New method determines the severity of autoimmune diseases

Breaking new ground 17. nov 2021 3 min Postdoctoral Fellow Kristian Juul-Madsen Written by Kristian Sjøgren

A new method can probably be used to diagnose and determine the severity of many inflammatory autoimmune diseases.

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Systemic lupus erythematosus (SLE) is an inflammatory autoimmune diseases that is difficult to diagnose because no diagnostic test has been developed. Instead, doctors must base their diagnosis on blood analysis, medical imaging and other means.

However, a new diagnostic test for SLE is in the works.

A new invention researchers use to measure the size of protein aggregates (proteins that clump together) can determine very precisely whether a person has SLE or not and the severity if they have it.

The research has been published in the Proceedings of the National Academy of Sciences of the United States of America.

“Our discovery has two aspects: developing the technology for diagnosing various autoimmune diseases and validating it for diagnosing SLE,” explains co-author Kristian Juul-Madsen, Postdoctoral Fellow, Department of Biomedicine, Aarhus University.

Dysregulated proteins clump together

Doctors would like to diagnose almost all diseases based on a blood test.

However, this requires identifying biomarkers for each specific disease in the blood.

Once a specific biomarker is known, doctors can determine the presence and/or concentration in the blood sample and base their diagnosis on this.

However, some diseases, including SLE, cannot be identified by the concentration of a specific protein but require determining whether specific proteins clump together.

Mannose-binding lectin is a protein that behaves differently among people with SLE than among people without SLE. The protein forms major oligomeric complexes that contribute to activating the immune response and stimulating the inappropriate autoimmune response that leads to SLE.

“Oligomerisation is a problem in various diseases: a defect in the coding of the protein causes the dysregulated proteins to clump together inappropriately. People with and without SLE have the same amount of mannose-binding lectin, but the size of the oligomers differs,” says Kristian Juul-Madsen.

Placing tiny fluorescent dots on proteins

Kristian Juul-Madsen has collaborated with Thomas Vorup-Jensen and others to develop a technology that can determine the degree to which mannose-binding lectin clumps together in a blood sample.

They use an antibody to bind fluorescent streptavidin-coupled quantum dots to mannose-binding lectins in blood samples from people suspected of having SLE.

The quantum dots emit narrow-spectrum light at 655 nanometres that is 1,000 times more intense than the light emitted by conventional fluorescent molecules.

The researchers then use nanoparticle tracking analysis to study these fluorescent quantum dots under a microscope and record how the proteins move.

The mannose-binding lectins that are clumped together in large complexes among people with SLE move slowly, whereas small proteins move quickly.

The speed of the fluorescent quantum dots can thus be used to diagnose SLE.

“An ingenious thing about this technique is that it requires minimal preparation. We just have to filter the blood sample to extract the cells and dilute it and then analyse it. We use the movements of the proteins to determine how large the protein complexes are and whether the person has SLE or not,” explains Kristian Juul-Madsen.

The researchers have patented the technology.

Determining the severity of SLE

The researchers had to demonstrate that this technology works in the real world, and they also did this.

They used blood samples from 40 people with SLE and a cohort of healthy people as controls.

The researchers analysed the blood samples blinded so they did not know who had SLE and who did not. Nevertheless, they accurately identified who had SLE and who did not and the severity of SLE.

Some people with SLE have comorbid conditions in the intestines or kidneys.

The researchers analysed the samples and stratified them according to the degree of protein clumping and found that the people with the most clumping not only had SLE but had the greatest severity, with one or more comorbid conditions.

“Our clinical partner was very pleased because diagnosing these people is very difficult and because our method could not only diagnose but also determine the severity,” says Kristian Juul-Madsen.

Developing the method for other diseases

According to Kristian Juul-Madsen, these results will inspire the researchers to take the next step towards clinical application.

The researchers only analysed blood samples from 40 of a cohort of 379 people with SLE in Denmark, and they want to analyse the rest to validate the initial results. This will also include investigating whether they can categorise the people with SLE into subgroups according to characteristics and severity.

The researchers will also investigate whether they can use the method to determine the prognosis for these people in the next 5, 10 or 20 years.

“This may help to guide the choice of biological treatment. We are also considering other inflammatory autoimmune diseases that are currently difficult to diagnose. We have promising results for people with rheumatoid arthritis that we will publish soon,” concludes Kristian Juul-Madsen.

Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus” has been published in the Proceedings of the National Academy of Sciences of the United States of America. In 2019, the Novo Nordisk Foundation awarded a grant to co-authors Thomas Vorup-Jensen for the project Molecular Barcodes for Integrin-mediated Phagocytosis of Protein Amyloids.

We investigate molecular mechanisms in chronic inflammation and autoimmune diseases to understand and design new biological therapies. Our interests a...

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