Skip to main content

Accelerated Atherosclerosis in Patients with Immune Mediated Disorders as a Model to Investigate the Link between Inflammation and Cardiovascular Disease: From Basic Mechanisms to Clinical Application

Objective

Atherosclerosis is a chronic inflammatory disease of the arterial wall with (auto)immune component, initiated in response to modified (phospho)lipids. Despite important advances in our understanding of the inflammatory response in atherosclerosis, the critical pathways responsible for the breakdown of immune tolerance to lipoproteins and other self-antigens remain largely unknown. An important feature of ruptured/thrombosed atherosclerotic lesions is the accumulation of apoptotic, and secondary necrotic, lipid-laden macrophages and smooth muscle cells due to defective efferocytosis (clearance of apoptotic cells). This leads to the formation of a large ‘necrotic’ lipid core, associated with enhanced vascular inflammation. Interestingly, defective efferocytosis has been associated with the development of autoimmunity, and patients with systemic lupus erythematosus who show increased accumulation of apoptotic material are at very high risk of accelerated atherosclerosis and myocardial infarction. We hypothesize that accumulation of apoptotic/secondary necrotic cells due to defective efferocytosis, together with modified lipids, activate critical immuno-inflammatory pathways in macrophages and B cells, and break immune tolerance in atherosclerosis and post-myocardial infarction. This is consistent with the critical role played by defective efferocytosis and macrophage activation in atherosclerotic lesion progression, and with our recent unsuspected data showing a critical role for B cell activation in driving lesion development in several models of atherosclerosis. We also propose that interactions between macrophages and B cells are essential for the perpetuation of the pathogenic immuno-inflammatory response in cardiovascular disease. Finally, we will harness this knowledge for a better identification of patients at risk of cardiovascular complications, and will target these pathways to limit the progression and complications of cardiovascular disease.

Field of science

  • /medical and health sciences/health sciences/inflammatory diseases
  • /medical and health sciences/clinical medicine/cardiology/cardiovascular diseases/arteriosclerosis
  • /natural sciences/biological sciences/biochemistry/biomolecules/lipids

Call for proposal

ERC-2011-StG_20101109
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 499 731
Principal investigator
Ziad Mallat (Prof.)
Administrative Contact
Renata Schaeffer (Ms.)

Beneficiaries (1)

THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
EU contribution
€ 1 499 731
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
Activity type
Higher or Secondary Education Establishments
Principal investigator
Ziad Mallat (Prof.)
Administrative Contact
Renata Schaeffer (Ms.)