Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Aims/hypothesis Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes. Methods We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes. Results We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p Conclusions/interpretation Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset.Peer reviewe

Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Aims/hypothesis Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes.Methods We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes.Results We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p</p

Association between Dopamine Receptor D2 (DRD2) Variations rs6277 and rs1800497 and Cognitive Performance According to Risk Type for Psychosis : A Nested Case Control Study in a Finnish Population Sample

Background There is limited research regarding the association between genes and cognitive intermediate phenotypes in those at risk for psychotic disorders. Methods We measured the association between established psychosis risk variants in dopamine D2 receptor (DRD2) and cognitive performance in individuals at age 23 years and explored if associations between cognition and these variants differed according to the presence of familial or clinical risk for psychosis. The subjects of the Oulu Brain and Mind Study were drawn from the general population-based Northern Finland 1986 Birth Cohort (NFBC 1986). Using linear regression, we compared the associations between cognitive performance and two candidate DRD2 polymorphisms (rs6277 and rs1800497) between subjects having familial (n=61) and clinical (n=45) risk for psychosis and a random sample of participating NFBC 1986 controls (n=74). Cognitive performance was evaluated using a comprehensive battery of tests at follow-up. Results Principal components factor analysis supported a three-factor model for cognitive measures. The minor allele of rs6277 was associated with poorer performance on a verbal factor (p=0.003) but this did not significantly interact with familial or clinical risk for psychosis. The minor allele of rs1800497 was associated with poorer performance on a psychomotor factor (p=0.038), though only in those at familial risk for psychotic disorders (interaction p=0.049). Conclusion The effect of two DRD2 SNPs on cognitive performance may differ according to risk type for psychosis, suggesting that cognitive intermediate phenotypes differ according to the type (familial or clinical) risk for psychosis.Peer reviewe

Optic nerve parameters and cognitive function in the Northern Finland Birth Cohort Eye study

Abstract Purpose: The optic nerve head (ONH) is a part of the brain that can be easily studied through the transparent medium of the eye. We explored the relationship between the properties of the optic nerve head, the retinal nerve fiber layer (RNFL) and cognitive function. Methods: Participants of the Northern Finland Birth Cohort (NFBC) 1966 underwent an ophthalmic and cognitive assessment after randomization at age 46. The ophthalmological parameters obtained were the disc area and the neuroretinal rim volume of the ONH and the average RNFL thickness. The surrogates used for cognitive function were the paired associates learning test (PAL), level of education, grade point average (GPA) and Humphrey 24–2 perimetric test time (HFA). We did exploratory research between the ophthalmological parameters and the surrogates for cognition and the correlations between the surrogates for cognition. Results: We found that a larger disc area was associated with a higher level of education, faster accomplishment of the HFA (R = −0.065) but a lower GPA (R = −0.084). An increase in neuroretinal rim volume was associated with fewer errors in the PAL test (R = −0.056), higher level of education, higher GPA (R = 0.072) and faster accomplishment of the HFA (R = −0.047). A thicker RNFL was associated with faster accomplishment of the HFA (R = −0.047). Conclusion: We were able to find statistically significant associations between the parameters of the optic nerve head, the RNFL and cognition in the NFBC Eye study. However, the correlations were negligible at best and of limited predictive value

Cytokine data obtained from synovial stromal cells of patients with rheumatoid arthritis or osteoarthritis

Abstract In this article, we share the raw cytokine data obtained from basal and stimulated synovial stromal cells cultured from patients with rheumatoid arthritis or osteoarthritis. This data article is related to the research article entitled “1,25D₃ and calcipotriol, its hypocalcemic analog, exert a long-lasting anti-inflammatory and anti-proliferative effect in synoviocytes cultured from patients with rheumatoid arthritis and osteoarthritis (1). Cytokine levels were analyzed by a magnetic bead–based multiplex assay (a panel of 27 important cytokines) in two separate sets of experiments. The first was conducted with IL-1β and 1,25(OH)₂D₃ and the other with TNFα, calcipotriol, i.e. the hypocalcemic analog 1,25(OH)₂D₃, and dexamethasone. The raw data of this article display the individual variation in basal secretion of cytokines and in their response to different stimuli

DNA methylation differences within INS, PTPN22 and IL2RA promoters in lymphocyte subsets in children with type 1 diabetes and controls

Abstract We elucidated the effect of four known T1D-susceptibility associated single nucleotide polymorphism (SNP) markers in three genes (rs12722495 and rs2104286 in IL2RA, rs689 in INS and rs2476601 in PTPN22) on CpG site methylation of their proximal promoters in different lymphocyte subsets using pyrosequencing. The study cohort comprised 25 children with newly diagnosed T1D and 25 matched healthy controls. The rs689 SNP was associated with methylation at four CpG sites in INS promoter: −234, −206, −102 and −69. At all four CpG sites, the susceptibility genotype AA was associated with a higher methylation level compared to the other genotypes. We also found an association between rs12722495 and methylation at CpG sites −373 and −356 in IL2RA promoter in B cells, where the risk genotype AA was associated with lower methylation level compared to the AG genotype. The other SNPs analyzed did not demonstrate significant associations with CpG site methylation in the examined genes. Additionally, we compared the methylation between children with T1D and controls, and found statistically significant methylation differences at CpG −135 in INS in CD8+ T cells (p = 0.034), where T1D patients had a slightly higher methylation compared to controls (87.3 ± 7.2 vs. 78.8 ± 8.9). At the other CpG sites analyzed, the methylation was similar. Our results not only confirm the association between INS methylation and rs689 discovered in earlier studies but also report this association in sorted immune cells. We also report an association between rs12722495 and IL2RA promoter methylation in B cells. These results suggest that at least part of the genetic effect of rs689 and rs12722495 on T1D pathogenesis may be conveyed by DNA methylation

Heterogeneity in the presentation of clinical type 1 diabetes defined by the level of risk conferred by human leukocyte antigen class II genotypes

Abstract Objectives: The association between human leukocyte antigen (HLA) class II genotypes and susceptibility to type 1 diabetes (T1D) is well established. This study aimed at examining whether there are differences in the presentation of T1D depending on the HLA genotype. Research Design and Methods: We divided the study participants (N = 5798) in the Finnish Pediatric Diabetes Register into two groups based on the T1D risk conferred by their HLA genotype (high and moderate-risk genotypes, Group 1 vs. other genotypes, Group 2). We then examined differences in clinical, metabolic, and immunological characteristics. Children included in the study were 0–14-year-old and diagnosed between January 2003 and December 2019. Results: Participants in Group 1 were younger at the time of diagnosis (P &lt; 0.001) and had more frequently family members affected by T1D (P &lt; 0.001). Diabetic ketoacidosis (DKA) was more frequent among participants in Group 2 (P = 0.014) who also had a longer duration of symptoms before diagnosis (P &lt; 0.001) and higher hemoglobin A1c (P = 0.001) at diagnosis. The HLA genotype was not, however, directly related to the DKA frequency. The frequency of islet cell antibodies (P &lt; 0.003), insulin autoantibodies (P &lt; 0.001), and islet antigen 2 autoantibodies (P &lt; 0.001) was higher in Group 1 whereas glutamic acid decarboxylase autoantibodies were more frequent (P &lt; 0.001) in Group 2. Group 1 had more participants with multiple autoantibodies (P = 0.027) whereas antibody negativity was more frequent in Group 2 (P = 0.003). Conclusions: These findings indicate disease heterogeneity in relation to both clinical disease presentation and humoral autoimmunity, in particular. This heterogeneity is, at least partly, defined by HLA Class II genotypes

HLA‐DQ‐conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine

Abstract This study investigated whether children with HLA-DQ-conferred risk for type 1 diabetes (T1D) have an altered immune response to the widely-used enterovirus vaccine, namely poliovirus vaccine, and whether initiation of autoimmunity to pancreatic islets modulates this response. Neutralizing antibodies induced by the inactivated poliovirus vaccine against poliovirus type 1 (Salk) were analysed as a marker of protective immunity at the age of 18 months in a prospective birth cohort. No differences were observed in antibody titers between children with and without genetic risk for T1D (odds ratio [OR] = 0.90 [0.83, 1.06], p = 0.30). In the presence of the genetic risk, no difference was observed between children with and without islet autoimmunity (OR = 1.00 [0.78, 1.28], p = 1.00). This did not change when only children with the autoimmunity before 18 months of age were included in the analyses (OR = 1.00 [0.85, 1.18], p = 1.00). No effect was observed when groups were stratified based on autoantigen specificity of the first-appearing autoantibody (IAA or GADA). The children in each comparison group were matched for sex, calendar year and month of birth, and municipality. Accordingly, we found no indication that children who are at risk to develop islet autoimmunity would have a compromised humoral immune response which could have increased their susceptibility for enterovirus infections. In addition, the proper immune response supports the idea of testing novel enterovirus vaccines for the prevention of T1D among these individuals