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Targeting the Type I Interferon Pathway to Treat Patients with Lupus

Perspective published in Science by Mary K. Crow, MD, discusses new research findings involving a proposed mechanism that could explain the overproduction of type I interferon

New research provides insight into a proposed mechanism involved in the production of type I interferon (IFN-I) in patients with systemic lupus erythematosus (SLE), according to a perspective in Science authored by Mary K. Crow, MD, physician-in-chief and chair of the Department of Medicine at Hospital for Special Surgery (HSS), in New York City. The perspective was written to accompany a study by Kim et al. in the same issue of the publication.

“Research identifying the role of type I interferon in autoimmune disease, particularly lupus, is progressing. The study by Kim et al. provides data on one of the mechanisms that might explain why interferon is being made in excess in lupus. It also supports therapeutic targeting of the interferon pathway in lupus,” said Dr. Crow, who is also chief of the Division of Rheumatology at HSS and NewYork-Presbyterian/Weill Cornell Medical Center.

Previous research has shown that the IFN-I family of innate immune cytokines contributes to the aberrant immune functions of SLE and several other autoimmune diseases. White blood cells from SLE patients demonstrate an IFN-I signature characterized by increased expression of hundreds of IFN-regulated genes. Sustained activation of the IFN pathway supports differentiation of T follicular helper cells, development of autoantibody-producing plasma cells and recruitment of inflammatory cells that produce tissue damage. Previous research has also shown that toll-like receptors, when stimulated by immune complexes, induce production of IFN-I in patients with SLE.

The study by Kim et al. describes a new mechanism for IFN-I production and identifies a role for mitochondrial stress in inducing oligomerization of VDAC, a molecule in the outer mitochondrial membrane that controls entry and exit of metabolites. Oligomerization of a protein refers to the interaction of more than one polypeptide chain. The researchers showed that interaction of amino-terminal amino acids of the protein VDAC1 with mitochondrial DNA (mtDNA) initiates pore creation. Mitochondria with increased mitochondrial reactive oxygen species (mROS) release small fragments of mtDNA into the cytosol, the aqueous component of the cytoplasm of a cell, through the VDAC pore, and this triggers induction of IFN-I. The transfer of mtDNA to the cytosol occurred under relatively benign conditions of mitochondrial stress, suggesting that induction of IFN-I through sensing of mtDNA could involve different environmental triggers.

“In a disease like lupus, there are many kinds of stressors that can trigger the disease or flares of the disease, such as ultraviolet light or excessive fatigue,” explained Dr. Crow. “There are many potential triggers that can make lupus worse.”

Kim et al. also demonstrated that inhibiting VDAC oligomerization in SLE mice reduced accumulation of cytosolic mtDNA, decreased expression of type I IFN-regulated genes and abrogated features of autoimmune disease in mice with SLE.

“Overall, this study points to this important cell structure, the mitochondria, which we typically think of as producing energy, as also having the role of sensing cell stress that leads to changes that allow the formation of this pore, the leakage of mitochondrial DNA, and activation of the immune response, as measured by production of interferon,” said Dr. Crow. “The study by Kim et al. suggests a novel mechanism that could account for the production of type I IFN.”

Dr. Crow pointed out that in this week’s New England Journal of Medicine, the TULIP-2 (Treatment of Uncontrolled Lupus via the Interferon Pathway–2) trial reported positive results for anifrolumab, an antibody that inhibits signaling through the type I IFN receptor in patients with SLE. “There is progress in developing therapies to inhibit interferon’s impact on the immune system and improve outcomes for patients with lupus,” said Dr. Crow.

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 14th consecutive year), No. 2 in rheumatology by U.S. News & World Report (2023-2024), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2023-2024). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a fourth consecutive year (2023). Founded in 1863, the Hospital has the lowest readmission rates in the nation for orthopedics, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.