Atherosclerosis and immunity: is it the opposite?
The immune system protects against atherosclerosis
NanoNewsNet based on CUMC materials: New Insights into How Immune System Fights AtherosclerosisScientists at Columbia University Medical Center (CUMC) have found that in response to atherosclerotic lesions, the immune system organizes a surprisingly reliable response mediated by anti-inflammatory T cells, which helps prevent the progression of the disease.
The results obtained during this study may help in the development of vaccines to combat atherosclerosis and other treatments based on immune mechanisms. The results of the work are published in open access in the online edition of The Journal of Clinical Investigation (Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs).
When encountering viruses, bacteria and other potential threats, the body immediately mobilizes dendritic cells, whose function is to present fragments of pathogens to T cells. That's what they're called – antigen-representing cells.
Immature dendritic cells are present in the skin, lungs and intestinal mucosa, where they encounter the antigen.
After meeting with the antigen, dendritic cells migrate to the lymph nodes, where they present this antigen to T cells, thereby activating the formation of pro-inflammatory effector T cells attacking the pathogen and anti-inflammatory regulatory T cells controlling the pro-inflammatory response.
In the picture: A T-lymphocyte (yellow) scans the dendritic cell for antigens.
"As a rule, the pro–inflammatory reaction dominates, and this is what was supposed to happen in the case of atherosclerosis," says the head of the study, CUMC Professor Ira Tabas, MD, PhD. "However, we found that the T-cell response to atherosclerosis is predominantly anti-inflammatory."
In their experiments, the scientists used mice with dendritic cells without the MyD88 signaling protein that initiates their maturation. Since immature dendritic cells cannot activate T cells, the removal of MyD88 effectively blocks the formation of both effector and regulatory T cells. In addition, the mice did not have LDL receptors (low-density lipoproteins), the absence of which made the animals predisposed to the development of atherosclerosis. The end result of all these genetic changes was an increase in the size of atherosclerotic lesions.
"This means that the dominant influence of dendritic cells in atherosclerosis is to promote the formation of protective regulatory T cells," Professor Tabas comments on the experimental results.
Earlier studies led scientists to the opposite conclusions: the immune response to atherosclerosis is dominated by the influence of effector (pro-inflammatory) T-cells.
"In those studies, dendritic cells were switched off at an earlier stage, which made it possible to develop a variety of compensatory processes," explains Dr. Tabas, such a discrepancy in the results. "Therefore, probably, other conclusions were drawn from them. In our model, we were able to exclude only the activation stage of T cells, leaving everything else intact."
Dr. Tabas and her colleagues found that regulatory T cells, as expected, suppress pro-inflammatory effector T cells and macrophages. In addition, they described a new mechanism that directly links the activation of regulatory T cells with protection against atherosclerosis: regulatory T cells secrete transforming growth factor-beta (TGF-β) - cytokine, or a signaling molecule that suppresses monocytic chemotactic protein-1 (MCP-1) – a protein that activates and attracts the zone of inflammation is another type of immune cells – monocytes.
"Now we know a specific mechanism that can explain the preclinical success of dendritic vaccines and which helps to understand how these vaccines can be improved," concludes Professor Tabas.
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