Skip to main content
SpringerLink
Log in

Apoptosis in rheumatoid arthritis

  • Chapter
Apoptosis and Inflammation

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Rheumatoid arthritis (RA) — a chronic inflammatory disease affecting synovial tissue in multiple joints — is associated with long-term morbidity and early mortality despite considerable advances in understanding its pathogenesis. Although the identity and role of specific inciting agents is uncertain, immune-mediated mechanisms are likely of crucial importance. The evidence to support a role of CD4+T cells in the immune response in RA patients is substantial, albeit circumstantial [1, 2]. The strongest arguments are: (1) the association of disease susceptibility and outcome with HLA-DR4 antigens and in particular with the “shared epitope” (2) the large number of CD4+T cells that infiltrate the rheumatoid synovium and express activation markers such as HLA-DR; and (3) the modest therapeutic efficacy of interventions directed at T cells. It has become increasingly clear, however, that other cells, in particular activated macrophages and fibroblast-like synoviocytes (FLS) play a critical role in clinical signs of inflammation and in destroying articular structures in chronic disease [3–6]. At present, it is unclear whether sustained T cell activation is required to perpetuate such processes. It is conceivable that after a first phase mediated via T cell dependent pathways, macrophage-and fibroblast-dependent processes become increasingly important as autonomous promoters of synovial inflammation and joint destruction (Fig.1).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Panayi GS, Lanchbury JS, Kingsley GH (1992) The importance of the T cell in initiating and mainaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 35: 729–735

    Article  PubMed  CAS  Google Scholar 

  2. Fox DA (1997) The role of T cells in the immunopathogenesis of rheumatoid arthritis. New perspectives. Arthritis Rheum 40: 598–609

    Article  PubMed  CAS  Google Scholar 

  3. Firestein GS, Zvaifler NJ (1990) How important are T cells in chronic rheumatoid synovitis. Arthritis Rheum 33: 768–773

    Article  PubMed  CAS  Google Scholar 

  4. Tak PP, Smeets TJM, Daha MR, Kluin PM, Meijers KAE, Brand R, Meinders AE, Breed-veld FC (1997) Analysis of the synovial cellular infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40: 217–225

    Article  PubMed  CAS  Google Scholar 

  5. Burmester GR, Stuhlmuller B, Keyszer G, Kinne RW (1997) Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis? Arthritis Rheum 40: 5–18

    Article  PubMed  CAS  Google Scholar 

  6. Firestein GS (1996) Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed agressors? Arthritis Rheum 39: 1781–1790

    Article  PubMed  CAS  Google Scholar 

  7. Henderson B, Revell PA, Edwards JC (1988) Synovial lining cell hyperplasia in rheumatoid arthritis: dogma and fact. Ann Rheum Dis 47: 348–349

    Article  PubMed  CAS  Google Scholar 

  8. Lalor PA, Mapp PI, Hall PA, Revell PA (1987) Proliferative activity of cells in the synovium as demonstrated by a monoclonal antibody, Ki67. Rheumatol Int 7: 183–186

    Article  PubMed  CAS  Google Scholar 

  9. Qu ZH, Garcia CH, Orourke LM, Planck SR, Kohli M, Rosenbaum JT (1994) Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia — Results of proliferation cell nuclear antigen/cyclin, C-myc, and nucleolar organizer region staining. Arthritis Rheum 37: 212–220

    Article  PubMed  CAS  Google Scholar 

  10. Morales Ducret J, Wayner E, Elices MJ, Alvaro-Gracia JM, Zvaifler NJ, Firestein GS (1992) Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J Immunol 149: 1424–1431

    PubMed  CAS  Google Scholar 

  11. Tak PP, Thurkow EW, Daha MR, Kluin PM, Smeets TJM, Meinders AE, Breedveld FC (1995) Expression of adhesion molecules in early rheumatoid synovial tissue. Clin Immunol Immunopathol 77: 236–242

    Article  PubMed  CAS  Google Scholar 

  12. Kriegsmann J, Keyszer GM, Geiler T, Brauer R, Gay RE, Gay S (1995) Expression of vascular cell adhesion molecule-1 mRNA and protein in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. Lab Invest 72: 209–214

    PubMed  CAS  Google Scholar 

  13. Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL (1989) Anchorage-independent growth of synoviocytes from arthritic and normal joints: stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factorbeta and retinoids. J Clin Invest 83: 1267–1276

    Article  PubMed  CAS  Google Scholar 

  14. Geiler T, Kriegsmann J, Keyszer GM, Gay RE, Gay S (1994) A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum 37: 1664–1671

    Article  PubMed  CAS  Google Scholar 

  15. Muller-Ladner L, Kriegsmann J, Franklin BN, Matsumoto S, Geiler T, Gay RE, Gay S (1996) Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 149: 1607–1615

    PubMed  CAS  Google Scholar 

  16. Murphy G, Hembry RM (1992) Proteinases in rheumatoid arthritis. J Rheumatol 19: 61–64

    Google Scholar 

  17. Hembry RM, Bagga MR, Reynolds JJ, Hamblen DL (1995) Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP-1 and TIMP-2, in synovia from patients with osteo-and rheumatoid arthritis. Ann Rheum Dis 54: 25–32

    Article  PubMed  CAS  Google Scholar 

  18. Firestein GS, Paine MM, Littman BH (1991) Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids. Arthritis Rheum 34: 1094–1105

    Article  PubMed  CAS  Google Scholar 

  19. Scott BB, Weisbrot LM, Greenwood JD, Bogoch ER, Paige CJ, Keystone EC (1997) Rheumatoid arthritis synovial fibroblast and U937 macrophage/monocyte cell line interaction in cartilage degradation. Arthritis Rheum 40: 490–498

    Article  PubMed  CAS  Google Scholar 

  20. Zvaifler NJ, Tsai V, Alsalameh S, Vonkempis J, Firestein GS, Lotz M (1997) Pannocytes: Distinctive cells found in rheumatoid arthritis articular cartilage erosions. Am J Pathol 150: 1125–1138

    PubMed  CAS  Google Scholar 

  21. Tak PP, Kummer JA, Hack CE, Daha MR, Smeets TJM, Erkelens GW, Meinders AE, Kluin PM, Breedveld FC (1994) Granzyme positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue. Arthritis Rheum 37: 1735–1743

    Article  PubMed  CAS  Google Scholar 

  22. Muller-Ladner U, Kriegsmann J, Tschopp J, Gay RE, Gay S (1995) Demonstration of granzyme A and perforin messenger RNA in the synovium of patients with rheumatoid arthritis. Arthritis Rheum 38: 477–484

    Article  PubMed  CAS  Google Scholar 

  23. Firestein GS, Yeo M, Zvaifler NJ (1995) Apoptosis in rheumatoid arthritis synovium. J Clin Invest 96: 1631–1638

    Article  PubMed  CAS  Google Scholar 

  24. Yanni G, Whelan A, Feighery C, Bresnihan B (1992) Analysis of cell populations in rheumatoid arthritis synovial tissues. Semin Arthritis Rheum 21: 393–399

    Article  PubMed  CAS  Google Scholar 

  25. Tak PP, Hintzen RQ, Teunissen JJM, Smeets TJM, Daha MR, Van Lier RAW, Kluin PM, Meinders AE, Swaak AJG, Breedveld FC (1996) Expression of the activation antigen CD27 in rheumatoid arthritis. Clin Immunol Immunopathol 80: 129–138

    Article  PubMed  CAS  Google Scholar 

  26. Nakajima T, Aono H, Hasunuma T, Yamamoto K, Shirai T, Hirohata K, Nishioka K (1995) Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum 38: 485–491

    Article  PubMed  CAS  Google Scholar 

  27. Matsumoto S, Muller-Ladner U, Gay RE, Nishioka K, Gay S (1996) Ultrastructural demonstration of apoptosis, Fas and Bd-2 expression of rheumatoid synovial fibroblasts. J Rheumatol 23: 1345–1352

    PubMed  CAS  Google Scholar 

  28. Sugiyama M, Tsukazaki T, Yonekura A, Matsuzaki S, Yamashita S, Iwasaki K (1996) Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 55: 442–449

    Article  PubMed  CAS  Google Scholar 

  29. Savill J, Fadok V, Henson P, Haslett C (1993) Phagocyte recognition of cells undergoing apoptosis. Immunol Today 14: 131–136

    Article  PubMed  CAS  Google Scholar 

  30. Sumida T, Hoa TTM, Asahara H, Hasunuma T, Nishioka K (1997) T cell receptor of Fas-sensitive T cells in rheumatoid synovium. J Immunol 158: 1965–1970

    PubMed  CAS  Google Scholar 

  31. Cantwell MJ, Hua T, Zvaifler NJ, Kipps TJ (1997) Deficient Fas ligand expression by synovial lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 40: 1644–1652

    Article  PubMed  CAS  Google Scholar 

  32. Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H (1995) Metalloproteinase-mediated release of human Fas ligand. J Exp Med 182:1777–1783

    Article  PubMed  CAS  Google Scholar 

  33. Gravallese EM, Darling JM, Ladd AL, Katz JN, Glimcher LH (1991) In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. Arthritis Rheum 34: 1076–1084

    Article  PubMed  CAS  Google Scholar 

  34. Hasunuma T, Kayagaki N, Asahara H, Motokawa S, Kobata T, Yagita H, Aono H, Sumida T, Okumura K, Nishioka K (1997) Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 40: 80–86

    Article  PubMed  CAS  Google Scholar 

  35. Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J (1997) T cell cytokine pattern in the joint of patients with Lyme arthritis and its regulation by cytokines and anticytokines. Arthritis Rheum 40: 69–79

    Article  PubMed  CAS  Google Scholar 

  36. Nagata S, Suda T (1995) Fas and Fas ligand: 1pr and gld mutations. Immunol Today 16: 39–43

    Article  PubMed  CAS  Google Scholar 

  37. Ito MR, Terasaki S, Itoh J, Katoh H, Yonehara S, Nose M (1997) Rheumatic diseases in an MRL strain of mice with a deficit in the functional Fas ligand. Arthritis Rheum 40: 1054–1063

    Article  PubMed  CAS  Google Scholar 

  38. Smeets TJM, Dolhain RJEM, Breedveld FC, Tak PP (1998) Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and from patients with reactive arthritis. J Pathol 186: 75–81

    Article  PubMed  CAS  Google Scholar 

  39. Berke G (1997) The Fas-based mechanism of lymphocytotoxicity. Hum Immunol 54: 1–7

    Article  PubMed  CAS  Google Scholar 

  40. Talanian RV, Yang XH, Turbov J, Seth P, Ghayur T, Casiano CA, Orth K, Froelich CJ (1997) Granule-mediated killing: Pathways for granzyme B-initiated apoptosis. J Exp Med 186: 1323–1331

    Article  CAS  Google Scholar 

  41. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397–440

    Article  PubMed  CAS  Google Scholar 

  42. Chu CQ, Field M, Allard S, Abney E, Feldmann M, Maini RN (1992) Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. Br J Rheumatol 31: 653–661

    Article  PubMed  CAS  Google Scholar 

  43. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNFalpha induced apoptosis by NFKB. Science 274: 787–789

    Article  PubMed  Google Scholar 

  44. Girard D, Paquet ME, Paquin R, Beaulieu AD (1996) Differential effects of interleukin15 (IL-15) and IL-2 on human neutrophile: Modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15. Blood 88: 3176–3184

    PubMed  CAS  Google Scholar 

  45. Bulfonepaus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H, Kunzendorf U (1997) Interleukin-15 protects from lethal apoptosis in vivo. Nature Med 3: 1124–1128

    Article  CAS  Google Scholar 

  46. Salmon M, Scheel-Toellner D, Huissoon AP, Pilling D, Shamsadeen N, Hyde H, Dupuy d’Angeac A, Bacon PA, Emery P, Akbar AN (1997) Inhibition of T cell apoptosis in the rheumatoid synovium. J Clin Invest 99: 439–446

    Article  PubMed  CAS  Google Scholar 

  47. McInnes IB, Almughales J, Field M, Leung BP, Huang FP, Dixon R, Sturrock RD, Wilkinson PC, Liew FY (1996) The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nature Med 2: 175–182

    Article  PubMed  CAS  Google Scholar 

  48. Thurkow EW, Van der Heijden IM, Breedveld FC, Smeets TJM, Daha MR, Kluin PM, Meinders AE, Tak PP (1997) Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared to patients with Yersinia-induced arthritis and osteoarthritis. J Pathol 181: 444–450

    Article  PubMed  CAS  Google Scholar 

  49. Mountz JD, Wu J, Cheng J, Zhou T (1994) Autoimmune disease. A problem of defective apoptosis. Arthritis Rheum 37: 1415–1420

    Article  PubMed  CAS  Google Scholar 

  50. Zdichaysky M, Schorpp C, Nickels A, Koch B, Pfreundschuh M, Gause A (1996) Analysis of bcl-2(+) lymphocyte subpopulations in inflammatory synovial infiltrates by a double immunostaining technique. Rheumatol Int 16: 151–157

    Article  Google Scholar 

  51. Roivainen A, Jalava J, Pirila L, Yli-Jama T, Tiusanen H, Toivanen P, Ylijama T (1997) H-ras oncogene point mutations in arthritic synovium.Arthritis Rheum40: 1636–1643

    Article  PubMed  CAS  Google Scholar 

  52. Firestein GS, Nguyen K, Aupperle KR, Yeo M, Zvaifler NJ (1996) Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am J Pathol 149: 2143–2151

    PubMed  CAS  Google Scholar 

  53. Nickels A, Selter H, Pfreundschuh M, Montenarh M, Koch B (1997) Detection of p53 in inflammatory tissue and lymphocytes using immunohistology and flow cytometry: a critical comment. J Clin Pathol 50: 654–660

    Article  PubMed  CAS  Google Scholar 

  54. Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR (1997) Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA 94: 10895–10900

    Article  PubMed  CAS  Google Scholar 

  55. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunamus TM, Cebula TA, Koch WH, Andrews AW, Allen JS et al (1991) DNA deaminating ability and geno-toxicity of nitric oxide and its progenitors. Science 254: 1001–1003

    Article  PubMed  CAS  Google Scholar 

  56. Nguyen T, Brunson T, Cresp CL, Penman BW, Wishnok JS, Tannenbaum SR (1992) DNA damage and mutation in human cells exposed to nitric oxidein vitro. Proc Natl Acad Sci USA 89: 3030–3034

    Article  PubMed  CAS  Google Scholar 

  57. Aupperle KR, Boyle DL, Hendrix M, Zvaifler NJ, Barbosa M, Firestein GS (1998) Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene. Am J Pathol 152: 1091–1098

    PubMed  CAS  Google Scholar 

  58. Santhanam U, Ray A, Sehgal PB (1991) Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci USA 88: 7605–7609

    Article  PubMed  CAS  Google Scholar 

  59. Messmer UK, Brune B (1996) Nitric oxide-induced apoptosis: p53-dependent and p53 independent signalling pathways. Biochem J 319: 299–305

    PubMed  CAS  Google Scholar 

  60. Fujita T, Ishido S, Muramatsu S, Itoh M, Hotta H (1996) Suppression of actinomycin D-induced apoptosis by the NS3 protein of hepatitis C virus. Biochem Biophys Res Commun 229: 825–831

    Article  PubMed  CAS  Google Scholar 

  61. Okamoto K, Fujisawa K, Hasunuma T, Kobata T, Sumida T, Nishioka K (1997) Selective activation of the JNK/AP-1 pathway in Fas-mediated apoptosis of rheumatoid arthritis synoviocytes. Arthritis Rheum 40: 919–926

    Article  PubMed  CAS  Google Scholar 

  62. Tsuboi M, Eguchi K, Kawakami A, Matsuoka N, Kawabe Y, Aoyagi T, Maeda K, Nagataki S (1996) Fas antigen expression on synovial cells was down-regulated by interleukin-113. Biochem Biophys Res Commun 218: 280–285

    Article  PubMed  CAS  Google Scholar 

  63. Kawakami A, Eguchi K, Matsuoka N, Tsuboi M, Kawabe Y, Aoyagi T, Nagataki S (1996) Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cellsin vitroby transforming growth factor beta 1. Arthritis Rheum 39: 1267–1276

    Article  PubMed  CAS  Google Scholar 

  64. Prasad KVS, Ao Z, Yoon Y, Wu MX, Rizk M, Jacquot S, Schlossman SF (1997) CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci USA 94: 6346–6351

    Article  PubMed  CAS  Google Scholar 

  65. Kohem CL, Brezinschek RI, Wisbey H, Tortorella C, Lipsky PE, Oppenheimermarks N (1996) Enrichment of differentiated CD45RB(dim), CD27-memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 39: 844–854

    Article  PubMed  CAS  Google Scholar 

  66. Scott S, Pandolfi F, Kurnick JT (1990) Fibroblasts mediate T cell survival: a proposed mechanism for retention of primed T cells. J Exp Med 172: 1873–1876

    Article  PubMed  CAS  Google Scholar 

  67. Dechanet J, Merville P, Durand I, Banchereau J, Miossec P (1995) The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium. J Clin Invest 95: 456–463

    Article  PubMed  CAS  Google Scholar 

  68. Merville P, Dechanet J, Desmouliere A, Durand I, de Bouteiller O, Garrone P, Banchereau J, Liu YJ (1996) Bcl-2+ tonsillar plasma cells are rescued from apoptosis by bone marrow fibrobslasts. J Exp Med 183: 227–236

    Article  PubMed  CAS  Google Scholar 

  69. Richardson BC, Lalwani ND, Johnson KJ, Marks RM (1994) Fas ligation triggers apoptosis in macrophages but not endothelial cells. Eur J Immunol 24: 2640–2645

    Article  PubMed  CAS  Google Scholar 

  70. Migita K, Eguchi K, Ichinose Y, Kawabe Y, Tsukada T, Aoyagi T, Nagataki S (1997) Effects of rapamycin on apoptosis of rheumatoid synovial cells. Clin Exp Immunol 108: 199–203

    Article  PubMed  CAS  Google Scholar 

  71. Hui A, Kulkarni GV, Hunter WL, Mcculloch CAG, Cruz TF (1997) Paclitaxel selectively induces mitotic arrest and apoptosis in proliferating bovine synoviocytes. Arthritis Rheum 40: 1073–1084

    Article  PubMed  CAS  Google Scholar 

  72. Zhang HD, Yang YP, Horton JL, Samoilova EB, Judge TA, Turka LA, Wilson JM, Chen YH (1997) Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 100: 1951–1957

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0656, USA

    Paul P. Tak & Gary S. Firestein

Authors
  1. Paul P. Tak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary S. Firestein
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Oncology Research, Smith Kline Beecham Pharmaceuticals, UW 2110 709 Swedeland Road, King of Prussia, PA, 19406, USA

    James D. Winkler (Assistant Director) (Assistant Director)

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Basel AG

About this chapter

Cite this chapter

Tak, P.P., Firestein, G.S. (1999). Apoptosis in rheumatoid arthritis. In: Winkler, J.D. (eds) Apoptosis and Inflammation. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8741-0_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8741-0_9

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9752-5

  • Online ISBN: 978-3-0348-8741-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation