A new study finds a potential therapeutic target for lupus

A recent study published in JCI found that neutrophil endoplasmic reticulum, the organelle that normally makes proteins in the cell, is found to be stressed in the autoimmune disorder lupus. This stress activates a molecule called IRE1α, which appears to play a critical role in lupus pathogenesis in mice.

A multidisciplinary research group at the University of Michigan, spanning microbiology, dermatology, and rheumatology, found that IRE1α directs the release of extracellular neutrophil receptors, or NETn, from lupus neutrophils. NETs are sticky, net – like structures that cause inflammation when released at the wrong time or place.

NETns play an important role in the pathogenesis of lupus and other autoimmune diseases, where they stimulate the formation of autoantibody and contribute to bleeding and damage of blood vessels.

Thanks to the work of study authors Basel Abuaita, Ph.D. and Mary X. O’Riordan, Ph.D., microbiologist and immunologist at Michigan Medicine, the research group knew that the IRE1α pathway was important for neutrophil activity in models of other disease that potentially fatal, Staphylococcus aureus infection.

“Because lupus contains too many neutrophils, we hypothesized that the IRE1α pathway may be part of the story in this disease as well,” says Gautam Sule, Ph.D., a postdoctoral man in rheumatology at Michigan Medicine. “This is what prompted this collaboration, and the result was that a rarely activated IRE1α pathway was found in patients’ lupus neutrophils, which closely follows disease depth.”

However, there were particular challenges in this new study, because according to study author Jason S. Knight, MD, Ph.D., a rheumatologist at Michigan Medicine, studying neutrophils is not easy.

“Although neutrophils are the most common circulating white blood cells, they are difficult to work with in the laboratory because they do not live long and do not have a good cell line system to reproduce their functions,” he says.

This meant that the research team had to clean neutrophils from human blood every day for their tests but, fortunately, the work paid off.

While the team now understands more about the neutrophil biology in lupus, they say more excavation remains to be done and the next steps will include a study of a larger group. most patients with lupus, and other related diseases such as antiphospholipid syndrome.

“This was a huge partnership of basic cell biologists and translational scientists. This project would not have been possible if only one of our organizations had tried it,” he said. Knight. “We are fortunate to have a place like UM where these partnerships are not only possible but actively encouraged.”