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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.
Biliary atresia
Published in Prem Puri, Newborn Surgery, 2017
There is a mouse model of BA where just-born mice can be inoculated with rotavirus (or reovirus or CMV) and who developed jaundice with intrahepatic histology similar to that of BA.36,37 The nature of the cholangiodestructive pathway can be examined relatively easily, and it can be shown that there is early upregulation of interferon inducers Irf7 and Irf9 genes (proinflammatory genes), with IFN-γ having greater expression at the time of bile duct obstruction.38–40
SARS-CoV Infections in Humans
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
ORF 6 is 63 amino acid residues in size and is found in the membranes of the rough endoplasmic reticulum. Its expression in the target cells of patients’ specimen has been detected.81 ORF 6 is considered to be one of the important virulent factors for SARS-CoV. ORF 6 might act as an antagonist to IFN, suppressing IFN induction and the IFN signaling pathways.98,99 ORF 6 binds to karyopherin a2 (KPNA2), inhibiting recruitment of KPNB1 (a component of classical nuclear import complex) and preventing translocation of ISGF3 (STAT1/STAT2/IRF-9) to the nuclei indirectly.98 ORF 6 appears to play an important role in assisting SARS-CoV to evade the host innate immune responses. When ORF 6 was expressed in the host cells, double-membrane structures were formed, recapturing features observed during viral replications.98,100 Together with the finding of colocalization of this protein with nonstructural protein nsp3, ORF 6 may also play a role in viral replication.99,100
Correlation of the transcription factors IRF4 and BACH2 with the abnormal NFATC1 expression in T cells from chronic myeloid leukemia patients
Published in Hematology, 2022
Yikai Zhang, Xiangbo Zeng, Xianfeng Zha, Jing Lai, Guangxiao Tan, Shaohua Chen, Xibao Yu, Yangqiu Li, Ling Xu
The IRF transcription factor family consists of nine members, IRF1 to IRF9. This family plays an important role in regulating innate and adaptive immune responses and tumorigenesis. IRF4 is closely related to IRF8 and was initially identified as a nuclear factor [50]. This protein plays an important role in the differentiation and functional regulation of CD4+ and CD8+ T cells [51]. In mice, Irf4 is necessary for the protective effects of CD8+ T cells during infection [35]. A recent study has further shown that IRF4 is an important regulatory factor in the formation of CD8+ memory T cells, and it is necessary for the effective reactivation of CD8+ T cells [36]. Moreover, the results predicted by hTFtarget database shown that IRF4 may regulate the expression of NFATC1, while our recent results have also demonstrated that NFATC1 is necessary for human CD8+ T cells to perform their normal immune function [30]. These results suggested that T cell dysfunction in CML patients may be associated with the reduced expression of IRF4 and NFATC1.
Type I interferon detection in autoimmune diseases: challenges and clinical applications
Published in Expert Review of Clinical Immunology, 2021
Vassilis E. Papadopoulos, Charalampos Skarlis, Maria-Eleftheria Evangelopoulos, Clio P. Mavragani
Type I IFNs transduce their signal through binding to IFNα/β receptor (IFNAR) (composed by two subunits, IFNAR1 and IFNAR2), leading to autophosphorylation of receptor-associated kinases, namely Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which are attached to IFNAR1 and IFNAR2, respectively. This leads to the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2, which consequently assemble, forming the STAT1/2 heterodimer. The latter binds to IRF9, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3). ISGF3 translocates to the nucleus where it binds to the interferon-stimulated response elements (ISRE) inducing their transcription and the subsequent upregulation of hundreds of interferon-stimulated genes (ISG) also known as IFN signature [9,11,12] (Figure 3).
New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors
Published in Immunological Medicine, 2020
The current review finally highlights the role of IFN-γ in the adverse events seen with JAK inhibition. An increased risk of herpes zoster is most specifically related to the use of JAK inhibitors among patients with RA or other immune-mediated diseases [56,57]. It is also worth noting that the risk of infection with other viruses, such as cytomegalovirus and Epstein-Barr virus, has not been increased with JAK inhibition [58], suggesting a special connection between JAK-STAT pathway and immunity to VZV. Given the findings that patients with multiple myeloma, which is associated with humoral immunity defects, present with increased herpes zoster incidence only after treatment with the proteasome inhibitor bortezomib [59], cell-mediated immunity may play a greater role than humoral immunity in the host defense against VZV. Both type I IFN and IFN-γ have been shown to act on the cells to restrict VZV replication and spread [60,61]. IFN-γ-IRF1 axis was more potent than IFN-α-IRF9 axis in blocking VZV infection of primary human fibroblasts [60]. Conversely, in some cell lines (e.g., MeWo melanoma cells), IFN-β, but not IFN-γ, exerted an anti-VZV activity [61]. The defensive role of type I IFN against VZV infection is also supported by a clinical trial revealing an increased incidence of herpes zoster with the use of anifrolumab, a human anti-type I IFN receptor monoclonal antibody, for patients with systemic lupus erythematosus [62]. The safety profiles of a JAK2 selective inhibitor fedratinib suggest a dominant role of JAK1 over JAK2 in the immune response against VZV [63,64].