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Inflammatory Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Anti-MDA5 antibody (melanoma differentiation-associated protein 5) was first identified as CADM-140 antigen. It is a cytoplasmic RNA-specific helicase that belongs to a family of retinoic acid-inducible gene (RIG) I-like receptors. It is associated with amyopathic DM or DM/PM spectrum (non-ARS). These patients are clinically asymptomatic with minimal skin features. There is no perifascicular pathology, but MHC class-I may show either widespread or perifascicular expression. The majority of these cases have high prevalence of rapid progressive interstitial lung disease leading to early death.
Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
RNA sensing occurs through the activity of retinoic acid gene-I (RIG-I)-like receptors (RLR). These classically serve to sense the presence of RNA species generated during viral infection and can detect both single (ss) and double-stranded (ds) RNA. Three RLRs have been described: RIG-I, melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I and MDA5 consist of two amino-terminal caspase-associated recruitment domains (CARDs), which signal the presence of RNA species that bind a DEAD box (N-terminal) helicase/ATPase domain that is normally repressed by a carboxy-terminal regulatory domain (CTD). RIG-I detects short dsRNA species that possess 5′ end di- and tri-phosphorylated sequences generated by oligoadenylate synthetase (OAS) and RNaseL processing of RNA viruses or Pol III generated dsRNA species from dsDNA viruses. Upon RNA binding and ubiquitination by Riplet and TRIM25, RIG-I binds mitochondrial antiviral-signaling protein (MAVS) to activate two pathways, which together converge on the production of myeloid interferons: TANK-binding kinase-1 (TBK1) and IκB kinase epsilon (IKKe) phosphorylation and activation of IRF3 and IRF7 or induction of NF-κB on repression of IκB. The interferons induced are secreted and activate IFN receptor signaling and the induction of interferon-stimulated genes through the activation of STAT1, STAT2, and IRF9. MDA-5 senses long dsRNA species in a ubiquitin-independent pathway. The third member of the RLR family is less well understood; it binds RNA species but lacks a CARD domain.
Future and Novel Unexplored Indications of Retinoids
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Acitretin has been explored as a potential latency reversing agent for HIV following demonstration of enhanced retinoic acid-inducible gene-I (RIG-I) signaling ex vivo (66). Pharmacologic stimulation of the RIG-I pathway has been proposed as an alternative mechanism to kill cells in the latent HIV reservoir, following viral reactivation. The results from a further study though failed to show any significant effect of acitretin on the HIV reservoir (84). Acitretin is the preferred drug for treatment of psoriasis and other responsive conditions in HIV patients. The effect on HIV viral load is a potential area requiring further research.
Enhancing anti-tumor efficacy and immune memory by combining 3p-GPC-3 siRNA treatment with PD-1 blockade in hepatocellular carcinoma
Published in OncoImmunology, 2022
Liwei Shao, Xin Yu, Qiuju Han, Xinke Zhang, Nan Lu, Cai Zhang
In recent years, the application of RNA interference (RNAi) technology has provided a way to inhibit gene expression and replication in vitro and in vivo.13 In addition, it has been reported that short interfering RNAs (siRNAs) may trigger innate immunity through “off-target” immunostimulatory effects by binding and activating Toll-like receptors (TLRs; e.g., TLR3, 7, and 8), retinoic acid inducible gene I (RIG-I), or protein kinase RNA (PKR).14 RIG-I is a key sensor of RNA in the cytoplasm of cells; it recognizes RNA with a 5ʹ-triphosphate group (5ʹ-3p siRNA) in a sequence-independent manner.15 It has been reported that as RIG-I agonists, 3p-siRNAs, can induce type I IFN production by multiple cell types, which plays an important role in activating the innate immune system.16,17
Application in Gene Editing in Ovarian Cancer Therapy
Published in Cancer Investigation, 2022
Shuang Luo, Yujiao Wang, Yongyu Tao, Shuo Li, Zirui Wang, Wei He, Hangxing Wang, Nan Wang, Jianwei Xu, Hailiang Song
Previous studies have reported that overexpression of microRNA-21 (miR-21) (32) and knockout of BIRC5 with the lentivirus CRISPR-Cas9 (33) can also inhibit the growth of tumor cells. The poor prognosis of OC patients is due to the proliferation and metastasis of tumor cells, which lead to a high recurrence rate for patients in the later stage. Wolf et al. found that the expression of RIG-I is related to the recurrence of patients in the later stage (34). Liu et al. found that ATAD2 could be used to identify OC cases with high proliferation characteristics. The high expression of these two genes was related to the advanced disease stage and poor prognosis, so they could be used as a marker of cell proliferation in OC and for the prognosis of patients (35). Therefore, reducing the expression of RIG-I and ATAD2 can improve the prognosis of patients.
Trial watch: intratumoral immunotherapy
Published in OncoImmunology, 2021
Juliette Humeau, Julie Le Naour, Lorenzo Galluzzi, Guido Kroemer, Jonathan G. Pol
RIG-I-like receptors are key sensors of virus infection as well as host-derived RNA. Their detection induces the transcription of immune genes including IFN-I. As a consequence, synthetic RIG-I agonists have been synthesized and evaluated in preclinical and clinical studies as vaccine adjuvants, or potentiators of anticancer immunotherapies.151,180–182 For instance, the completed Phase I NCT03739138 aimed to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity of i.t. injections of MK-4621 delivered via a nucleic acid delivery system, JetPEI™, as monotherapy, and in combination with pembrolizumab in patients with advanced/metastatic solid tumors with no available results yet (Table 2).