Homing in on a Target

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Researchers clarify disease mechanisms and therapeutic targets in axial spondyloarthritis.
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Axial spondyloarthritis is a debilitating form of arthritis, for which there is no cure. Researchers are investigating the underlying disease mechanisms with the aim of developing molecularly targeted treatment

UHN researchers have shed light on a potential therapeutic target for axial spondyloarthritis, a chronic inflammatory disease that affects the joints and other tissues. 

In a new study published in Science Translational Medicine, an international research team led by Schroeder Arthritis Institute Scientist Dr. Nigil Haroon examined how a particular protein contributes to the disease.

Patients with axial spondyloarthritis have elevated levels of a protein called macrophage migration inhibitory factor (MIF) in their blood and tissues. MIF regulates inflammatory immune responses and the levels of this protein in a patient’s blood are associated with disease severity.

“Axial spondyloarthritis is a devastating disease, and we have very few therapeutic options for most patients,” explains Dr. Haroon. “Because MIF activates inflammatory pathways, we examined whether it contributes to the clinical features of the disease and whether we can target it for treatment.”

Using experimental models of the disease, the researchers observed that MIF is produced in large quantities by a type of white blood cell. They also found that increasing the levels of MIF or these specialized cells was sufficient to induce disease symptoms, such as inflammation of the skin and joints. In contrast, inhibiting the production or activity of MIF reduced disease severity.

The researchers also determined how MIF triggers inflammation. “We found that MIF increases the production of a subtype of T cells—immune cell that causes inflammation,” explains Dr. Akihiro Nakamura, a rheumatologist and first author of the study. “This is in line with what we see in the clinic, because blood and joint fluids from patients with the disease contain high levels of these T cells.”

This study indicates that MIF plays an important role in axial spondyloarthritis and is a potential therapeutic target for this disease and other inflammatory conditions. If a drug can reduce levels of MIF in patients, it may slow or stop the progression of the disease.

“Moving forward, we need to further characterize how MIF causes T cells to change and induce inflammation,” says Dr. Haroon. “Although more research is needed, our study lays a strong foundation for clinical trials to test the safety and efficacy of new therapeutics that target this protein.”

This work was supported by the Canadian Institutes of Health Research, the Arthritis Society, the American College of Rheumatology Research Fund, the National Institutes of Health, the Natural Sciences Research Council, the Canada Foundation for Innovation, the Ontario Research Fund, IBM, the Ian Lawson van Toch Fund, the Krembil Foundation and the UHN Foundation. M Kapoor holds a Tier 1 Canada Research Chair in Synthetic Neuro-Immunology and Stem Cell Bioengineering.

Nakamura A, Zeng F, Nakamura S, Reid KT, Gracey E, Lim M, Leng L, Jo S, Park YS, Kusuda M, Machhar R, Boroojeni SF, Wu B, Rossomacha E, Kim TH, Ciccia F, Rockel JS, Kapoor M, Inman RD, Jurisica I, Crome SQ, Bucala R, Haroon N. Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease. Sci Transl Med. 2021 Oct 20. doi: 10.1126/scitranslmed.abg1210.

Dr. Nigil Haroon (L) is a rheumatologist, Scientist at the Schroeder Arthritis Institute and Co-Director of UHN’s spondylitis program. Dr. Akihiro Nakamura (R) is a rheumatologist, a spondylitis program fellow and a PhD candidate in Dr. Haroon’s laboratory.