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Research Update: Atherosclerosis and Autoimmunity

The long Arm of the Dendritic Cells: The Link between Atherosclerosis and Autoimmune Diseases

Inflammation has been closely linked to autoimmunogenic processes in atherosclerosis. In fact, patients who are suffering from an autoimmune disease have an increased incidence of “hardening of the arteries”, concretely atherosclerosis (the spelling “arteriosclerosis” is also common). In the case of rheumatoid arthritis (RA) the patients have a 30 to 60% higher risk of suffering a heart attack or stroke!

picture shows a beating heart

It is an accepted fact: Rheumatoid arthritis patients have a higher risk of suffering a heart attack or stroke. But where is the connection between the two types of disease?

pDCs: the link between atherosclerosis and autoimmunity

Now clinical researchers at Munich Ludwig-Maximilians-University (LMU) have uncovered a mechanism which establishes a causal link between the two types of disease. The immunological process may help to explain the link between autoimmunity and atherosclerosis.

The mechanism described is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). The pDCs respond to DNA released from damaged and dying cells by secreting interferon proteins. The research, which is done in collaboration with scientists from Rudolf Virchow Center at Wuerzburg University, shows that stimulation of pDCs by a specific DNA-protein complex contributes to the progression of atherosclerosis. These findings may have implications for new strategies for the treatment of a whole spectrum of conditions that are associated with chronic inflammatory reactions.

What is atherosclerosis? What is causing the disease?

Atherosclerosis is a major cause of death in industrialised societies. The angiopathy is named due to the formation of insoluble deposits on the walls of major arteries. These deposits as a consequence of chronic, localized inflammation reactions are also called atherosclerotic plaques.

By reducing blood flow, the atherosclerotic plaques can provoke heart attacks and strokes. A class of immune cells called dendritic cells plays a crucial role in facilitating the development of these plaques. The term “dendritic cells” refers to a heterogeneous population of cells that makes up part of the immune system. Among these cell types represented in this population are the so-called plasmacytoid dendritic cells (pDC). However, the potential significance of pDCs for atherosclerosis had not been explored until now.

picture shows an dendritic cell

Are dendritic cells the “missing link” between atherosclerosis and autoimmunity?

Recently, a team of researchers led by Yvonne Döring, PhD, from Munich LMU, and Alma Zernecke, PhD, from Wuerzburg University, has shown how pDCs promote the development of atherosclerosis. The scientists worked out, why autoimmune diseases patients show a predisposition to atherosclerosis.

Hoggish macrophages promote atherosclerosis

Using laboratory mice as an experimental model, the researchers demonstrated that pDCs contribute to early steps in the formation of atherosclerotic lesions in the blood vessels. Stimulation of plasmacytoid dendritic cells causes them to secrete large amounts of interferons that strongly stimulate inflammation.

The pDCs themselves are stimulated by the self-antigens that set off the autoimmune reactions which result in conditions like psoriasis and SLE.
Yvonne Döring, PhD, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany

The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in the plaques. Macrophages normally act as a “clean-up crew”, removing cell debris and fatty deposits by ingesting and degrading them. However, macrophages can also “overindulge”, taking up more fat than they can digest.

When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process.

The newly discovered involvement of pDCs in the development of atherosclerosis establishes a direct link between this disorder and autoimmune reactions, and reveals why the stimulation of pDC […] contributes to the progression of atherosclerosis.
Christian Weber, PhD, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

The stimulation of pDCs provides the link between atherosclerosis and autoimmune diseases, such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus (SLE). “The pDCs themselves are stimulated by the self-antigens that set off the autoimmune reactions which result in conditions like psoriasis and SLE,” Yvonne Döringexplains. Indeed, it is well known that the secretion of interferons by activated pDCs contributes to the genesis of a number of autoimmune diseases.

New approaches to atheriosclerosis treatment

In point of fact the newly discovered involvement of pDCs in the development of atherosclerosis establishes a direct link between atherosclerosis and autoimmune reactions.

The research results described in this post reveal, why stimulation of plasmacytoid dendritic cells – which in fact is a characteristic feature of autoimmune diseases – contributes to the progression of atherosclerosis. Finally, these findings may also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases.

Author of this article:  Tobias Stolzenberg

References:

Döring Y, Manthey H, Drechsler M, Lievens D, Megens R, Soehnlein O, Busch M, Manca M, Koenen RR, Pelisek J, Daemen MJ, Lutgens E, Zenke M, Binder CJ, Weber C, Zernecke A. Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis. Circulation. 2012;125(13):1673-83. – doi: 10.1161/CIRCULATIONAHA.111.046755 – the link will open to the abstract in Circulation.

The picture of the dendritic cell is taken from the Wikimedia Commons project.

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