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Targeting the Type I Interferon Pathway to Treat Patients with Lupus

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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.

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Schedule27 Sep 2023