Why autoimmune disorders happen: DNA attached to nanoparticles found to contribute to lupus symptoms

Autoimmune diseases are mysterious. It wasn't until the 1950s that scientists realized that the immune system could harm the organs of its own body. Even today, the fundamental causes and inner workings of most autoimmune diseases remain poorly understood, limiting the treatment options for many of these conditions.

Over the past several years, however, research has found clues for how autoimmune diseases might arise. This research has shown that DNA attached to small particles within the bloodstream is a likely culprit involved in many autoimmune diseases, especially systemic lupus erythematosus, or just lupus for short, which primarily affects young women and can cause kidney damage.

However, due to the large variety in sizes of both particles and DNA in the blood, testing to what extent and under what circumstances these DNA-particle combinations play a role in disease has been extremely difficult.

Researchers have now developed a way to systematically test how these DNA-bound particles interact with the immune system. By using tiny particles of specific sizes, attaching DNA strands of certain lengths and exposing the resulting complexes to immune cells in a lab dish, the researchers show a better fundamental understanding of these diseases may be possible.

The results were published in the Proceedings of the National Academy of Sciences.

5 common autoimmune diseases | Credit: NIH MedlinePlus Magazine

This new approach identified the cellular pathway that causes the harmful response to these hybrid particles, and showed that DNA bound to the surfaces of nanoparticles is protected from being degraded by enzymes.

While DNA is usually locked away within a cell's nucleus, it often gets into the bloodstream when cells die or are attacked by viruses and bacteria. While most so-called "cell-free DNA" only lasts minutes before being broken down by the body, in some people and situations, it can persist for much longer. In recent work, high levels of cell-free DNA have been closely related to the severity of lupus symptoms, and many doctors are now testing ways to use it to monitor disease activity.

Cell-free DNA may escape elimination largely by forming complexes with other molecules or attaching itself to naturally occurring particles. Depending on the origin of the DNA, it can range in length from a few hundred base pairs to several thousand. And the particles it can attach to range from 100 to 1000 nanometers in diameter.

The first important observation the team made was that DNA attached to nanoparticles was protected from degrative enzymes and that larger nanoparticles provided more protection.

The researchers think the enzymes might not be able to access the DNA to destroy it because of the shape the DNA makes with the surface of the nanoparticle.

The results showed that the macrophages responded to all types of DNA-particle complexes by producing inflammatory signals for other cells to follow, a hallmark of many autoimmune diseases.

This approach gives researchers a way to drill down and pinpoint factors that they wouldn't be able to with a purely biological system.

Faisal Anees et al, DNA corona on nanoparticles leads to an enhanced immunostimulatory effect with implications for autoimmune diseases, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2319634121