New evidence on the role of neutrophils in T1D

Scientists studying the pathogenesis of type 1 diabetes (T1D) – one of the most common and debilitating chronic autoimmune disease – have focused for a long time on T lymphocytes, which already in the ‘70s were considered the main responsible for the attack to the pancreas. A research coordinated by Manuela Battaglia, deputy director of the Diabetes Research Institute (DRI) of IRCCS Ospedale San Raffaele, in collaboration with the Pediatric and the Infantile Orthopedic Units of the same institute and other international research centers, shows the key role of neutrophils, a group of cells which have been long ignored. The results have been published today in JCI Insights and might pave the way to new strategies to prevent and treat T1D.

T1D is an autoimmune disease in which the immune system attacks and destroys pancreatic beta cells, the only cells of our organism able to produce insulin, a hormone that regulates sugar metabolism and its transformation into energy. At the moment, the only available therapy for T1D patients are daily injections of insulin, whose shortage may lead to death in few hours.


Neutrophils during NET release (DNA in red and MPO in green).

In the last decades researchers studying T1D have focused mainly on T lymphocytes while other immune cells – like neutrophils – have hardly been considered. T cells belong to the so-called adaptive immunity, i.e. a subsystem of the overall immune system that sustains the development of specific responses (depending on the interactions with the environment) and the generation of immunological memory. On the other hand, neutrophils are part of the innate immunity and they trigger immediate and aggressive – although less specific – reactions against threats. Only recently, studies of neutrophils in subjects with autoimmune diseases (e.g. systemic lupus and scleroderma) have casted light on their role as triggers of auto-inflammation.

In collaboration with TrialNet, the group guided by Manuela Battaglia analyzed the blood tests of 389 people at risk for T1D and discovered that people with a lower number of neutrophils have less functioning beta cells. “Essentially, the lower the number of circulating neutrophils the less the body can produce insulin” says Manuela Battaglia.

Willing to carry on their investigation, researchers analyzed sections of pancreas collected from donors all over the world at four different disease stages. “The analysis of tissues proved that patients at risk for T1D already show progressive infiltration of neutrophils into their pancreas”. Moreover, the histological analysis shows the presence of a phenomenon called NETs, i.e. neutrophils release their nucleus’ content, including their DNA, triggering inflammation and increasing the risk of autoimmunization.

Finally, in collaboration with the Benaroya Research Institute in Seattle, the group analyzed the gene expression profiles of circulating neutrophils and observed that they are altered in patients at risk for T1D: the gene expression profiles highlights an abnormal content in the types and amounts of protein synthetized. Importantly, this abnormal neutrophil behaviour  precedes the production of specific T1D-autoantibodies as well as the activation of T lymphocytes, indicating that neutrophils may have a crucial role at very early stages of  T1D pathogenesis.

“Overall, these results suggest that neutrophils might have a key role in the development of T1D. We cannot ignore them anymore if we want to understand the disease and defeat it” adds Manuela Battaglia. “We hope our data will be validate by independent investigators and more research focused on innate immunity will be carried on by other scientists to better understand type 1 diabetes, a disease that today remains incurable.”

Federica Vecchio, Nicola Lo Buono, Angela Stabilini, Laura Nigi, Matthew J. Dufort, Susan Geyer, Paola Maria Rancoita, Federica Cugnata, Alessandra Mandelli, Andrea Valle, Pia Leete, Francesca Mancarella, Peter S. Linsley, Lars Krogvold, Kevan C. Herold, Helena Elding Larsson, Sarah J. Richardson, Noel G. Morgan, Knut Dahl-Jørgensen, Guido Sebastiani, Francesco Dotta, Emanuele Bosi, the DRI_Biorepository Group, the Type 1 Diabetes TrialNet Study Group, Manuela Battaglia. Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight. 2018; 3(18): e122146.