more progressed and severe state of arthritis than those not reacting with Cl.
Anti-calpastatin antibodies were also detected in synovial fluids from RA patients who had anti-calpastatin in sera. IgG fractions from sera containing anti-calpastatin antibodies selectively blocked the function of calpastatin and recovered the proteolytic activity of calpain in dose-dependent manner. In contrast, IgG from normal sera or patient sera without anti-calpastatin antibodies did not recover the calpain activity.
These results strongly suggest that the production of autoantibodies to calpastatin in patients with RA is not merely epiphenomenon but may be involved in pathogenic mechanisms by inhibiting the function of clpastatin and increasing the calpain activity in synovial tissue. Less

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Mimori T et al.: "Autoantibodies to calpastatin(an endogenous inhibitor for calcium-dependent neutral protease,calpain)in systemic rheumatic diseases" Proc Natl Acad Sci USA. 92. 7267-7271 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T et al.: "A pathogenic role of autoantibodies to calpastatin in patients with rheumatoid arthritis." Arthritis Rheum. 38. S165 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 三森経世: "慢性関節リウマチと抗カルパスタチン抗体" 臨床検査. 39. 966-967 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nojima T,Mimori T et al.: "Detection of autoantibodies in patients with rheumatoid arthritis" Jpn J Rheumatol. 6. 189-200 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Update on structures targeted by the immune system in myositis" Current Opinion in Rheumatol. 8. 521-527 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 三森経世: "炎症と抗カルパスタチン抗体" Clinical Calcium. 6. 65-67 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T et al: "Autoantibodies to human calpastatin (endogenous inhibitor for calcium-dependent neutral protease, calpain) in systemic rheumatic diseases." Proc Natl Acad Sci USA. 93 (16). 7267-7271 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Rheumatoid arthritis and anti-calpastatin antibodies." Rinsho Kensa. 39 (8). 966-967 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T et al: "A pathogenic role of autoantibodies to calpastatin in patients with rheumatoid arthritis." Arthritis Rheum. 38. S165 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Suwa A,Mimori T et al: "Autoantibodies to DNA-dependent protein kinase : Probes for the catalytic subunit." J Clin Invest. 97 (6). 1417-1421 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nojima T,Mimori T et al: "Detection of autoantibodies in patients with rheumatoid arthritis." Jpn J Rheumatol. 6 (2). 189-200 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Chung U,Mimori T et al: "The interaction between Ku antigen and RFE1 protein mediates negative gene regulation by extracellular calcium." J Biol Chem. 271 (15). 8593-8 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kuwana M,Minori T et al: "Enhancement of anti-DNA topoisomerase I autoantibody responce after lung cancer in patients with systemic sclerosis." Arthritis, Rheum. 39 (4). 686-691 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Okumura K,Mimori T et al: "Sp1 family proteins recognize the U5 repressive element of the long terminal repeat of human T-cell leukemia virus type I through binding to the CACCC core motif." J Biol Chem. 271 (22). 12944-50 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Immunologic tests of rheumatic diseases." Medical Practice. 13 (5). 693-695 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Laboratory diagnosis of rheumatoid arthritis." Naika. 78 (2). 222-225 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsumura M,Mimori T et al: "Novel autoantibodies directed against the common tertiary configuration of transfer RNA in a patient with interstitial lung disease." Arthritis Rheum. 39 (8). 1308-1312 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Fujii T,Mimori T et al: "Detection of autoantibodies to nucleolar transcription factor NOR90/hUBF in sera of patients with rheumatic diseases by recombinant autoantigen-based assays." Arthritis Rheum. 39 (8). 1313-1318 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Arnett FC,Mimori T et al: "Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis." Arthritis Rheum. 39 (9). 1507-1518 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Inflamation and anti-calpastain antibodies." Clinical Calcium. 6. 65-67 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mimori T: "Update on structures targeted by the immune systems in miositis." Curr Opin in Rheumatol. 8 (6). 521-527 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nojima T,Mimori T et al: "Detection of autoantibodies in patients with rheumatoid arthritis" Jpn J Rheumatol. 6. 189-200 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 三森経世: "リウマチ性疾患の検査の進めかたとデータの読みかた-免疫学的検査から" Medical Practice. 13. 693-695 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 三森経世: "慢性関節リウマチの臨床検査" 内科. 78. 222-225 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Mimori T: "Update on structures targeted by the immune system in myositis" Current Opinion in Rheumatol. 8. 521-527 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 三森経世: "炎症と抗カルパスタチン抗体" Clinical Calcium. 6. 65-67 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 安岡秀剛,三森経世ほか: "抗カルパスタチン抗体が認識する自己抗原エピトープその臨床的意義" リウマチ(印刷中).

    • Related Report
      1996 Annual Research Report
  • [Publications] Mimori T et al: "Autoantibodies to calpastatin (an endogenous inhibitor for calciumdependent neutral protease, calpain) in systemic rheumatic diseases" Proc Natl Acad Sci USA. 92. 7267-7271 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Mimori T et al: "A pathogenic role of autoantibodies to calpastatin in patients with rheumatoid arthritis." Arthritis Rheum. 38. S165 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Oka T, Mimori T et al: "Molecular cloning and characterization of autoantigens recognized by sera from patients with rheumatoid arthritis." Arthritis Rheum. 38. S166 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 三森経世: "慢性関節リウマチと抗カルパスタチン抗体" 臨床検査. 39. 966-967 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 三森経世: "診断マーカーとしての自己抗体-使い方と読み方-" Medical Practice. 12. 1307-1311 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nojima T, Mimori T et al: "Detection of autoantibodies in patients with rheumatoid arthritis." Jpn J Rheumatol. (in press).

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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