Autoantibodies help prevent a broken heart
Autoantibodies help prevent a broken heart
Contributed by Dr Jeremy F Brooks Ph.D.
Although the focus of my blogs is usually on antibodies in the context of infectious diseases, today I am writing about a strange but exciting finding that antibodies can protect against heart disease.
Cardiovascular disease is a leading cause of mortality worldwide, mostly due to stroke (lack of blood supply to brain) and heart attack (lack of blood supply to cardiac muscle). Severe cardiovascular events related to ischaemia (lack of blood supply) and thrombosis (blood clot) are usually caused by atherosclerosis – a lipid-driven chronic inflammatory disease that forms atheroma (plaques) in arteries of the body (see diagram).
Elevated levels of plasma LDL (low-density lipoproteins) and subsequent retention in subendothelial spaces (see diagram) precipitates the formation of plaques. Oxidation of trapped LDL forms lipid-derived antigens that are recognised by the immune system leading to inflammation. B cells are clearly involved in the disease because mice lacking B cells but with hypercholesterolemia have markedly reduced atherosclerosis. Additionally, plaques and plasma in both mice and human contain antibodies that target oxidated LDL antigens. It has been observed that these antibodies can play both protective and pathogenic roles, but it has been difficult to isolate the exact mechanisms involved.
A new paper published in the journal Nature from the Ramiro laboratory at the Centro Nacional De Investigaciones Cardiovasculares (CNIC) in Spain seeks to address this knowledge gap.
The investigators take advantage of a mouse model lacking the receptor for LDL, leading to elevated levels of circulating LDL cholesterol. When these mice are fed a high-fat diet, they develop atherosclerosis. During this process, they progressively accumulate activated B cells and plasma cells, which generated antibodies against LDL and oxidation-modified LDL. The researchers then perform a high-throughput screen to identify more broadly what these B cells and plasma cells are responding to in mice with atherosclerosis.
Many of the antibodies could recognise antigens expressed in the heart of atherosclerotic mice. They focused on one antibody in particular – named A12 – which had strong plaque reactivity. To determine the specificity of this antibody, they precipitated aorta extracts with A12 antibodies and subjected it to mass spectrometry – a technique that would tell them the unknown antigen bound by A12. This identified and was confirmed to be the protein ALDH4A1. Antibodies reactive to ALDH4A1 could be found in mice and humans with atherosclerosis but not healthy controls, and elevated ALDH4A1 expression was an independent risk factor for atherosclerosis in humans. Their data thus far implicated an autoantibody that may be important in disease and can be used as a biomarker of atherosclerosis.
Because antibodies reactive with ALDH4A1 are common, the researchers wanted to understand whether A12 was pathogenic or protective. They administered it to mice via serial intravenous injections. Compared to mice that received saline, those mice that received A12 antibodies had reduced plaque size and reduced levels of circulating LDL. This meant that the A12 autoantibody present in atherosclerotic mice was helping rather than harming.
The researchers identify an important antibody-antigen pair that has potential diagnostic and therapeutic utility. Their experimental system will allow them to identify many other previously unknown plaque-reactive antibodies that may serve as therapeutic tools. Taken together, these experiments unmask a novel role for B cells in atherosclerosis development and how autoantibodies are not always bad.
Dr Jeremy Brooks is a postdoctoral fellow in the Zikherman laboratory at UCSF. Jeremy’s work focuses on antibodies and the immune cells that produce them. Correspondence can be addressed to jeremy.brooks@ucsf.edu
