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Vasculitis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Michelle L. Robinette, Eli Miloslavsky, Zachary S. Wallace
Other monogenic syndromes with associated vasculitis include interferonopathies, inflammasopathies, and relopathies (15). Among these, vasculitis occurs most frequently among some interferonopathies, which mechanistically share increased type I interferon signatures but can diverge in phenotype (36–38). For example, heterozygous gain-of-function mutations in TMEM173, encoding stimulator of interferon genes (STING) downstream of several cytosolic DNA sensors, cause early-onset cutaneous leukocytoclastic vasculitis in STING-associated vasculopathy with onset in infancy (SAVI). In COPA syndrome, autosomal dominant mutations in the coatomer protein complex subunit alpha (COPA) similarly result in prolonged function of activated STING. However, this syndrome presents with a different vascular phenotype than SAVI and is characterized by pediatric-onset pulmonary capillaritis that mimics isolated pulmonary AAV as well as teenage-onset glomerular disease with multiple histopathologic subtypes (39). Additionally, a variety of disease-associated mutations occur in the DNA exonuclease TREX1 and can cause cutaneous vasculopathy reminiscent of SAVI and DADA2 or CNS vasculopathy, with clinically divergent but overlapping phenotypes and inheritance patterns among the four named disease entities (40).
Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
Type 1 interferons are among the first cytokines produced during a viral infection and promote both innate and adaptive immunity. Interferon beta has shown an antiviral effect against SARS-CoV and MERS-CoV in in vitro studies and animal models. Clinical studies of SARS-CoV-2 found that a proportion of patients with severe COVID-19 had impaired type I interferon activity. However, preliminary results from the SOLIDARITY randomized clinical trial with 200 patients showed no efficacy of subcutaneous interferon alone or with lopinavir–ritonavir [32]. This result contrasted with the findings from another study by Monk et al. 2021 [31], which supported the in vitro study results and suggested that the interferon pathway is an important inflammatory factor in SARS-CoV-2 infection, and IFN-β-1 may be considered as a safe and effective treatment against SARS-CoV-2 in the early phases of the illness.
Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
More than 20 distinct IFN genes and proteins have now been identified in animals and humans. They are typically divided into three classes: Type I IFN, Type II IFN, and Type III IFN, all of which are important for fighting viral infections and for regulating the immune system. Type I IFNs, of which IFN-α used for cancer therapy is a member, bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) consisting of IFNAR1 and IFNAR2 chains. Type I interferons produced in humans include IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω, and are generally produced when the body identifies that a viral infection has occurred. They are produced by monocytes and fibroblasts, and the production of IFN-α is inhibited by another cytokine interleukin-10. Once activated, Type I interferons signal the production of molecules that can prevent viruses from producing and replicating their RNA and DNA. Thus, IFN-α is also used to treat hepatitis B and C infections. IFN-β is used to treat multiple sclerosis rather than cancer. IFN-γ-1b (ImmukinTM) is used to treat severe malignant osteopetrosis (as well as chronic granulomatous disease), and is also described below.
Glomerular endothelial expression of type I IFN-stimulated gene, DExD/H-Box helicase 60 via toll-like receptor 3 signaling: possible involvement in the pathogenesis of lupus nephritis
Published in Renal Failure, 2022
Takao Karasawa, Riko Sato, Tadaatsu Imaizumi, Shun Hashimoto, Masashi Fujita, Tomomi Aizawa, Koji Tsugawa, Shogo Kawaguchi, Kazuhiko Seya, Kiminori Terui, Hiroshi Tanaka
Sustained activation of type I interferon (IFN) has been reported to play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and the development of lupus nephritis (LN) [1,2]. Therefore, the involvement of innate immune system upregulation via regional Toll-like receptor (TLR) signaling, such as TLR3, TLR7, and TLR9, is believed to be involved in LN pathogenesis [3–7]. Considering that viral infections may trigger the development of inflammatory renal disease, upregulation of regional TLR3 signaling reportedly plays a role, at least partly, in the pathogenesis of glomerular diseases (GN), including LN [3,6,7]. Interestingly, the activation of TLR3 and downstream immune responses can be induced by both infectious organisms and endogenous ligands, leading to the development of “pseudo” antiviral immunity-related inflammations in the kidney [6]. Therefore, this theory is probably involved in the pathophysiology of LN [6,7].
Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Xuan Huang, Xiaoyong Zhang, Mengji Lu
The results of the preclinical studies presented in this review suggest that the TLR7/8-targeting agents under investigation were safe, well tolerated, and not associated with severe adverse events in the given applications. However, the efficacy observed in human clinical trials was not as satisfactory. For example, the TLR7 agonist GS-9620 suppressed viral replication and induced surface antigen seroconversion in woodchuck and chimpanzee models. In contrast, it did not reduce HBsAg levels in patients with chronic HBV infection. There is a limitation to increasing the drug dosage due to the risk of side effects, such as cytokine-storms. AZD8848 has a prolonged effect on allergic rhinitis even after treatment cessation in rats. Agonist-induced cytokines, especially type I interferon, have resulted in severe systemic influenza-like symptoms in healthy volunteers as reported in two clinical trials (NCT01560234 and NCT01818869) [135]. Therefore, the optimization process of the application of TLR agonists and antagonists may be conceptualized as a ‘3S’ strategy as described below:
Measuring IFN activity in suspected SLE: a valuable step?
Published in Expert Review of Clinical Immunology, 2021
Jose Rubio, Vasileios C. Kyttaris
Similar to type I interferon, its function is to inhibit viral replication but is also important for anti-bacterial immunity. The only member of this group is IFN-γ that is mainly produced by activated Th1 CD4+ lymphocytes, CD8+ lymphocytes, and NK cells and plays a role in the innate and adaptive immune responses. It has been established that IFN-γ overactivation promotes a chronic pro-inflammatory cascade contributing to organ damage accrual in SLE patients [24]. Additional evidence suggests that various genetic polymorphisms involving interferon-γ and its receptor are associated with an increased susceptibility to SLE [25,26]. Concerning preclinical lupus, type II interferon positivity was found, at least in one study, to precede autoantibody accrual and increased IFN-α [19] (see Table 1). High levels of IFN-γ, as far as 4 or more years before SLE classification, were observed to be predictive of elevated IFN-α activity and future SLE classification. These findings suggest that IFN-γ signaling is highly active at the preclinical SLE stage. It was hypothesized that this upregulated IFN-γ activity enhances neoantigen presentation and promotes accumulation of pathogenic autoantibodies which in turn lead to dysregulated interferon-α signaling, increasing the likelihood that preclinical lupus evolves to clinical SLE.