Editorial Slides VP Watch December 11, 2002 Volume 2, Issue 49

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Editorial Slides VP Watch December 11, 2002 -
Volume 2, Issue 49
HSP-65, An Autoantigen for Plaque Development or
Plaque Vulnerability?

Yehuda Shoenfeld, MD Sheba Medical Center, Tel
Hashomer,Israel
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• A large number of studies have been reported on
  associations of coronary artery disease (CAD) in
  human and certain persistent bacterial and viral
  infections. 1

3

• In 1978, Fabricant et al showed that experimental
  infection of germ-free chickens with an avian
  herpes virus induces arterial disease that
  resembles human atherosclerosis. 2

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Atherosclerosis as an Autoimmune Disease
Autoantigens - Oxidized LDL - Heat Shock
Protein 65 - b2 Glycoprotein I - ???
5
Traditional Framingham risk factors fail to
fully account for accelerated atherosclerosis in
systemic lupus erythematosus. 3

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Criteria Needed to Establish An Autoimmune
Etiology. Witebsky-Rose criteria 4
It should be possible to 1. Demonstrate
immunological reactivity to a self-antigen.
Characterize or isolate the inciting
autoantigen. 2. Induce immunological reactivity
against that same antigen by immunization of
experimental animals. 3. Show pathological
changes (similar or identical to those found in
human disease) in the appropriate organs/tissues
of an actively-sensitized animal. 4. As in 4 but
following passive transfer of auto-Abs or
auto-reactive T cells.
7

• Human heat shock proteins (HSPs)
• are expressed on endothelial cells in
• response to stressors such as
• hypertension, smoking, lipoproteins
• - etc. 5
• HSPs offer a target for autoimmunity
• under such circumstances. 5

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Anti-HSP-65 and Atherosclerosis

• Carotid atherosclerosis
• Coronary heart disease
• Myocardial infarction
• Arteriosclerosis
• Coronary angioplasty
• Myocardial infarction

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Expression Of Heat Shock Protein-70 By Dendritic
Cells

• In early intimal lesions, HSP70 is
  over-expressed exclusively by dendritic cells,
  which suggests that dendritic cells might be
  involved in the early phases of atherogenesis. 6

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T Lymphocytes in atheroma

• 20 of the infiltrating inflammatory
• cells are T-lymphocytes. 6, 7
• T- lymphocytes are in an
• activated state memory cells,
• CD4 TCRab . 6, 7

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Enhanced fatty formation in C57BL/6J mice by
immunization with heat shock protein-65Jacob
George, Yehuda Shoenfeld, Arnon Afek, Boris
Gilbourd, Pnina Keren, Aviv Shaish, Juri
Kopolovic, George Wick, Dror HaratsArterioscler
Thromb Vasc Biol,19505-510,1999
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Cellular and Humoral Immune Responses to Heat-
Shock Protein 65 Are Both Involved In Promoting
Fatty-Streak Formation In LDL-Receptor Deficient
Mice Jacob George, Aron Afek, Boris Gilburd,
Yehuda Shoenfeld, Dror Harats. J Am Coll Cardiol
2001 38 900-905.
Antibodies and lymphocytes reactive to HSP65
promote fatty-streak formation in mice, providing
direct evidence for the proatherogenic properties
of cellular and humoral immunity to HSP65.
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Adoptive transfer of b2 glycoprotein I (b2GPI)
reactive lymphocytes enhances early
atherosclerosis in LDL-receptor deficient mice
Lymphocytes obtained from draining LN (mostly T
cells) and splenocytes increased atherogenesis.
Deletion of T cells prevented atherogenesis.
Ultimate evidence for autoimmunity and immune
system in atherosclerosis. Importance of T
cells in the process.
Jacob George, Dror Harats, Boris Gilburd, Arnon
Afek, Aviv Shaish, Juri Kopolovic, Yehuda
Shoenfeld. Circulation 102 1822 - 1827, 2000.
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Postulated Mechanisms to Link Infections And
Vascular Disease
Infection of arterial wall - SMC proliferation
associated with p53 inactivation - Local
inflammation
Systemic Infection Endothelial dysfunction due
to circulating endotoxin
Atherogenesis Plaque Rupture Thrombosis
Classic risk factors ? HDL ? Fibrinogen ?
Triglycerides
Autoimmunity - HSP60 cross-reactivity with
bacterial antigens
Systemic inflammation ? CRP ? Leukocyte count ?
Cytokines
Adapted from J. Danesh et al. Chronic infection
and coronary heart disease is there a link?.
Lancet 350 (1997), pp. 430436.
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• As reported in VP Watch this week, Lamb et al
  used a BCG immunization model to assess the role
  of HSP in the association between infection and
  CAD. 7

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• They immunized rabbits with BCG vaccine (n10) or
  saline (n10) and subsequently fed a cholesterol
  diet for 10 weeks. 7
• Plasma IgG specific for mycobacterial antigen A60
  and human HSP-60, but not for human HSP-70, rose
  following BCG immunization, reaching a peak after
  8 weeks. 7

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Effect of BCG immunization on atherosclerosis in
thoracic aorta of cholesterol-fed rabbits
aortic area covered by lesion

Plt0.05
The percentage aortic area staining positively
for oil red O was calculated. Each point is the
meanSE for seven rabbits. Statistical analysis
was performed using unpaired t-tests. Plt0.05.
Lamb DJ, Ferns GA. The magnitude of the immune
response to heat shock protein-65 following BCG
immunization is associated with the extent of
experimental atherosclerosis. Atherosclerosis.
2002 Dec165(2)231-40.
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• The percentage aortic area covered by
  atherosclerotic plaque was greater in animals
  immunized with BCG compared to controls.7
• The authors did not find any correlation between
  anti-A60 antibody titers and plaque area. 7

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Conclusion

• Immunization with an HSP-containing BCG vaccine,
  using doses equivalent to those used for
  tuberculosis prophylaxis, has pro-atherogenic
  consequences in the cholesterol-fed rabbits.
• This effect may be mediated in part by immune
  response directed against BCG-associated HSP.

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Questions

• - Is heat shock protein 65 the main culprit
  autoantigen for atherosclerosis?
• - Knowing the role of HSP-65 in other autoimmune
  diseases such as rheumatoid arthritis, how
  specific can HSP-65 be for atherosclerosis?

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Questions

• Should we look for a single specific antigen for
  atherosclerosis in all patients?
• Or do different antigens exist in different
  patients or even within the same patient?

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Questions

• Do you think that the role of these autoantigens
  may vary at different stages of the disease? Do
  you think that some may contribute to plaque
  development and others may induce plaque
  complication?
• Knowing that high LDL is necessary for
  atherosclerosis and HSP only enhances
  atherosclerosis, is it appropriate to say that
  HSP-65 may be more important in plaque
  complication (vulnerability) than plaque
  generation?

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References

• J. Danesh, R. Collins and R. Peto , Chronic
  infection and coronary heart disease is there a
  link?. Lancet 350 (1997), pp. 430436.
• CG Fabricant, J Fabricant, MM Litrenta and CR
  Minick, Virus-induced atherosclerosis. J Exp Med
  148 (1978), pp. 335340.
• Esdaile JM, et al Arthritis Rheum 2001, 44
  2311-7
• Krenn V, Souto-Carneiro MM, Kim HJ, Berek C,
  Starostik P, Konig A, Harms H, Muller-Hermelink
  HK Histopathology and molecular pathology of
  synovial B-lymphocytes in rheumatoid arthritis.
  Histol Histopathol. 2000 Jul15(3)791-8. Review.
• George J, Harats D, Shoenfeld Y.Clin Rev Allergy
  Immunol. 18 73-86, 2000.
• Bobryshev YV, Lord RS. J Vascular Surgery 35
  368-75, 2002
• A. Kinnunen et al. Scand J Immunol 2001 54
  76-81.
• Lamb DJ, Ferns GA.The magnitude of the immune
  response to heat shock protein-65 following BCG
  immunisation is associated with the extent of
  experimental atherosclerosis. Atherosclerosis.
  2002 Dec165(2)231-40.