Sunday, October 14, 2012

Immune Related Mechanisms

Bacterial Infections and LPS 

Chronic infections and bacterial products such as LPS are associated with atherosclerosis and are found in atherosclerotic lesions [1].  Bacterial and viral infections can promote endothelial dysfunction, proliferation of endothelial cells, increase pro-inflammatory cytokines and lower HDL-C [2] [3].  LPS increases pro-inflammatory cytokines, platelet aggregation and induces endothelial cells to produce ROS that can oxidise LDL.  LPS also increases LDL-C and cholesterol synthesis perhaps because LDL-C is used by the innate immune system to bind to and neutralise LPS.  The LPS-LDL-C can be taken up by macrophages [2] 

Pro-inflammatory cytokines promote monocyte adhesion to endothelial cells [2], endothelial dysfunction, oxidative stress, apoptosis of endothelial cells are associated with worse outcomes [4].  The role of pro-inflammatory cytokines in heart disease is well illustrated by the association between RA and CVD (OR 3.17) [5].  Aspirin reduces MI by 55.7% in people with high CRP and 13.9% in people with low CRP [6] 

LPS induces mitochondrial dysfunction, which may be one of its major mechanisms of action.  People with periodontitis have 60% lower CoQ10, 78% lower citrate synthase and double the ROS.  These measures of mitochondrial function were almost completely returned to normal with CoQ10 supplementation [7] 

Chronic infections and bacterial products such as LPS are associated with CVD:

  • High levels of CD14, a receptor on monocytes for LPS, is associated with atherosclerosis and is increased by IL-1, TNF-a and glucocorticoids [8]
  • C. pneumoniae antibodies are associated with a 2-7 times increased risk of CHD [2]
  • An allele that reduces the expression of TLR4 (a receptor for LPS) has lower pro-inflammatory cytokines and an odds ratio for atherosclerosis of 0.54 [9]
  • 43% of people with antibodies to herpes virus developed restenosis (narrowing of blood vessel), compared to 8% without antibodies.  Restenosis correlated with chronic infections rather than acute infections [3]
  • High LPS is associated with atherosclerosis in smokers (OR 14.7) and ex-smokers (OR 9.5), but not non-smokers (OR 1.7 NS).  However non-smokers with a chronic infection and high LPS had an OR of 5.4 [10]
  • Either C. pneumoniae or H. pylori DNA was found in the artery wall of 50% of patients undergoing surgery for atherosclerosis, compared with 0% in the healthy controls [11]
  • LPS is associated with increased triglycerides and troponin and decreased HDL-C [12]
  • C. pneumoniae (OR 3.06) and H. pylori (OR 3.82) infections are associated with myocardial infarction [13] 

* Some of the heart problems in endurance athletes could be explained by LPS.  At high intensities of exercise blood flow to the intestines can drop to 20%, which disturbs normal functioning and may cause exercise-induced abdominal symptoms and bacterial translocation.  After a marathon 68% of athletes had mild endotoxemia and IL-6 levels were 27 times higher [14] 

** CVD is a common complication of AIDS, affecting 70-80% of people who have it [15] 


Myeloperoxidase (MPO) is found in neutrophils, monocytes and some macrophages, and is stored in an inactive form until these cells become active.  It produces hypochlorous acid (HOCl) from H2O2 and Cl- and oxidises tyrosine to tyrosyl radical by using H2O2.  HOCl and the tyrosyl radical are cytotoxic and are used by neutrophils to produce a respiratory burst [16]. 

Evidence to support the role of MPO in CVD:

  • MPO is active in atheroma, MPO oxidation products are found in atheroma and attract leukocytes [16]
  • People with CVD have more MPO products such as (nitrotyrosine and chlorotyrosine) [16]
  • MPO can modify HDL particles and ~50% of HDL particles in atherosclerotic lesions have some kind of MPO modification [16]
  • MPO promotes endothelial dysfunction by: reducing NO bioavailability, producing HOCl which inhibits NOS, chlorinating arginine and by producing ROS and RNS which uncouple NOS leading to SO production rather than NO [16]
  • MPO promotes endothelial cell apoptosis [16]
  • LDL/HDL from atherosclerotic lesions contains 100/6 times more 3-NO2Tyr compared with circulating LDL/HDL from healthy controls [17] 

MPO levels are very strongly associated with CVD:

  • Leukocyte and blood MPO is associated with CAD (OR of 11.9 and 20.4) [18]
  • MPO is associated with endothelial dysfunction (OR of 6.4) [19]
  • MPO modified HDL is associated with CVD (OR of 6 and 16 (depends on the MPO oxidation product) [20]
  • 60-66% of Americans have the GG genotype, which increases MPO and is associated with CV events (HR of 5.5) [21].
  • The AA genotype has an OR of 0.135 and the AG genotype has an OR of 0.639 [22]

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