DNA networks in research into autoimmune renal diseases

Daniel Appelgren is investigating a type of renal disease in which the immune system attacks and damages the kidneys. In the long term, he hopes to develop new treatments for these autoimmune diseases, which are currently incurable. He has been awarded a grant of SEK 1.25 million from the Ingrid Asp Foundation to carry out renal research at LiU.

Daniel Appelgren seeks to understand what happens when the immune system causes damage to the patient’s own body in autoimmune diseases.Daniel Appelgren.Daniel Appelgren. Photo credit Emma Busk Winquist

“What is it that goes wrong in autoimmunity? Is there a mechanism that pushes the immune system too hard? Or is there a function that should have softened the reaction, but fails to function properly? Or is it a combination of both?” he asks.

His research concentrates on a group of autoimmune diseases in which inflammation damages principally the small blood vessels in the body, such as in the kidneys, nose and lungs (see “Brief facts” below). These diseases are known as “ANCA-associated vasculitis”, and involve the immune system forming antibodies (ANCAs) in the blood that react against various substances. In seven of ten people who are affected by the disease, the damage is to the small blood vessels in the kidneys.

Most of us seldom think about how important our kidneys are. They purify the blood unceasingly and make sure that unwanted substances are excreted by urination. Each kidney filters around 180 litres a day, which is quite impressive when you consider that an adult human body contains approximately five litres of blood. And even if we primarily associate the kidneys with urination, they also play an important role in regulating blood pressure and the salt/fluid balance in the body. Thus, if the kidneys stop working, the body will experience problems with, among other things, eliminating harmful waste products, keeping the right blood pressure, and maintaining the proper salt balance.

“Most of the patients in our studies are around 60-70 years old. The course of the disease is serious, and when the kidneys in particular are damaged, the patient’s condition can deteriorate extremely rapidly. Even using current treatments, mortality five years after disease onset is as high as 25%”, says Daniel Appelgren, associate senior lecturer in the Department of Health, Medicine and Caring Sciences.

Current treatments can keep the disease under control in most cases. But the maintenance treatment must be kept up for several years, sometimes for the rest of life, and – even so – up to half of patients experience relapse in which the disease re-enters an active phase.

“We don’t have any treatment that can cure these diseases. I hope that our research will help us identify potential points of attack for new treatments, and evaluate the new treatment possibilities that we have already found. We would also like to know which patients run the greatest risk of experiencing relapse. This is why one of our goals is to identify new, relevant biomarkers that the healthcare system can use to follow disease progression, and adapt treatment accordingly”, says Daniel Appelgren.

Accelerate too hard or brake too softly?

When the body detects an infection, the immune system should be activated, such that an inflammation response is triggered to rid the body of the infecting bacteria. When this is complete, the inflammation should end. During autoimmune diseases, an inflammation is active that does not, unfortunately, end by itself, and this leads to damage to the body. Daniel Appelgren believes that several different things must fail to work properly to produce the reaction of the immune system seen in autoimmune diseases.

The first line of research is looking at whether the inflammatory reaction is too intense. He is studying “inflammatory DNA”, which can be released by several different cell types in the immune system. The DNA is in itself inflammatory, and may also contain other components, such as proteins, that can activate other cells of the immune system and help to capture and kill bacteria. Daniel Appelgren has shown that the levels of one type of inflammatory DNA are elevated in the blood of patients. This inflammatory DNA is known as “neutrophil extracellular traps” (abbreviated as “NETs”). It looks like a net, and is therefore often called a “DNA net”.

microscopy image showing DNA nets.Immune cells (neutrophils) releasing neutrophil extracellular traps (NETs). NETs are inflammatory structures consisting of DNA (blue) and different proteins, such as myeloperoxidase (green). Photo credit Daniel Appelgren “One interesting thing is that the proteins in the DNA structures that are released from the immune cells are the same proteins that the body reacts to and forms antibodies against in patients with these autoimmune diseases. And it’s also interesting that this occurs in a similar manner in several other diseases, such as the autoimmune disease systemic lupus erythematosus (SLE)”, says Daniel Appelgren.

Most research into inflammatory DNA has been carried out on cells known as “neutrophils”, which were the first cell type that researchers discovered could release DNA nets. Daniel Appelgren and his colleagues have subsequently shown that another type of immune cell, lymphocytes, can also release inflammatory DNA, and he now plans to study this in ANCA-associated vasculitis. One of the aspects he plans to look at, in collaboration with researchers in Australia, is how this mechanism works and what happens when it is blocked.

The second line of research concerns a type of immune cell that regulates the inflammatory reaction. Daniel Appelgren studies cells known as “regulatory B-cells”, which can secrete signal substances that dampen the immune response. Preliminary results from his research suggest that certain regulatory functions in these cells are impaired in patients.

Similarities between autoimmune diseases

“What I find interesting is that similar questions arise in several autoimmune diseases. Even if the immune system reacts against different substances and different organs in the body are affected, there may be similar faults behind these diseases”, says Daniel Appelgren. One example is the release of DNA NETs from neutrophils, which is being studied in many autoimmune diseases.

The curiosity that drives him forwards in research has also contributed to widening his interests. He has a research collaboration with Christopher Sjöwall, for example, associate professor in the Department of Biomedical and Clinical Sciences who works with SLE. If it is true that similar mechanisms lie behind the different diseases, it’s possible that new knowledge from discoveries related to one disease will give impetus to research into similar autoimmune diseases. Collaboration with doctors working in the clinic at Linköping University Hospital is a very important part of the research.

The research grant of SEK 1.25 million from the Ingrid Asp Foundation makes continued research possible.

“It means a great deal to me to receive such a large research grant at this time. It makes it possible for me to continue with all the projects and rewarding collaborations I’ve started, and means that I can lay long-term plans”, says Daniel Appelgren.

The Ingrid Asp Foundation also contributes to the financing of a professorship in renal medicine at LiU. Annette Bruchfeld, professor and doctor, was appointed to this position in August 2020, and will work on inflammatory renal diseases and vasculitis.

Translated by George Farrants

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What is ANCA-associated vasculitis?

  • ANCA-associated vasculitis, where “vasculitis” describes inflammation in blood vessels and “ANCA” is an acronym for “anti-neutrophil cytoplasmic antibodies”. The antibodies target one sort of immune cell, the neutrophils.
  • The group includes granulomatosis with polyangiitis (previous known as “Wegener's granulomatosis”), eosinophilic granulomatosis with polyangiitis (previously known as “Churg-Strauss syndrome”), and microscopic polyangiitis.
  • Many other conditions can cause impaired kidney function. A total of approximately 700 million people around the world are affected by chronic renal disease and impaired kidney function.

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