The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM. Arq Bras Endocrinol Metab. 2013;57(9):667-76 Keywords Autoimmunity; type 1 diabetes mellitus; viral infection; IFIH1 RESUMO O diabetes melito tipo 1 (T1DM) é uma doença autoimune crônica e progressiva caracterizada por descompensações metabólicas frequentemente acompanhadas por desidratação e cetoacidose. Os agentes virais parecem ter um papel importante no desencadeamento da destruição autoimune que leva ao desenvolvimento do T1DM. Entre as cepas virais estudadas até agora, a família dos enterovírus foi consistentemente associada ao surgimento da doença em humanos. Um dos mediadores do dano viral é o RNA fita dupla (RNAfd) gerado durante a replicação e transcrição de RNA e DNA viral. O gene IFIH1 codifica um receptor citoplasmático pertencente à família dos pattern-recognition receptors (PRRs) que reconhece o RNAfd, tendo um papel importante na resposta imune inata desencadeada por infecção viral. A ligação do RNAfd a essa PRR desencadeia a liberação de citocinas pró-inflamatórias como interferons (IFNs), os quais exibem uma potente ação antiviral e têm como objetivo proteger as células não infectadas e induzir apoptose naquelas já contaminadas. O gene IFIH1 parece ter uma participação importante no desenvolvimento de algumas doenças autoimunes. Por isso, esse gene é um candidato ao desenvolvimento do T1DM. Dentro desse contexto, o objetivo da presente revisão foi abordar o papel do IFIH1 no desenvolvimento do T1DM. Arq Bras Endocrinol Metab.2013;57(9):667-76 Descritores Autoimunidade; diabetes melito tipo 1; infecção viral; IFIH1

Toll‐like receptors signaling network in pre‐eclampsia: An updated review

“…In general, through recognition and attachment to pathogen‐associated molecular patterns (PAMPs) expressed on the surface or released by the pathogens, these effector cells result in the induction of the innate immune responses (Bouças, de Souza, Bauer, & Crispim, ).These procedures include: the production of chemokines which are chemo‐attractants for recruitment of immune cells to the site of injury and inflammation; secretion of inflammatory cytokines such as interleukin‐1 (IL‐1), IL‐6 and TNF‐α, and promoting the activation of other innate immune cells such as monocytes/macrophages and neutrophils in infectious conditions (Saito et al, ). PAMPs are recognized by a set of innate immunity receptors called pattern recognition receptors (PRRs) which consist of three major members including: Retinoic acid–inducible gene I (RIG‐I)‐like helicases (RLHs) typically capable of detecting dsRNA and triggering the innate antiviral responses (Bouças, Oliveira Fdos, Canani, & Crispim, ; Wilkins & Gale, ). NODlike receptors (NLRs) such as NOD1 and NOD2 that promote autophagy and inflammatory signaling to remove pathogens in host cells, and different members of the NLRP family that participate in the formation of inflammasome complexes (Liu, Rhebergen, & Eisenbarth, ). TLRs play a key role in the innate immune system through the production of Type I interferon (IFN‐I) and activation of mitogen‐activated protein kinase (MAPK), activator protein 1 (AP1), nuclear factor‐κB (NF‐kB) signaling pathways (Bouças et al, ).…”

Role of Innate Immunity in Preeclampsia: A Systematic Review

“…IFIH1 and RIG-I are cytoplasmic PRRs that recognize different intracellular dsRNAs generated during viral replication. 8 After binding with dsRNA, IFIH1 and RIG-I will activate signaling pathways leading to NF-κB and interferon regulatory factor (IRF)-3 activation, ultimately driving the production of pro-inflammatory cytokines, chemokines, and IFN-I. Then, IFN-I binds to its receptor and activates the JAK/STAT pathway to drive the expression of IFN-regulated genes and the innate immune response.…”

“…Then, IFN-I binds to its receptor and activates the JAK/STAT pathway to drive the expression of IFN-regulated genes and the innate immune response. 8,9,49 The role of IFIH1 and RIG-I in PE is still uncertain since only 1 study investigated these receptors in cases and controls 15 (Table 1). No study has evaluated the association between polymorphisms in IFIH1 or RIG-I genes and PE.…”

“…Detection of invading microorganisms is carried out by pattern recognition receptors (PRRs), which recognize highly conserved pathogen-associated molecular patterns (PAMPs) derived from virus, bacteria, and fungi. 6,7 Three groups of PRRs are known: (1) retinoic acidinducible gene I (RIG-I)-like helicases (RLHs) that recognize double-stranded RNA (dsRNA) derived from viral RNA, playing a role in the immune response triggered by viral infections 8,9 ; (2) nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), including NOD1 and NOD2 that induce autophagy processes, and different NLRPs, which regulate inflammasome formation, leading to caspase-1 activation, and consequent cleavage of the cytokines interleukin (IL)-1b and IL-18 into their active forms 10 ; (3) toll-like receptors (TLRs) that recognize different triggers derived from bacterial, viral, and fungal cell wall components, activating a variety of cellular responses including the production of type I interferon (IFN-I) and activation of nuclear factor KB (NF-kB) and mitogen-activated protein kinases (MAPK) pathways. [11][12][13][14] Innate immunity dysfunction in women with PE may be triggered by invading microorganisms as well as endogenous danger-associated molecular patterns (DAMPs).…”

Human gene polymorphisms and their possible impact on the clinical outcome of SARS-CoV-2 infection

“…The IFN induced with helicase C domain 1 (IFIH1) gene is located on chromosome 2q24.2, is induced by IFN type I, and encodes MDA5, an intracellular sensor of viral RNA [117]. It has been reported that the lower frequency of the T allele at the locus rs1990760 of IFIH1 in the African-American population might be associated with COVID-19 infection outcome due to decreased expression of IFN-β [118].…”