Researchers from Vanderbilt University Medical Center and the University of Michigan Medical School have been awarded a five-year, $3.6 million grant from the National Institutes of Health (NIH) to determine how the immune system drives inflammatory arthritis in patients with psoriasis.
The research potentially may lead to better ways to treat psoriatic arthritis, a debilitating yet poorly understood joint disease that affects approximately 1 million people in the United States.
In their grant application, the researchers noted, “The results of this research will bring clarity to the long-standing questions of how psoriatic arthritis arises, why it does not respond to many of our current therapies for psoriasis of the skin, and what existing FDA-approved (drugs) may be repurposed to treat this devastating disease.”
Grant number R01AR084312 was awarded April 10 by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH.
Nicole Ward, PhD, professor and vice chair for Basic Research in the Department of Dermatology at VUMC, and Johann Gudjonsson, MD, PhD, an authority on inflammatory skin diseases at the University of Michigan Medical School, are the grant’s co-principal investigators.
One-third of patients with psoriasis, a chronic skin disease, develop inflammatory arthritis, which leads to permanent joint damage and crippling disability.
The pathogenesis of the disease, or how it develops, remains unclear, and there are no biomarkers, making diagnosis and treatment difficult and challenging, said Ward, who holds the Lloyd E. King Jr. Directorship in Dermatology Research at VUMC.
Ward and her colleagues have developed a mouse model of psoriatic arthritis that is yielding insights into the role that antibody-producing white blood cells called B cells may play in driving the disease.
Different populations of B cells are known to modulate the immune system. Regulatory B (Breg) cells can suppress immune responses, while effector B (Beff) cells promote them. Until recently, however, B cells have been “overlooked” in studies of psoriatic arthritis, Ward said.
The new mouse model reflects what has been observed in patients — a decrease in Breg cells, a rise in Beff cells, and an increase in another type of white blood cells, T helper cells (specifically, Th1 and Th17 cells), which normally activate immune responses against infection.
The team of dermatologists, rheumatologists, and basic scientists led by Ward and Gudjonsson will test a paradigm-shifting hypothesis: that too many Beff cells and too few Breg cells drive the development of psoriatic arthritis by promoting T helper cell inflammation.
Aided by cutting-edge technologies, including single cell RNA sequencing and spatial RNA sequencing, they will genetically engineer specific cells to over-express or knock out genes of interest and control gene expression over time.
Once the contributions of individual cells to psoriatic arthritis have been determined in the mouse model, the researchers will try to translate and validate their findings in the synovial tissues of affected joints from humans with the disease.
This, in turn, may help researchers identify drugs already approved by the U.S. Food and Drug Administration for other uses that may be repurposed to target psoriatic arthritis at its cellular and molecular roots.
Co-investigators from VUMC include Rachel Bonami, PhD, assistant professor of Medicine in the Division of Rheumatology and Immunology, and, from Michigan, Samar Gupta, MD, Michelle Kahlenberg, MD, PhD, and Lam Tsoi, PhD.
Preliminary data included in the grant proposal was generated with financial support from the National Psoriasis Foundation. Ward is a member of the foundation’s Scientific Advisory Committee.
