Association of IDDM and Attenuated Response of 2′,5′-Oligoadenylate Synthetase to Yellow Fever Vaccine

Abstract

Basal and yellow fever vaccination-induced 2',5'-oligoadenylate synthetase (2',5'A) activity was determined in blood mononuclear cells (peripheral blood lymphocytes [PBLs]) from insulin-dependent diabetes mellitus (IDDM) and matched control subjects. The live attenuated yellow fever vaccine represented a primary stimulus in all subjects. First, basal 2',5'A activity increased severalfold in response to yellow fever vaccination. In IDDM subjects, this increase was significantly lower (P = .025). Second, the 2',5'A activity increased proportionately to the higher basal 2',5'A activity in IDDM subjects. In control subjects, the increase in 2',5'A activity was not dependent on the basal activity. There was no relationship between basal or stimulated 2',5'A activity and age, sex, duration of IDDM, age at onset of IDDM, metabolic control, or HLA-DQ beta-chain gene polymorphism. There is a direct relationship between 2',5'A activity and latent viral infections associated with the presence of double-stranded RNA and with cellular interferons (IFNs) formed in response to viral infections. The higher basal 2',5'A activity (P = .05) in relation to the stimulated activity may therefore signify a latent infection or the presence of double-stranded RNA in PBLs of IDDM subjects. In vitro stimulation of PBLs showed increased IFN sensitivity in IDDM subjects. Analysis of 2',5'A activity is proposed to be a sensitive measure of the activation of the IFN system and the level of latent infectivity.

Increased Level of Interferon‐α in Blood of Patients with Insulin‐Dependent Diabetes Mellitus: Relationship with Coxsackievirus B Infection

“…Therefore, it can be produced spontaneously by cells but be undetectable in plasma, which may explain the results obtained for 3 patients in this study (IFNa mRNA positive, IFN-a-protein negative). The results of our experiments provide direct evidence for the activation of the IFN-a system and can explain that IFN-dependent 2 ,5 oligoadenylate synthetase activity was high in the blood lymphocytes of patients with IDDM in studies by Bonnevie-Nielsen et al [22,23].…”

Murine Pancreatic Beta TC3 Cells Show Greater2′,5′-Oligoadenylate Synthetase (2′5′<

“…We have also reported that the frequencies of genotypes carrying the genetic variant associated with elevated activity were significantly higher in individuals with type 1 diabetes than in nondiabetic control subjects [14]. Thus, our original findings of persistently elevated 2′5′AS activity in type 1 diabetes patients compared to controls [12, 13] were at least partly genetically determined. In other words, elevated 2′5′AS activity might be due to both genetic and environmental factors.…”

“…Recently we have described a new splice variant, adding a new enzyme isoform to this family: OAS1-p52 [11]. We have suggested that processes within the antiviral 2′5′AS system might contribute to the etiopathogenesis of type 1 diabetes [12]. In several independent studies, we observed significantly increased 2′5′AS activity in patients with type 1 diabetes compared to healthy controls [12, 13].…”

“…We have suggested that processes within the antiviral 2′5′AS system might contribute to the etiopathogenesis of type 1 diabetes [12]. In several independent studies, we observed significantly increased 2′5′AS activity in patients with type 1 diabetes compared to healthy controls [12, 13]. More recently, we found a highly significant association between basal 2′5′AS activity and an A/G splice acceptor site single nucleotide polymorphism (SNP) in the OAS1 gene, indicating that basal activity of this enzyme is strongly genetically controlled [11].…”

Yellow Fever

“…Levels of this enzyme are increased in lymphocytes by day 4 postvaccination and reach a maximum at day 7. This enzyme catalyzes the production of 2Ј-5Ј oligoadenylates, which activates latent RNAase, which degrades viral mRNA and impairs cellular protein synthesis ( Bonnevie-Nielsen et al, 1989. Natural killer cells have also been shown to play a role early in virus infection ( Fagraeus et al, 1982 ).…”