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Scientists have discovered a new mechanism by which web-like DNA structures called neutrophil extracellular traps (NETs)—a bacteria-fighting weapon in the immune system’s arsenal—provoke the onset of autoimmune diseases such as multiple sclerosis (MS).

In a study published in the journal Nature Communications on January 26, titled “Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2,” researchers from The Australian National University (ANU) demonstrate NETs activate T cells and enhance the differentiation of a subset of proinflammatory T cells called Th17 that are a key player in autoimmune diseases and are crucial for immunity against fungal and bacterial infections. The innate stimulation of an adaptive immune cell-type generates a feedback loop that amplifies autoimmunity.

“This discovery is significant as it provides a novel therapeutic target to disrupt these harmful inflammatory responses,” said Alicia Wilson, PhD, from the Johannes Gutenberg-University Mainz in Germany, who is first-author of the paper. “It opens the doors to the development of new therapies targeting this harmful NET-Th17 interaction, hopefully improving treatments for MS and other autoimmune conditions in the future.”

“My group mainly works with a multiple sclerosis laboratory model,” said Anne Bruestle, senior author of the paper and associate professor at the department of immunology and infectious disease at ANU. “We realized that neutrophil extracellular traps (NETs) are up in the blood before symptoms are seen. So, we wondered if these NETs might have an enhancing effect on inflammatory Th17 cells.”

NETs, that resemble spider webs in structure and function, are extruded from activated neutrophils, a type of white blood cell. NETs trap and kill bacteria, protecting the body from infection. This new study shows NETs also function to abnormally increase the strength of Th17 cells.

Scanning electron microscope image of NETs engulfing fungal cells in an infected mouse lung (WikiCommons/Urban CF, et al, PloS Pathog, 2009).

Beneficial under normal conditions, Th17 cells can cause undesirable inflammation when over-activated, promoting autoimmune diseases. “We found that the NETs cause Th17 cells to become more powerful, which enhances their detrimental effects,” said Bruestle.

“We describe a new way how NETs can directly activate Th17 cells and even more important, how to block this unwanted activation,” said Bruestle. “This has implications for a variety of Th17 cell associated autoimmune conditions such as multiple sclerosis or psoriasis where we believe inhibiting NET-induced activation of Th17 cells might be a novel treatment concept.”

Understanding the mechanism that enables NETs to turn friendly Th17 cells into foes can help develop targeted therapies for autoimmunity. Bruestle and a team of international researchers believe a drug called mCBS, originally designed to treat sepsis, could be used to target Th17 cells and treat MS. The drug was developed by Christopher Parish, PhD, and his team at ANU.

“Because we see in both mice and humans that a group of proteins in NETs called histones can activate Th17 cells and cause them to become harmful, it makes sense that our histone-neutralising drug, mCBS, which was developed to treat sepsis, may also be able to inhibit the undesirable effects of NETs which are linked to driving MS,” said Parish.

Bruestle said, “We used the recently described histone/NET inhibitor, mCBS. This inhibitor is currently under phase 1b/2 clinical trial in sepsis and acute respiratory distress syndrome (ARDS)—a known complication in severe COVID-19 cases.”

Bruestle added, “While we cannot prevent autoimmune diseases such as MS, thanks to these types of therapies we hope to treat the condition and make it more manageable for people living with MS.”

Bruestle and her team are currently using inhibitors of NET-Th17 interactions in models of Th17-mediated autoimmunity to develop and optimize treatment options for autoimmune conditions such as MS.

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