Published: 2021-12-14 10:57 | Updated: 2021-12-14 14:28

Reverse strategy finds diagnostic marker of autoimmune disease

Illustraion of woman with itchy rashes.
By searching among patients with various skin diseases, researchers identified a disease linked to autoimmunity against the skin protein TGM1. Illustration: Getty Images

Instead of searching for proteins that the immune system reacts against in a specific autoimmune disease, researchers have taken the opposite approach to find diseases linked to a certain protein. By searching among patients with various skin diseases, they identified a disease linked to autoimmunity against the skin protein TGM1. The strategy, which is presented in the journal PNAS, can facilitate the diagnosis and treatment of autoimmune diseases.

Autoimmune diseases occur when the immune system reacts incorrectly and attacks the individual’s own body. The immune system’s cells and antibodies then react against the body’s proteins, known as autoantigens. Knowing which autoantigens are associated with a specific disease is important to understand the disease mechanisms, which in turn can facilitate diagnosis and treatment. Traditionally, research has focused on individual diseases to identify autoantigens.

In this new study, researchers at Uppsala University and Karolinska Institutet in Sweden and Osaka City University in Japan took the opposite approach: they focused on a suspected autoantigen and then conducted a broad search for a matching disease. They started with a skin protein called transglutaminase 1 (TGM1). It has previously been linked to a hereditary skin disease and belongs to a protein family with many known autoantigens. To find out if TGM1 was also involved in an autoimmune disease, they searched for it in over 500 patients with various autoimmune and unexplained skin diseases.

Led to disease discovery

Portrait of Nils dressed in white shirt, jacket and a tie.
Nils Landegren, researcher at Uppsala University and Karolinska Institutet. Photo: Hans Ericksson/SSMF

“Eventually, we found a match,” says Nils Landegren, medical doctor and researcher specialising in autoimmune diseases at Uppsala University and affiliated researcher at the Department of Medicine, Solna, Karolinska Institutet, who led the study. “We saw that patients with the cancer-associated and severe blister-causing skin disease paraneoplastic pemphigus presented antibodies against TGM1. We confirmed the findings in a larger group of patients and could conclude that TGM1 antibodies were completely specific for paraneoplastic pemphigus.”

The study illustrates a new approach to identifying biomarkers. The researchers believe that this approach can be used in studies of all sorts of autoimmune diseases, and that this could be a way to leverage the growing amount of openly available data on gene expression and function.

“We believe that TGM1 antibodies can be valuable as a diagnostic marker in investigations of blister-forming diseases. Patients that test positive should be quickly investigated to eliminate the possibility of undiscovered cancers,” says Nils Landegren.

Funding was provided by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Society for Medical Research, the Göran Gustafsson Foundation and the Novo Nordisk foundation, among others. The contributing researchers have applied for a patent for the diagnostic use of TGM1 antibodies.

This news article is based on a press release from Uppsala University.

Publication

”A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen”. Nils Landegren, Norito Ishii, Maribel Aranda Guillen, Horður Ingi Gunnarsson, Fabian Sardh, Åsa Hallgren, Mona Ståhle, Eva Hagforsen, Maria Bradley, Per-Henrik Edqvist, Fredrik Ponten, Outi Mäkitie, Liv Eidsmo, Lars Norlén, Adnane Achour, Ingrid Dahlbom, Ilma Korponay-Szabo, Daniel Agardh, Mohammad Alimohammadi, Daniel Eriksson, Takashi Hashimoto, Olle Kämpe. PNAS, 13 December 2021, doi: 10.1073/pnas.2100687118.