Oxidation-specific epitopes in atherosclerosis
During the development of atherosclerotic lesions, low-density lipoproteins (LDL) deposit in the wall of large and medium-sized arteries, where they become oxidized and are taken up by infiltrating macrophages resulting in the formation of foam cells. This process is also characterized by inflammatory reactions and the accumulation of oxidized LDL as well as apoptotic cells in the vascular wall. Notably, both oxidized LDL and apoptotic cells carry the same oxidation-specific epitopes (OSE), which represent danger-associated molecular patterns that are recognized by the innate immune system.
We hypothesize that OSE are key drivers of the inflammatory response in atherosclerosis. Therefore we are investigating how macrophages sense OSE and study the functional consequences of this in the development of atherosclerotic lesions. Key areas include the identification of the receptors and molecular pathways that are mediating these effects, and the development of strategies to inhibit these specific inflammatory responses.
Natural antibodies and the complement system in atherosclerosis
Natural antibodies are pre-existing germline-encoded antibodies that are primarily of the IgM class and secreted by a specialized subset of B1 cells. They play an important role in the first line defense against microbial infections and provide important “house keeping” functions by recognizing damaged self antigens. Natural IgM protect mice from atherosclerotic lesion formation, and data from our group demonstrated that a large part of natural IgM antibodies has specificity for OSE. Ongoing projects focus on the identification of the mechanism by which natural IgM mediate atheroprotection and whether the recognition of OSE is a critical part of this. Moreover, we are pursuing strategies that focus on the therapeutic induction of natural IgM.
More recently we discovered that complement factor H (CFH) specifically binds and neutralizes one type of OSE, namely malondialdehyde modifications. CFH is a major inhibitor of complement activation and genetic variants of it have been associated with a number of disease conditions. We are currently investigating if and how this newly found property of CFH plays a role in atherosclerosis and other inflammatory diseases.
Techniques and infrastructure of the research group
The group utilizes mouse models of atherosclerosis in combination with various immune deficient models for morphometric analyses of the extent of atherosclerosis and assessment of lesion phenotype by immunohistochemistry. Major techniques used include a wide array of immunological assays, flow cytometry, FACSorting, adoptive in vivo cell transfer and bone marrow transplantation; the biochemical generation of oxidized lipid antigens/ligands and standard molecular biology and cell culture techniques. Group members have access to a fully equipped cell culture facility, FACS sorter and analyzers, microtiter plate readers, ultracentrifuge, HPLC, FPLC, PCR equipment (incl. multichannel Real-time PCR), next generation sequencing equipment, cryo- and microtome, and a fluorescent microscope with imaging equipment.