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. 1995 Apr 25;92(9):3893–3897. doi: 10.1073/pnas.92.9.3893

T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein.

S Stemme 1, B Faber 1, J Holm 1, O Wiklund 1, J L Witztum 1, G K Hansson 1
PMCID: PMC42068  PMID: 7732003

Abstract

Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T lymphocytes and macrophages and high expression of HLA class II molecules are indicative of a local immunologic activation in the atherosclerotic plaque, but the antigen(s) involved has not yet been identified. We established T-cell clones from human atherosclerotic plaques using polyclonal mitogens as stimuli and exposed the clones to potential antigens in the presence of autologous monocytes as antigen-presenting cells. Four of the 27 CD4+ clones responded to oxidized low density lipoprotein (oxLDL) by proliferation and cytokine secretion; this response was dependent on autologous antigen-presenting cells and restricted by HLA-DR. All clones that responded to oxLDL secreted interferon gamma upon activation, but only one produced interleukin 4, suggesting that the response to oxLDL results in immune activation and inflammation but may not be a strong stimulus to antibody production. No significant response to oxLDL could be detected in CD4+ T-cell clones derived from the peripheral blood of the same individuals. Together, the present data suggest that the inflammatory infiltrate in the atherosclerotic plaque is involved in a T-cell-dependent, autoimmune response to oxLDL.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams D. O. Molecular interactions in macrophage activation. Immunol Today. 1989 Feb;10(2):33–35. doi: 10.1016/0167-5699(89)90298-3. [DOI] [PubMed] [Google Scholar]
  2. Amento E. P., Ehsani N., Palmer H., Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb. 1991 Sep-Oct;11(5):1223–1230. doi: 10.1161/01.atv.11.5.1223. [DOI] [PubMed] [Google Scholar]
  3. Barath P., Fishbein M. C., Cao J., Berenson J., Helfant R. H., Forrester J. S. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990 Feb 1;65(5):297–302. doi: 10.1016/0002-9149(90)90291-8. [DOI] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. doi: 10.1146/annurev.bi.52.070183.001255. [DOI] [PubMed] [Google Scholar]
  6. Camejo G., Hurt-Camejo E., Rosengren B., Wiklund O., López F., Bondjers G. Modification of copper-catalyzed oxidation of low density lipoprotein by proteoglycans and glycosaminoglycans. J Lipid Res. 1991 Dec;32(12):1983–1991. [PubMed] [Google Scholar]
  7. Cybulsky M. I., Gimbrone M. A., Jr Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991 Feb 15;251(4995):788–791. doi: 10.1126/science.1990440. [DOI] [PubMed] [Google Scholar]
  8. Ehlers S., Smith K. A. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Emeson E. E., Robertson A. L., Jr T lymphocytes in aortic and coronary intimas. Their potential role in atherogenesis. Am J Pathol. 1988 Feb;130(2):369–376. [PMC free article] [PubMed] [Google Scholar]
  10. Fogelman A. M., Van Lenten B. J., Warden C., Haberland M. E., Edwards P. A. Macrophage lipoprotein receptors. J Cell Sci Suppl. 1988;9:135–149. doi: 10.1242/jcs.1988.supplement_9.7. [DOI] [PubMed] [Google Scholar]
  11. Fong L. G., Fong T. A., Cooper A. D. Inhibition of mouse macrophage degradation of acetyl-low density lipoprotein by interferon-gamma. J Biol Chem. 1990 Jul 15;265(20):11751–11760. [PubMed] [Google Scholar]
  12. Frostegård J., Wu R., Giscombe R., Holm G., Lefvert A. K., Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb. 1992 Apr;12(4):461–467. doi: 10.1161/01.atv.12.4.461. [DOI] [PubMed] [Google Scholar]
  13. Geng Y. J., Hansson G. K. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest. 1992 Apr;89(4):1322–1330. doi: 10.1172/JCI115718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Geng Y., Hansson G. K., Holme E. Interferon-gamma and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Circ Res. 1992 Nov;71(5):1268–1276. doi: 10.1161/01.res.71.5.1268. [DOI] [PubMed] [Google Scholar]
  15. Griffith R. L., Virella G. T., Stevenson H. C., Lopes-Virella M. F. Low density lipoprotein metabolism by human macrophages activated with low density lipoprotein immune complexes. A possible mechanism of foam cell formation. J Exp Med. 1988 Sep 1;168(3):1041–1059. doi: 10.1084/jem.168.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hansson G. K., Hellstrand M., Rymo L., Rubbia L., Gabbiani G. Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med. 1989 Nov 1;170(5):1595–1608. doi: 10.1084/jem.170.5.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hansson G. K., Holm J., Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PMC free article] [PubMed] [Google Scholar]
  19. Hansson G. K. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J. 1993 Jan;69(1 Suppl):S38–S41. doi: 10.1136/hrt.69.1_suppl.s38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hansson G. K., Jonasson L., Holm J., Claesson-Welsh L. Class II MHC antigen expression in the atherosclerotic plaque: smooth muscle cells express HLA-DR, HLA-DQ and the invariant gamma chain. Clin Exp Immunol. 1986 May;64(2):261–268. [PMC free article] [PubMed] [Google Scholar]
  21. Hansson G. K., Jonasson L., Holm J., Clowes M. M., Clowes A. W. Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ Res. 1988 Oct;63(4):712–719. doi: 10.1161/01.res.63.4.712. [DOI] [PubMed] [Google Scholar]
  22. Hoff H. F., O'Neil J., Chisolm G. M., 3rd, Cole T. B., Quehenberger O., Esterbauer H., Jürgens G. Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arteriosclerosis. 1989 Jul-Aug;9(4):538–549. doi: 10.1161/01.atv.9.4.538. [DOI] [PubMed] [Google Scholar]
  23. Jonasson L., Holm J., Skalli O., Bondjers G., Hansson G. K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986 Mar-Apr;6(2):131–138. doi: 10.1161/01.atv.6.2.131. [DOI] [PubMed] [Google Scholar]
  24. Jonasson L., Holm J., Skalli O., Gabbiani G., Hansson G. K. Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest. 1985 Jul;76(1):125–131. doi: 10.1172/JCI111934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kim R. S., LaBella F. S. Comparison of analytical methods for monitoring autoxidation profiles of authentic lipids. J Lipid Res. 1987 Sep;28(9):1110–1117. [PubMed] [Google Scholar]
  26. Lampson L. A., Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed] [Google Scholar]
  27. Libby P., Hansson G. K. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991 Jan;64(1):5–15. [PubMed] [Google Scholar]
  28. Mackay C. R., Marston W. L., Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med. 1990 Mar 1;171(3):801–817. doi: 10.1084/jem.171.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. McMurray H. F., Parthasarathy S., Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest. 1993 Aug;92(2):1004–1008. doi: 10.1172/JCI116605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  31. Moyer C. F., Sajuthi D., Tulli H., Williams J. K. Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. Am J Pathol. 1991 Apr;138(4):951–960. [PMC free article] [PubMed] [Google Scholar]
  32. Palinski W., Ord V. A., Plump A. S., Breslow J. L., Steinberg D., Witztum J. L. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994 Apr;14(4):605–616. doi: 10.1161/01.atv.14.4.605. [DOI] [PubMed] [Google Scholar]
  33. Palinski W., Rosenfeld M. E., Ylä-Herttuala S., Gurtner G. C., Socher S. S., Butler S. W., Parthasarathy S., Carew T. E., Steinberg D., Witztum J. L. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1372–1376. doi: 10.1073/pnas.86.4.1372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Palinski W., Ylä-Herttuala S., Rosenfeld M. E., Butler S. W., Socher S. A., Parthasarathy S., Curtiss L. K., Witztum J. L. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis. 1990 May-Jun;10(3):325–335. doi: 10.1161/01.atv.10.3.325. [DOI] [PubMed] [Google Scholar]
  35. Rosenfeld M. E., Palinski W., Ylä-Herttuala S., Butler S., Witztum J. L. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis. 1990 May-Jun;10(3):336–349. doi: 10.1161/01.atv.10.3.336. [DOI] [PubMed] [Google Scholar]
  36. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  37. Salonen J. T., Ylä-Herttuala S., Yamamoto R., Butler S., Korpela H., Salonen R., Nyyssönen K., Palinski W., Witztum J. L. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992 Apr 11;339(8798):883–887. doi: 10.1016/0140-6736(92)90926-t. [DOI] [PubMed] [Google Scholar]
  38. Sjögren-Jansson E., Jeansson S. Large-scale production of monoclonal antibodies in dialysis tubing. J Immunol Methods. 1985 Nov 28;84(1-2):359–364. doi: 10.1016/0022-1759(85)90442-9. [DOI] [PubMed] [Google Scholar]
  39. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  40. Steinbrecher U. P. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. J Biol Chem. 1987 Mar 15;262(8):3603–3608. [PubMed] [Google Scholar]
  41. Steinbrecher U. P., Parthasarathy S., Leake D. S., Witztum J. L., Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3883–3887. doi: 10.1073/pnas.81.12.3883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Steinbrecher U. P., Witztum J. L., Parthasarathy S., Steinberg D. Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. Arteriosclerosis. 1987 Mar-Apr;7(2):135–143. doi: 10.1161/01.atv.7.2.135. [DOI] [PubMed] [Google Scholar]
  43. Stemme S., Holm J., Hansson G. K. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb. 1992 Feb;12(2):206–211. doi: 10.1161/01.atv.12.2.206. [DOI] [PubMed] [Google Scholar]
  44. Stemme S., Rymo L., Hansson G. K. Polyclonal origin of T lymphocytes in human atherosclerotic plaques. Lab Invest. 1991 Dec;65(6):654–660. [PubMed] [Google Scholar]
  45. Williams A. F., Galfrè G., Milstein C. Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes. Cell. 1977 Nov;12(3):663–673. doi: 10.1016/0092-8674(77)90266-5. [DOI] [PubMed] [Google Scholar]
  46. Ylä-Herttuala S., Palinski W., Butler S. W., Picard S., Steinberg D., Witztum J. L. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994 Jan;14(1):32–40. doi: 10.1161/01.atv.14.1.32. [DOI] [PubMed] [Google Scholar]
  47. Ylä-Herttuala S., Palinski W., Rosenfeld M. E., Parthasarathy S., Carew T. E., Butler S., Witztum J. L., Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. doi: 10.1172/JCI114271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. van der Wal A. C., Das P. K., Bentz van de Berg D., van der Loos C. M., Becker A. E. Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989 Aug;61(2):166–170. [PubMed] [Google Scholar]

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