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Natural antibodies prevent atherosclerosis and inflammation of the liver

Abbildung: Atherosklerotische Läsion
New approach for strengthening the body's own defensive mechanisms

(Vienna, 03-03-2016) It has long been known that excessive LDL cholesterol in the blood is dangerous as it penetrates vascular walls, causes chronic inflammation and leads to atherosclerosis. A group of antibodies, present in the body from birth, counteracts these inflammations and the resulting illnesses, a discovery made by scientists from Christoph Binder's research group, group leader at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and professor for atherosclerosis research at the Medical University of Vienna; the results were published in the study "Cell Reports". The researchers have established a promising approach for new therapies.

Heart attack and stroke – the two most common causes of death worldwide – are, for the most part, caused by atherosclerosis. The arterial walls become chronically inflamed and cholesterol is deposited. However, the body is not defenceless: Some defence cells produce antibodies that bind and neutralize the cholesterol – as proven by Christoph Binder's work group for immunity and atherosclerosis in cooperation with Lars Nitschke from the University of Erlangen and Ronit Shiri-Sverdlov from Maastricht University; the researchers concurrently established an approach for strengthening the body's own protective mechanisms.

Cholesterol is actually an important building block for each cell. It is transported through the vessels together with certain proteins in the form of LDL (low-density lipoprotein). However, chemical reactions with oxygen radicals – i.e. oxidisation – may quickly occur when LDL is stored in the vascular walls, which renders it not only unusable but also harmful: The cholesterol triggers an inflammation that leads to the intrusion of scavenger cells, so-called macrophages, in the arterial walls that remove the oxidised LDL again.

However, consistently high concentrations of oxidised LDL lead to fatal consequences: The macrophages store more and more of it and ultimately swell to become so-called "foam cells" while releasing additional messenger substances that bring in more scavenger cells and prolong the inflammatory reaction. The result: life-threatening damage to vessels that can lead to heart attack and stroke.

A certain group of white blood cells – B-1 cells – work against this: These cells produce naturally occurring antibodies from birth that bind oxidised LDL and neutralise it, disrupting the inflammation. The immune cells also carry a molecular regulator that reduces their activity as Sabrina Gruber, lead author of the study and doctoral student at the CeMM, explained.

"We were able to show that the deactivation of this regulator, the so-called 'Siglec-G' protein, caused an increased propagation of B1-cells and antibodies, which protect vessels and the liver from inflammation," said Gruber. The scientists proved this with special laboratory mice that lacked the gene for Siglec-G. The development of atherosclerosis, which is frequently accompanied by inflammation of the liver, was massively reduced despite an extremely fat-rich diet and consistently high cholesterol values.

The researchers achieved the same result when they exclusively removed Siglec-G from B-cells, thus excluding a participatory effect from other cells. The production of specific natural antibodies was increased beyond the normal extent and counteracted the consequences of oxidised LDL that triggers inflammation.

"Our study clearly shows that increased levels of these naturally occurring antibodies prevent atherosclerosis and inflammation," summed up Christoph Binder. "These mechanisms could be used in a therapy by, e.g., blocking Siglec-G with a specific medication." A completely new and promising approach that strengthens the body's own defensive mechanisms and thus counteracts the deadly consequences of a fatty diet that leads to cardiovascular diseases.

Service: Cell Reports
„Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells“. Sabrina Gruber, Tim Hendrikx, Dimitrios Tsiantoulas, Maria Ozsvar-Kozma, Laura Göderle, Ziad Mallat, Joseph L. Witztum, Ronit Shiri-Sverdlov, Lars Nitschke, und Christoph J. Binder.