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The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes.

Virella G, Lopes-Virella MF - Front Endocrinol (Lausanne) (2012)

Bottom Line: In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification.The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals.But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Medical University of South Carolina Charleston, SC, USA.

ABSTRACT
The main causes of morbidity and mortality in diabetes are macro and microvascular complications, including atherosclerosis, nephropathy, and retinopathy. As the definition of atherosclerosis as a chronic inflammatory disease became widely accepted, it became important to define the triggers of vascular inflammation. Oxidative and other modifications of lipids and lipoproteins emerged as major pathogenic factors in atherosclerosis. Modified forms of LDL (mLDL) are pro-inflammatory by themselves, but, in addition, mLDLs including oxidized, malondialdehyde (MDA)-modified, and advanced glycation end (AGE)-product-modified LDL induce autoimmune responses in humans. The autoimmune response involves T cells in the arterial wall and synthesis of IgG antibodies. The IgG auto-antibodies that react with mLDLs generate immune complexes (IC) both intra and extravascularly, and those IC activate the complement system as well as phagocytic cells via the ligation of Fcγ receptors. In vitro studies proved that the pro-inflammatory activity of IC containing mLDL (mLDL-IC) is several-fold higher than that of the modified LDL molecules. Clinical studies support the pathogenic role of mLDL-IC in the development of macrovascular disease patients with diabetes. In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification. In type 2 diabetes, high levels of MDA-LDL in IC predicted the occurrence of myocardial infarction. There is also evidence that mLDL-IC are involved in the pathogenesis of diabetic nephropathy and retinopathy. The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals. But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes.

No MeSH data available.


Related in: MedlinePlus

Comparison of the pathways responsible for the anti-apoptotic and pro-apoptotic effects of immune complexes containing oxidized LDL (oxLDL-IC) and malondialdehyde-modified LDL (MDA-LDL-IC). OxLDL-IC activate cell proliferation pathways through Syk, a pathway that leads to activation of Akt and NFkB. The activation of Akt leads prevents the inactivation of anti-apototic gene products (Bcl-xL in the diagram). S1P-mediated activation of Akt and proliferation genes has been suggested by previously published data from our group (Hammad et al., 2006). This could result from the direct activation of SK1 by Syk, or as a consequence of the release of growth factors, upon ligation of the corresponding receptor, which activate S1k via PKC. As for the pro-apoptotic properties of MDA-LDL-IC, two possible pathways could be involved. One would result from the simultaneous activation of SK2 (whose phosphorylation is less stable than that of SK1) and S1PP. This would result in a reduced generation of S1P, and accumulation of ceramides, which in turn would inhibit anti-apoptotic genes (Bcl-2 in the diagram) and allow the activation of the pro-apoptotic intrinsic pathway. An alternative (and not exclusive) pathway to reach the same effect would involve the degradation of internalized MDA and release of highly charged phospholipids whose interaction with a CD36-TLR2 complex would activate the generation of ROS and increased cellular stress.
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Figure 1: Comparison of the pathways responsible for the anti-apoptotic and pro-apoptotic effects of immune complexes containing oxidized LDL (oxLDL-IC) and malondialdehyde-modified LDL (MDA-LDL-IC). OxLDL-IC activate cell proliferation pathways through Syk, a pathway that leads to activation of Akt and NFkB. The activation of Akt leads prevents the inactivation of anti-apototic gene products (Bcl-xL in the diagram). S1P-mediated activation of Akt and proliferation genes has been suggested by previously published data from our group (Hammad et al., 2006). This could result from the direct activation of SK1 by Syk, or as a consequence of the release of growth factors, upon ligation of the corresponding receptor, which activate S1k via PKC. As for the pro-apoptotic properties of MDA-LDL-IC, two possible pathways could be involved. One would result from the simultaneous activation of SK2 (whose phosphorylation is less stable than that of SK1) and S1PP. This would result in a reduced generation of S1P, and accumulation of ceramides, which in turn would inhibit anti-apoptotic genes (Bcl-2 in the diagram) and allow the activation of the pro-apoptotic intrinsic pathway. An alternative (and not exclusive) pathway to reach the same effect would involve the degradation of internalized MDA and release of highly charged phospholipids whose interaction with a CD36-TLR2 complex would activate the generation of ROS and increased cellular stress.

Mentions: Furthermore, the anti-apoptotic effect of oxLDL-IC seems to involve additional pathways, including activation of sphingosine kinase 1, which causes the levels of anti-apoptotic sphingosine-1-phosphate (S1P) to increase. S1P activates phospholipase C (PLC) and, through the generation of diacylglycerol, the Ras/ERK, and phosphokinase C are activated. PLC also activates the P13K-dependent pathway, which results in Akt activation (Hundal et al., 2003; Hammad et al., 2006; Chen et al., 2010; Figure 1).


The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes.

Virella G, Lopes-Virella MF - Front Endocrinol (Lausanne) (2012)

Comparison of the pathways responsible for the anti-apoptotic and pro-apoptotic effects of immune complexes containing oxidized LDL (oxLDL-IC) and malondialdehyde-modified LDL (MDA-LDL-IC). OxLDL-IC activate cell proliferation pathways through Syk, a pathway that leads to activation of Akt and NFkB. The activation of Akt leads prevents the inactivation of anti-apototic gene products (Bcl-xL in the diagram). S1P-mediated activation of Akt and proliferation genes has been suggested by previously published data from our group (Hammad et al., 2006). This could result from the direct activation of SK1 by Syk, or as a consequence of the release of growth factors, upon ligation of the corresponding receptor, which activate S1k via PKC. As for the pro-apoptotic properties of MDA-LDL-IC, two possible pathways could be involved. One would result from the simultaneous activation of SK2 (whose phosphorylation is less stable than that of SK1) and S1PP. This would result in a reduced generation of S1P, and accumulation of ceramides, which in turn would inhibit anti-apoptotic genes (Bcl-2 in the diagram) and allow the activation of the pro-apoptotic intrinsic pathway. An alternative (and not exclusive) pathway to reach the same effect would involve the degradation of internalized MDA and release of highly charged phospholipids whose interaction with a CD36-TLR2 complex would activate the generation of ROS and increased cellular stress.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375400&req=5

Figure 1: Comparison of the pathways responsible for the anti-apoptotic and pro-apoptotic effects of immune complexes containing oxidized LDL (oxLDL-IC) and malondialdehyde-modified LDL (MDA-LDL-IC). OxLDL-IC activate cell proliferation pathways through Syk, a pathway that leads to activation of Akt and NFkB. The activation of Akt leads prevents the inactivation of anti-apototic gene products (Bcl-xL in the diagram). S1P-mediated activation of Akt and proliferation genes has been suggested by previously published data from our group (Hammad et al., 2006). This could result from the direct activation of SK1 by Syk, or as a consequence of the release of growth factors, upon ligation of the corresponding receptor, which activate S1k via PKC. As for the pro-apoptotic properties of MDA-LDL-IC, two possible pathways could be involved. One would result from the simultaneous activation of SK2 (whose phosphorylation is less stable than that of SK1) and S1PP. This would result in a reduced generation of S1P, and accumulation of ceramides, which in turn would inhibit anti-apoptotic genes (Bcl-2 in the diagram) and allow the activation of the pro-apoptotic intrinsic pathway. An alternative (and not exclusive) pathway to reach the same effect would involve the degradation of internalized MDA and release of highly charged phospholipids whose interaction with a CD36-TLR2 complex would activate the generation of ROS and increased cellular stress.
Mentions: Furthermore, the anti-apoptotic effect of oxLDL-IC seems to involve additional pathways, including activation of sphingosine kinase 1, which causes the levels of anti-apoptotic sphingosine-1-phosphate (S1P) to increase. S1P activates phospholipase C (PLC) and, through the generation of diacylglycerol, the Ras/ERK, and phosphokinase C are activated. PLC also activates the P13K-dependent pathway, which results in Akt activation (Hundal et al., 2003; Hammad et al., 2006; Chen et al., 2010; Figure 1).

Bottom Line: In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification.The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals.But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Medical University of South Carolina Charleston, SC, USA.

ABSTRACT
The main causes of morbidity and mortality in diabetes are macro and microvascular complications, including atherosclerosis, nephropathy, and retinopathy. As the definition of atherosclerosis as a chronic inflammatory disease became widely accepted, it became important to define the triggers of vascular inflammation. Oxidative and other modifications of lipids and lipoproteins emerged as major pathogenic factors in atherosclerosis. Modified forms of LDL (mLDL) are pro-inflammatory by themselves, but, in addition, mLDLs including oxidized, malondialdehyde (MDA)-modified, and advanced glycation end (AGE)-product-modified LDL induce autoimmune responses in humans. The autoimmune response involves T cells in the arterial wall and synthesis of IgG antibodies. The IgG auto-antibodies that react with mLDLs generate immune complexes (IC) both intra and extravascularly, and those IC activate the complement system as well as phagocytic cells via the ligation of Fcγ receptors. In vitro studies proved that the pro-inflammatory activity of IC containing mLDL (mLDL-IC) is several-fold higher than that of the modified LDL molecules. Clinical studies support the pathogenic role of mLDL-IC in the development of macrovascular disease patients with diabetes. In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification. In type 2 diabetes, high levels of MDA-LDL in IC predicted the occurrence of myocardial infarction. There is also evidence that mLDL-IC are involved in the pathogenesis of diabetic nephropathy and retinopathy. The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals. But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes.

No MeSH data available.


Related in: MedlinePlus