The lymphocyte in inflammatory angiogenesis

  • Ewa Paleolog
  • Mohammed Ali Akhavani
Part of the Progress in Inflammation Research book series (PIR)


The ability of immune cells to recognise foreign pathogens, while simultaneously maintaining tolerance towards proteins produced by the body’s own cells, forms the basis of mammalian immunity. At the heart of the immune system are the lymphocytes, which orchestrate the adaptive immune response through clonal expansion upon recognition of a specific antigen. The plasticity of the immune system allows exquisite control of the body’s defences. However, the adaptive immune system can also be directed towards host proteins (‘self antigens’). The reasons for this failure in immunity are varied, and include a genetic basis or evasion of the host immune response by viruses. Nevertheless, the consequences — autoimmune diseases such as rheumatoid arthritis (RA) — are frequently associated with inflammation, immune cell dysfunction and changes in the vasculature.


Rheumatoid Arthritis Immune Response Immune System Immune Cell Genetic Basis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Walsh DA, Pearson CI (2001) Angiogenesis in the pathogenesis of inflammatory joint and lung diseases. Arthritis Res 3: 147–153PubMedCrossRefGoogle Scholar
  2. 2.
    Bainbridge J, Sivakumar B, Paleolog E (2006) Angiogenesis as a therapeutic target in arthritis: Lessons from oncology. Curr Pharm Des 12: 2631–2644PubMedCrossRefGoogle Scholar
  3. 3.
    Sivakumar B, Harry LE, Paleolog EM (2004) Modulating angiogenesis: More vs less. JAMA 292: 972–977PubMedCrossRefGoogle Scholar
  4. 4.
    Winchester R (1994) The molecular basis of susceptibility to rheumatoid arthritis. Adv Immunol 56: 389–466PubMedCrossRefGoogle Scholar
  5. 5.
    Cope AP, Londei M, Chu NR, Cohen SB, Elliott MJ, Brennan FM, Maini RN, Feldmann M (1994) Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J Clin Invest 94: 749–760PubMedCrossRefGoogle Scholar
  6. 6.
    Isomaki P, Panesar M, Annenkov A, Clark JM, Foxwell BM, Chernajovsky Y, Cope AP (2001) Prolonged exposure of T cells to TNF down-regulates TCR zeta and expression of the TCR/CD3 complex at the cell surface. J Immunol 166: 5495–5507PubMedGoogle Scholar
  7. 7.
    Clark JM, Annenkov AE, Panesar M, Isomaki P, Chernajovsky Y, Cope AP (2004) T cell receptor zeta reconstitution fails to restore responses of T cells rendered hyporesponsive by tumor necrosis factor alpha. Proc Natl Acad Sci USA 101: 1696–1701PubMedCrossRefGoogle Scholar
  8. 8.
    Cope AP (2004) Altered signalling thresholds in T lymphocytes cause autoimmune arthritis. Arthritis Res Ther 6: 112–116PubMedCrossRefGoogle Scholar
  9. 9.
    Cope AP (2002) Studies of T-cell activation in chronic inflammation. Arthritis Res 4 Suppl 3: S197–211PubMedCrossRefGoogle Scholar
  10. 10.
    Weyand CM, Goronzy JJ, Takemura S, Kurtin PJ (2000) Cell-cell interactions in synovitis. Interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res 2: 457–463PubMedCrossRefGoogle Scholar
  11. 11.
    Weyand CM, Goronzy JJ (2003) Ectopic germinal center formation in rheumatoid synovitis. Ann NY Acad Sci 987: 140–149PubMedCrossRefGoogle Scholar
  12. 12.
    Wagner UG, Kurtin PJ, Wahner A, Brackertz M, Berry DJ, Goronzy JJ, Weyand CM (1998) The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovitis. J Immunol 161: 6390–6397PubMedGoogle Scholar
  13. 13.
    Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O—Fallon WM, Goronzy JJ, Weyand CM (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167: 1072–1080PubMedGoogle Scholar
  14. 14.
    Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C et al (2005) Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol 35: 1347–1359PubMedCrossRefGoogle Scholar
  15. 15.
    Weyand CM, Kang YM, Kurtin PJ, Goronzy JJ (2003) The power of the third dimension: Tissue architecture and autoimmunity in rheumatoid arthritis. Curr Opin Rheumatol 15: 259–266PubMedCrossRefGoogle Scholar
  16. 16.
    Sidky YA, Auerbach R (1975) Lymphocyte-induced angiogenesis: A quantitative and sensitive assay of the graft-vs.-host reaction. J Exp Med 141: 1084–1100PubMedCrossRefGoogle Scholar
  17. 17.
    Blake DR, Merry P, Unsworth J, Kidd BL, Outhwaite JM, Ballard R Morris CJ, Gray L, Lunec J (1989) Hypoxic-reperfusion injury in the inflamed human joint. Lancet I: 289–293CrossRefGoogle Scholar
  18. 18.
    Merry P, Grootveld M, Blake DR (1989) Hypoxic-reperfusion injury in inflamed joints. Lancet I: 1023CrossRefGoogle Scholar
  19. 19.
    Naughton DP (2003) Hypoxia-induced upregulation of the glycolytic enzyme glucose-6-phosphate isomerase perpetuates rheumatoid arthritis. Med Hypotheses 60: 332–334PubMedCrossRefGoogle Scholar
  20. 20.
    Lund-Olesen K (1970) Oxygen tension in synovial fluids. Arthritis Rheum 13: 769–776PubMedCrossRefGoogle Scholar
  21. 21.
    Sivakumar B, Akhavani M, Kang N, Taylor P, Paleolog E (2006) Hypoxia-driven angiogenesis is a key feature of tendon disease in rheumatoid arthritis. Rheumatology (Oxford) 45 (Suppl 1): i39Google Scholar
  22. 22.
    Etherington PJ, Winlove P, Taylor P, Paleolog E, Miotla J (2002) VEGF release is associated with reduced oxygen tensions in experimental inflammatory arthritis. Clin Exp Rheumatol 20: 799–805PubMedGoogle Scholar
  23. 23.
    Stevens CR, Blake DR, Merry P, Revell PA, Levick JR (1991) A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum 34: 1508–1513PubMedGoogle Scholar
  24. 24.
    Naughton D, Whelan M, Smith EC, Williams R, Blake DR, Grootveld M (1993) An investigation of the abnormal metabolic status of synovial fluid from patients with rheumatoid arthritis by high field proton nuclear magnetic resonance spectroscopy. FEBS Lett 317: 135–138PubMedCrossRefGoogle Scholar
  25. 25.
    Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV (2001) Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167: 6140–6149PubMedGoogle Scholar
  26. 26.
    Braun RD, Lanzen JL, Snyder SA, Dewhirst MW (2001) Comparison of tumor and normal tissue oxygen tension measurements using OxyLife or microelectrodes in rodents. Am J Physiol Heart Circ Physiol 280: H2533–2544PubMedGoogle Scholar
  27. 27.
    Naldini A, Carraro F, Silvestri S, Bocci V (1997) Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells. J Cell Physiol 173: 335–342PubMedCrossRefGoogle Scholar
  28. 28.
    Naldini A, Carraro F (1999) Hypoxia modulates cyclin and cytokine expression and inhibits peripheral mononuclear cell proliferation. J Cell Physiol 181: 448–454PubMedCrossRefGoogle Scholar
  29. 29.
    Krieger JA, Landsiedel JC, Lawrence DA (1996) Differential in vitro effects of physiological and atmospheric oxygen tension on normal human peripheral blood mononuclear cell proliferation, cytokine and immunoglobulin production. Int J Immunopharmacol 18: 545–552PubMedCrossRefGoogle Scholar
  30. 30.
    Makino Y, Nakamura H, Ikeda E, Ohnuma K, Yamauchi K, Yabe Y, Poellinger L, Okada Y, Morimoto C, Tanaka H (2003) Hypoxia-inducible factor regulates survival of antigen receptor-driven T cells. J Immunol 171: 6534–6540PubMedGoogle Scholar
  31. 31.
    Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F (2005) Hypoxia inducible factor (HIF) in rheumatology: Low O2! See what HIF can do! Ann Rheum Dis 64: 971–980PubMedCrossRefGoogle Scholar
  32. 32.
    Mazure NM, Brahimi-Horn MC, Berta MA, Benizri E, Bilton RL, Dayan F, Ginouves A, Berra E, Pouyssegur J (2004) HIF-1: Master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol 68: 971–980PubMedCrossRefGoogle Scholar
  33. 33.
    Brahimi-Horn C, Mazure N, Pouyssegur J (2005) Signalling via the hypoxia-inducible factor-1alpha requires multiple posttranslational modifications. Cell Signal 17: 1–9PubMedCrossRefGoogle Scholar
  34. 34.
    Kallio PJ, Okamoto K, O—Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L (1998) Signal transduction in hypoxic cells: Inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J 17: 6573–6586PubMedCrossRefGoogle Scholar
  35. 35.
    Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O—Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54PubMedCrossRefGoogle Scholar
  36. 36.
    Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20: 5197–5206PubMedCrossRefGoogle Scholar
  37. 37.
    Masson N, Ratcliffe PJ (2003) HIF prolyl and asparaginyl hydroxylases in the biological response to intra cellular O2 levels. J Cell Sci 116: 3041–3049PubMedCrossRefGoogle Scholar
  38. 38.
    Lando D, Gorman JJ, Whitelaw ML, Peet DJ (2003) Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem 270: 781–790PubMedCrossRefGoogle Scholar
  39. 39.
    Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T Wagner T, Jelkmann W, Jaakkola P, Metzen E (2004) Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J 381: 761–767PubMedCrossRefGoogle Scholar
  40. 40.
    Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279: 38458–38465PubMedCrossRefGoogle Scholar
  41. 41.
    Aprelikova O, Chandramouli GV, Wood M, Vasselli JR, Riss J, Maranchie JK, Linehan WM, Barrett JC (2004) Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. J Cell Biochem 92: 491–501PubMedCrossRefGoogle Scholar
  42. 42.
    Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1 alpha in normoxia. EMBO J 22: 4082–4090PubMedCrossRefGoogle Scholar
  43. 43.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732PubMedCrossRefGoogle Scholar
  44. 44.
    Hirota K, Semenza GL (2005) Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochem Biophys Res Commun 338: 610–616PubMedCrossRefGoogle Scholar
  45. 45.
    Hitchon C, Wong K, Ma G, Reed J, Lyttle D, El-Gabalawy H (2002) Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 46: 2587–2597PubMedCrossRefGoogle Scholar
  46. 46.
    Hollander AP, Corke KP, Freemont AJ, Lewis CE (2001) Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: Implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum 44: 1540–1544PubMedCrossRefGoogle Scholar
  47. 47.
    Giatromanolaki A, Sivridis E, Maltezos E, Athanassou N, Papazoglou D, Gatter KC et al (2003) Upregulated hypoxia inducible factor-1 alpha and-2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 5: R193–201PubMedCrossRefGoogle Scholar
  48. 48.
    Peters CL, Morris CJ, Mapp PI, Blake DR, Lewis CE, Winrow VR (2004) The transcription factors hypoxia-inducible factor 1 alpha and Ets-1 colocalize in the hypoxic synovium of inflamed joints in adjuvant-induced arthritis. Arthritis Rheum 50: 291–296PubMedCrossRefGoogle Scholar
  49. 49.
    Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T, Carmeliet P, Semenza GL, Sitkovsky MV (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1 alpha-deficient chimeric mice. Proc Natl Acad Sci USA 99: 2170–2174PubMedCrossRefGoogle Scholar
  50. 50.
    Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, Tanaka H (2005) TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol 174: 7592–7599PubMedGoogle Scholar
  51. 51.
    Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH, Freedman BD, Turka LA (2005) Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci USA 102: 17071–17076PubMedCrossRefGoogle Scholar
  52. 52.
    Auerbach R, Sidky YA (1979) Nature of the stimulus leading to lymphocyte-induced angiogenesis. J Immunol 123: 751–754PubMedGoogle Scholar
  53. 53.
    Moulton KS, Melder RJ, Dharnidharka VR, Hardin-Young J, Jain RK, Briscoe DM (1999) Angiogenesis in the huPBL-SCID model of human transplant rejection. Transplantation 67: 1626–1631PubMedCrossRefGoogle Scholar
  54. 54.
    Freeman MR, Schneck FX, Gagnon ML, Corless C, Soker S, Niknejad K, Peoples GE, Klagsbrun M (1995) Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: A potential role for T cells in angiogenesis. Cancer Res 55: 4140–4145PubMedGoogle Scholar
  55. 55.
    Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN (1998) Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis. Rheum 41: 1258–1265PubMedCrossRefGoogle Scholar
  56. 56.
    Jain A, Kiriakidis S, Brennan F, Sandison A, Paleolog E, Nanchahal J (2006) Targeting rheumatoid tenosynovial angiogenesis with cytokine inhibitors. Clin Orthop Relat Res 446: 268–277PubMedCrossRefGoogle Scholar
  57. 57.
    Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH (2004) Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol 24: 9038–9047PubMedCrossRefGoogle Scholar
  58. 58.
    Mor F, Quintana FJ, Cohen IR (2004) Angiogenesis-inflammation cross-talk: Vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 172: 4618–4623PubMedGoogle Scholar
  59. 59.
    Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E (2003) VEGF expression in human macrophages is NF-kappaB-dependent: Studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci 116: 665–674PubMedCrossRefGoogle Scholar
  60. 60.
    Melter M, Reinders ME, Sho M, Pal S, Geehan C, Denton MD, Mukhopadhyay, D, Briscoe DM (2000) Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo. Blood 96: 3801–3808PubMedGoogle Scholar
  61. 61.
    Cho CS, Cho ML, Min SY, Kim WU, Min DJ, Lee SS, Park SH, Choe J, Kim HY (2000) CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol 164: 5055–5061PubMedGoogle Scholar
  62. 62.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1 alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22: 7004–7014PubMedCrossRefGoogle Scholar
  63. 63.
    Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP (2006) PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442: 779–785PubMedCrossRefGoogle Scholar
  64. 64.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10: 858–864PubMedCrossRefGoogle Scholar
  65. 65.
    Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi K, Girschick HJ, Yavuz S, Lipsky PE (2000) Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 165: 6590–6598PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Ewa Paleolog
    • 1
    • 2
  • Mohammed Ali Akhavani
    • 1
    • 3
  1. 1.Kennedy Institute of Rheumatology, Faculty of MedicineImperial CollegeLondonUK
  2. 2.Division of Surgery, Oncology, Reproductive Biology & Anaesthetics, Faculty of MedicineImperial CollegeLondonUK
  3. 3.Restoration of Appearance and Function Trust (RAFT)Mount Vernon HospitalNorthwoodUK

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