Research & Education

Can an Overactive Immune Response Lead to Atherosclerosis?

Immune homeostasis plays an important role in health, as it ensures the elimination of potentially infectious or pathogenic agents and the repair of any damaged tissue while not targeting the self, commensal bacteria, or other nonpathogenic agents. An overactive immune response may contribute to low-grade chronic inflammation as one of the leading developments of atherosclerosis.

Trained Immunity and Chronic Inflammation

Although the adaptive immune system has a reputation for memory, more recent research demonstrates memory capacity in the innate immune system, known as trained immunity. This occurs through epigenetic and metabolic reprogramming of the cells. Unlike the memory of the adaptive immune system, the trained immune system is nonspecialized and can maintain an activated phenotype for a prolonged period to respond to a range of potential threats. Studies have determined oxidative low-density lipoprotein (LDL) is one of several mechanisms for inducing trained immunity by programming monocytes with a pre-atherogenic state such as the capacity to form foam cells and elevated expression of the cytokines and chemokines associated with atherosclerosis.

Trained immunity may allow for a quicker response to potential pathogens. It can also lead to a hyperactive immune response with stronger pro-inflammatory reactions upon re-stimulation, which may contribute to atherosclerosis.

In one study, patients with coronary artery disease had monocytes that produced higher levels of pro-inflammatory cytokines compared to healthy controls. Likewise, another study found that monocytes from patients with symptomatic atherosclerosis secreted more pro-inflammatory cytokines upon exposure to lipopolysaccharides (LPS) than the healthy controls and also those with asymptomatic atherosclerosis, thanks to epigenetic changes to the cells that created a pro-inflammatory phenotype.

How Infections Increase the Risk of Heart Disease

The association between trained immunity and atherosclerosis remains under investigation with mostly mechanistic studies and animal models. There are studies showing that certain infections increase the risk of developing heart disease. Pathogens, including Chlamydia pneumoniae, Porphyromonas gingivalis, Helicobacter pylori, influenza A virus, hepatitis C virus, human cytomegalovirus, and human immunodeficiency virus (HIV), correlate with higher risks of cardiovascular disease. Some of these pathogens have been found in the atherosclerosis plaques.

In a meta-analysis, cytomegalovirus infection was associated with a 22% increased relative risk of developing cardiovascular disease in the future, and an estimated 13.4% of the incidence of cardiovascular disease, which was due to infection by cytomegalovirus. A cross-sectional analysis found an association between a weighted measure of infectious burden (by testing for antibodies of five common pathogens) and carotid plaque thickness. Hospitalizations for pneumonia are also associated with a higher risk of developing cardiovascular disease in the next 10 years, and the risk was higher in the first year. Infections from childhood may also influence atherosclerosis development. A longitudinal population-based study found that severe childhood infections correlated with an increased risk of cardiovascular disease-related hospitalizations in adulthood.

Although mechanisms remain under investigation, these associations may be linked to a hyperactive immune response, including chronic inflammation, in part due to trained immunity. Diet and the gut microbiome aid in the development of a balanced immune system. Therefore, following a healthy diet and lifestyle, ensuring adequate nutrition, and supporting the gut microbiome may help maintain lower levels of inflammation and immune homeostasis.

By Kendra Whitmire, MS, CNS