The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Abstract

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

Infection of Human Retinal Pigment Epithelial Cells with Dengue Virus Strains Isolated during Outbreaks in Singapore

“…Importantly, this response was significantly higher in primary cell isolates infected with a DENV-1 strain from the 2005 Singapore epidemic than the same isolates infected with a DENV-1 strain from the 2007 epidemic. Although recognized as the major mechanism for controlling viral infection, a chronic or dysregulated type I IFN response has been linked to a range of systemic autoimmune diseases [50]; recently Roy and co-workers demonstrated involvement of this pathway in neuroinflammation in both animal models and human pathological specimens [51]. Thus, a type I IFN response may drive inflammatory pathology in dengue retinopathy, and our results are consistent with more pathology induced by DENV-1 strains from the 2005 Singapore epidemic in comparison to the 2007 epidemic.…”

Case Report: Interferon-Alpha-Induced Neuromyelitis Optica Spectrum Disorder

“…The IFNα is still widely used in the treatment of chronic viral infections, hematological malignancies, and certain cancers ( 25 ), whereas IFNβ preparations are recommended for multiple isoforms of MS ( 5 , 6 ). Opposing the beneficial actions of IFNI treatment, IFNI has gradually been recognized as a pro-inflammatory molecule that may not only unmask and aggravate underlying autoimmune processes, but also induce de novo autoimmune disorders, such as type-I diabetes, vitiligo, SLE, Sjögren syndrome, and autoimmune thyroid disease ( 26 – 28 ). Various neuroautoimmune diseases, including myasthenia gravis, inflammatory demyelinating polyneuropathy, and polymyositis, are also occasionally induced by IFNα therapy ( 29 , 30 ).…”

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

“…The cause of autoimmunity is multifactorial, but interplay between various immune cells is critical [ 2 ]. Aberrant IFN signaling, activation of the NLRP3 inflammasome, as well as B cells and Th17 cells, and even hyperactivation of cytototoxic CD8 + T cells is noted [ 162 , 163 , 164 , 165 ]. Also, T and natural killer cells from SLE patients show higher intracellular ROS levels of than B cells from healthy controls; at the same time, Keap1 and Nrf2 levels are elevated as an antioxidant defense mechanism [ 166 ].…”