T-cell reactivity against HSP60 relates to early but not advanced atherosclerosis



      Anti-heat-shock protein 60 (HSP60) antibody-levels have been linked to carotid atherosclerosis and cardiovascular risk in a variety of studies. The potential role of cellular immune reactions against HSP60 has so far attracted little attention in epidemiological research.

      Methods and results

      In vitro T-cell reactivity to various HSP60s and tuberculin was assessed in blood samples from a elderly subpopulation of the Bruneck study (100 men, 50–69 years) and the young participants of the ARMY study (141 men, 17–18 years), and analyzed for a potential association with common carotoid artery intima-media thickness (IMT). In vivo skin reaction against tuberculin was recorded in subjects of the Bruneck study and correlated with the in vitro proliferative response to tuberculin (P = 0.004). T-cells isolated from peripheral blood of all individuals proliferated upon stimulation with HSP60s. In multivariate linear regression analysis adjusted for standard risk factors, T-cell stimulation was significantly related to IMT in the ARMY (P = 0.005 for human HSP60 and P = 0.064 for mycobacterial HSP60) but not in the Bruneck study.


      T-cell reactivity against HSP60s correlated with IMT in male youngsters but not in men aged 50 and over, indicating a more prominent role of specific cellular immunity to HSP60s in the young and very early stages of atherosclerosis.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Virchow R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Zwanzig Vorlesungen. 1858.

        • Libby P.
        • Ridker P.M.
        • Maseri A.
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Wick G.
        • Knoflach M.
        • Xu Q.
        Autoimmune and inflammatory mechanisms in atherosclerosis.
        Annu Rev Immunol. 2004; 22: 362-403
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Millonig G.
        • Schwentner C.
        • Mueller P.
        • et al.
        The vascular-associated lymphoid tissue: a new site of local immunity.
        Curr Opin Lipidol. 2001; 12: 547-553
        • Xu Q.B.
        • Oberhuber G.
        • Gruschwitz M.
        • et al.
        Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens.
        Clin Immunol Immunopathol. 1990; 56: 344-359
        • Curry A.J.
        • Portig I.
        • Goodall J.C.
        • et al.
        T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens.
        Clin Exp Immunol. 2000; 121: 261-269
        • Benagiano M.
        • D’Elios M.M.
        • Amedei A.
        • et al.
        Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques.
        J Immunol. 2005; 174: 6509-6517
        • Young D.B.
        Heat-shock proteins: immunity and autoimmunity.
        Curr Opin Immunol. 1992; 4: 396-400
        • Xu Q.
        • Kiechl S.
        • Mayr M.
        • et al.
        Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis: clinical significance determined in a follow-up study.
        Circulation. 1999; 100: 1169-1174
        • Xu Q.
        • Dietrich H.
        • Steiner H.J.
        • et al.
        Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65.
        Arterioscler Thromb. 1992; 12: 789-799
        • Metzler B.
        • Mayr M.
        • Dietrich H.
        • et al.
        Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1905-1911
        • George J.
        • Afek A.
        • Gilburd B.
        • et al.
        Cellular and humoral immune responses to heat shock protein 65 are both involved in promoting fatty-streak formation in LDL-receptor deficient mice.
        J Am Coll Cardiol. 2001; 38: 900-905
        • Maron R.
        • Sukhova G.
        • Faria A.M.
        • et al.
        Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice.
        Circulation. 2002; 106: 1708-1715
        • Xu Q.
        • Kleindienst R.
        • Waitz W.
        • et al.
        Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65.
        J Clin Invest. 1993; 91: 2693-2702
        • Knoflach M.
        • Kiechl S.
        • Kind M.
        • et al.
        Cardiovascular risk factors and atherosclerosis in young males: ARMY study (atherosclerosis risk-factors in male youngsters).
        Circulation. 2003; 108: 1064-1069
        • Knoflach M.
        • Bernhard D.
        • Wick G.
        Anti-HSP60 immunity is already associated with atherosclerosis early in life.
        Ann NY Acad Sci. 2005; 1051: 323-331
        • Kiechl S.
        • Willeit J.
        The natural course of atherosclerosis.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1484-1498
        • Kiechl S.
        • Werner P.
        • Egger G.
        • et al.
        Active and passive smoking, chronic infections, and the risk of carotid atherosclerosis: prospective results from the Bruneck study.
        Stroke. 2002; 33: 2170-2176
        • Knoflach M.
        • Kiechl S.
        • Mayr A.
        • et al.
        Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies.
        Arch Intern Med. 2005; 165: 2521-2526
        • Willeit J.
        • Kiechl S.
        • Oberhollenzer F.
        • et al.
        Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck study.
        Arterioscler Thromb Vasc Biol. 2000; 20: 529-537
        • Willeit J.
        • Kiechl S.
        Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis. A population-based study.
        Arterioscler Thromb. 1993; 13: 661-668
        • Pignoli P.
        • Tremoli E.
        • Poli A.
        • et al.
        Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.
        Circulation. 1986; 74: 1399-1406
      2. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161:1376–95.

        • Ramage J.M.
        • Young J.L.
        • Goodall J.C.
        • et al.
        T cell responses to heat-shock protein 60: differential responses by CD4+ T cell subsets according to their expression of CD45 isotypes.
        J Immunol. 1999; 162: 704-710
        • van Eden W.
        • Thole J.E.
        • van der Zee R.
        • et al.
        Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis.
        Nature. 1988; 331: 171-173
        • Jepson A.
        • Fowler A.
        • Banya W.
        • et al.
        Genetic regulation of acquired immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa.
        Infect Immun. 2001; 69: 3989-3994
        • Kromer G.
        • Sundick R.S.
        • Schauenstein K.
        • et al.
        Analysis of lymphocytes infiltrating the thyroid gland of obese strain chickens.
        J Immunol. 1985; 135: 2452-2457
        • Song L.
        • Leung C.
        • Schindler C.
        Lymphocytes are important in early atherosclerosis.
        J Clin Invest. 2001; 108: 251-259
        • Stemme S.
        • Rymo L.
        • Hansson G.K.
        Polyclonal origin of T lymphocytes in human atherosclerotic plaques.
        Lab Invest. 1991; 65: 654-660
        • van Eden W.
        • van der Zee R.
        • Prakken B.
        Heat-shock proteins induce T-cell regulation of chronic inflammation.
        Nat Rev Immunol. 2005; 5: 318-330