Atherosclerosis is not a classic autoimmune disease, but it has a significant autoimmune component. The current scientific consensus places it in a proposed new category: chronic inflammatory diseases with a secondary autoimmune response. That distinction matters because the immune system doesn’t just react to foreign invaders in your arteries. It also attacks modified versions of your own cholesterol, creating a self-destructive loop that accelerates plaque buildup.
Why It Doesn’t Fit the Classic Definition
For a disease to qualify as a true autoimmune condition, it needs to check several boxes: the body produces antibodies against its own tissues, immune cells target a specific self-protein, and the disease can be transferred by those immune components. Atherosclerosis meets some of these criteria but not all of them in the way conditions like lupus or rheumatoid arthritis do.
In atherosclerosis, the immune system does produce autoantibodies and activate T cells and B cells against components of arterial plaque. But the disease starts with cholesterol accumulation and arterial damage, not with an immune system malfunction. The autoimmune response develops secondarily, meaning it layers on top of an existing inflammatory process rather than initiating it. Researchers writing in Circulation Research proposed that atherosclerosis belongs alongside Parkinson’s disease and emphysema in a new class of chronic inflammatory conditions where autoimmunity plays a supporting role, amplifying disease rather than driving it from the start.
How Your Immune System Turns Against Your Arteries
The autoimmune side of atherosclerosis begins with LDL cholesterol. When LDL particles get trapped in artery walls, they become chemically modified through oxidation. These oxidized LDL particles look different enough from normal cholesterol that the immune system treats them as foreign threats. Your body generates antibodies against oxidized LDL, and T cells begin targeting the modified particles and the cells that contain them.
One key target is a protein called apolipoprotein B-100, the main protein on LDL particles. Researchers have screened the entire sequence of this protein and identified specific segments that trigger strong antibody responses in humans. Interestingly, some of these autoantibodies appear protective. People with higher levels of antibodies against one particular segment (known as peptide 210) tend to have less severe atherosclerosis and fewer cardiovascular events. This dual nature, where the autoimmune response can either worsen or slow the disease, is one reason atherosclerosis doesn’t fit neatly into the autoimmune category.
Oxidized LDL also binds to a blood protein to form complexes that act as potent autoantigens. Antibodies against these complexes have been linked to arterial blood clots and are found at elevated levels in people with lupus and antiphospholipid syndrome, conditions where autoimmune-driven atherosclerosis is especially aggressive.
The Role of Molecular Mimicry
There’s another route the immune system takes toward attacking your arteries, and it starts with infections. Your body produces a stress protein called Heat Shock Protein 60 (HSP60) that is nearly identical in structure to versions found in bacteria like those causing tuberculosis, chlamydia pneumonia, and gum disease. Because these proteins are so similar across species, your immune system can’t always tell the difference.
Throughout life, infections and vaccinations build up a robust immune response against bacterial HSP60. That’s normally a good thing. But when cells lining your arteries become stressed by high blood pressure, smoking, or other cardiovascular risk factors, they start displaying human HSP60 on their surface. The immune system, primed by years of fighting bacteria, attacks these stressed arterial cells through cross-reactive antibodies. This friendly fire damages the inner lining of blood vessels, which is considered a key early event in plaque formation.
Patients with atherosclerosis show T cell and B cell responses that cross-react between bacterial and human HSP60, particularly from the bacteria responsible for periodontal disease. This helps explain the long-observed link between gum disease and heart disease: shared immune targets in the mouth and the arteries.
When the Immune Balance Tips
Your immune system contains built-in brakes. Regulatory T cells (Tregs) normally suppress excessive inflammation and help stabilize arterial plaques. They work by releasing anti-inflammatory signals and preventing other immune cells from proliferating. In animal studies, Tregs consistently protect against atherosclerosis.
The problem arises when pro-inflammatory T cells (called Th17 cells) outnumber Tregs. In people with coronary artery disease, studies show significantly more Th17 cells and fewer Tregs in their blood compared to healthy individuals. This imbalance correlates with unstable plaques, the kind most likely to rupture and cause heart attacks. Even something as simple as excess dietary salt can shift this balance by reducing Treg numbers and function, nudging the immune system toward a more autoimmune-like state. Animal studies have shown that reversing this imbalance with drugs significantly slows atherosclerosis progression.
People With Autoimmune Diseases Get More Atherosclerosis
Some of the strongest indirect evidence for the autoimmune connection comes from people who already have autoimmune diseases. A large meta-analysis found that people with lupus face roughly double the risk of cardiovascular events (heart attacks, strokes) compared to the general population. Those with rheumatoid arthritis have about 55% higher risk. These elevated rates persist even after accounting for traditional risk factors like smoking and high cholesterol, suggesting that the chronic immune activation driving these conditions also accelerates plaque development.
Circulating immune complexes containing oxidized LDL are found at particularly high levels in lupus patients, providing a direct molecular link between autoimmune activity and arterial disease in these populations.
Anti-Inflammatory Treatments That Work
If inflammation and autoimmunity drive part of atherosclerosis, then targeting those pathways should reduce heart attacks. That hypothesis was confirmed in a landmark trial of over 10,000 heart attack survivors. Patients who received an injection every three months of a drug that blocks a specific inflammatory signal (interleukin-1β) experienced fewer subsequent heart attacks and cardiovascular deaths, with no change in their cholesterol levels. At four years, inflammatory markers dropped 37% more than in the placebo group at the most effective dose. The results were significant enough to reshape how cardiologists think about atherosclerosis: not just a cholesterol storage problem, but an active inflammatory disease.
In 2023, the FDA approved a low-dose anti-inflammatory medication (colchicine, long used for gout) specifically to reduce heart attacks, strokes, and cardiovascular death in people with established atherosclerosis. This marked the first time a purely anti-inflammatory drug, rather than a cholesterol-lowering one, received approval for cardiovascular prevention. It works by dampening immune cell activity in the artery wall.
Vaccines Against Atherosclerosis
The autoimmune component of atherosclerosis has opened a surprising research direction: vaccines. The concept is to train the immune system to tolerate the self-antigens found in plaque rather than attack them, essentially teaching the body not to wage war on its own arteries. Researchers have tested vaccines targeting oxidized LDL, apolipoprotein B-100, and several other plaque-related proteins.
In animal models, these vaccines reduce plaque size and improve plaque stability. However, no atherosclerosis vaccine has reached clinical use. The field remains in preclinical stages, with the most recent work exploring new targets like ion channel proteins involved in arterial inflammation. The concept is sound, but translating it from mice to humans has proven challenging, and no clinical trials in people have yet delivered results.