- Neutrophils, a type of immune cell, combat infections by expelling a ‘spider web’ full of antimicrobial compounds called neutrophil extracellular traps (NETs), but these can also mistakenly attack the body’s own cells.
- An MS Australia-supported study has discovered how NETs might be involved in the damaging immune response seen in some immune-mediated conditions, such as multiple sclerosis (MS).
- A drug currently in clinical trials for other diseases may be the answer to blocking this damaging immune response.
Neutrophils, a type of immune cell, can combat infection by expelling threads of ‘sticky’ DNA full of antimicrobial compounds from inside the cell. The threads act like a spider’s web to ensnare and kill bacteria. These complexes are known as neutrophil extracellular traps (NETs). While this process forms an important part of the body’s defence against infection, NETs are a double-edged sword and can also mistakenly kill the body’s own cells, leading to immune-mediated diseases.
In a study partly funded by MS Australia, researchers have discovered how NETs might be involved in the damaging immune response seen in various autoimmune conditions, such as MS. NETs are covered in lots of proteins, most of which are known as histones. These provide structural support for the DNA but are also implicated in tissue damage and found in high levels in some immune-mediated diseases. While both NETs and histones are known to increase in immune-mediated diseases, it is unknown what role they play in this process.
The study, led by Associate Professor Anne Bruestle from the Australian National University and published in the prestigious journal, Nature Communications found that NETs can boost the production of another type of immune cell, specifically a T cell called Th17. Like NETs, Th17 is important in fighting bacterial and fungal infections but is also linked to the development of autoimmune diseases such as MS. Using an inhibitor called mCBS to block the toxic effects of the histones, the researchers found that histones on NETs were largely responsible for the production of Th17 in both mouse and human cells, as well as in laboratory models. Further investigation in the laboratory revealed that these histones target receptors (proteins that receive signals for a cell) on T cells that drive additional biological processes causing them to develop intoTh17 cells.
This work reveals for the first time, the mechanism by which NETs can lead to autoimmunity driven by T cells. Beyond this, histones and NETs have been detected in sepsis, COVID-19, deep vein thrombosis (DVT) and several autoimmune diseases, with the level of histones correlating with severity in DVT.
The histone inhibitor mCBS is currently undergoing clinical trials for sepsis and COVID-19. Associate Professor Bruestle’s colleagues developed this drug at the Australian National University, which you can read more about here. It is hoped that these clinical trials will pave the way for the use of mCBS as a potential therapy to block the action of histones in immune-mediated diseases such as MS.