Complexes in the blood may help identify type 1 diabetes development

Image: Charmaine Simeonovic

Researchers have identified a striking feature of blood cells in type 1 diabetes (T1D) that might aid early intervention therapies against the disease.

In a study recently published in JCI Insight, researchers at The Australian National University investigated the interaction between two kinds of blood cells— platelets and neutrophils—during T1D development.

They found that platelet-neutrophil aggregates or PNAs circulating in the blood characterise T1D development in both humans and a mouse model of T1D.

Neutrophils and platelets are both crucial blood cells in our body.

Imagine you are scratched by a rose thorn and start to bleed. Numerous platelets become activated within a short amount of time and bind to the damaged vessels to stop the bleeding. 

Meanwhile, neutrophils, the most abundant immune cells in the blood and usually activated against invading micro-organisms, can also be stimulated by activated platelets.

However, overactive platelets and neutrophils can potentially cause havoc in our bodies.

In the case of T1D, where the immune system targets and destroys insulin-producing beta cells in the pancreas, the researchers have observed a significant increase in interactions between activated platelets and neutrophils, even before the onset of T1D.

"Activated platelets can bind to resting neutrophils, activate them, and cause them to migrate out of the blood into the pancreas and to release damaging cell components," said Associate Professor Charmaine Simeonovic at The John Curtin School of Medical Research (JCSMR), who is the corresponding author of the study.

The components released from activated neutrophils, including DNA and proteins called histones, form web-like structures known as neutrophil extracellular traps, or NETs. 

NETs labelled with SYTOX Green. Image: Jessica Garrett, Sarah Popp

Histones in these toxic webs can activate platelets, which in turn activate more neutrophils to unleash NETs, driving a vicious cycle of platelet-neutrophil activation. 

During the development of T1D, this cycle fuelled by PNAs appears to supplement T cell (another white blood cell) immune mechanisms, destroying beta cells in the pancreas.

The team, including researchers in Milan, Italy, found through blood tests that children with a high risk of developing T1D and children at T1D onset had significantly elevated PNA levels in their blood compared to healthy controls. Following disease onset, the increased PNA levels rapidly declined.

Similarly, PNA levels in the blood, and also in islets, rose in non-obese diabetic (NOD) mice during the development of T1D disease, with NET components detected in the pancreatic islets. Importantly, NETs and histones were found to damage islets/beta cells in tissue culture experiments.

"Our findings suggest that blood PNA levels can act as an early biomarker of impending T1D onset for a neutrophil-associated subtype of T1D, " said Associate Professor Simeonovic. 

The results warrant future clinical evaluations to determine the potential for PNAs to be predictive T1D biomarkers.

"Biomarkers of pre-T1D offer potential for early intervention therapies to protect the survival of beta cells and thereby delay or prevent the clinical onset of T1D," said Associate Professor Simeonovic.

This study was supported by an Innovation Grant from the JDRF Australian Type 1 Diabetes Clinical Research Network (Grant # 3-SRA-2018-602-M-B) through a special initiative of the Australian Research Council (ARC).