Cross-reactive immune responses between enteroviruses and islet cell autoantigens

Ohjaaja Merja Roivainen/MIBO/ENV

The novel hexapeptide motif found in the acyltransferases LpxA and LpxD of lipid A biosynthesis is conserved in various bacteria

AbstractTwo bacterial acyltransferases (LpxA of Escherichia coli, LpxD of E. coli and Salmonella typhimurium) have previously been shown to consist of a very unusual tandem-repeat structure with tens of repeating hexapeptides (24 hexapeptides in LpxA, 26 in LpxD). By sequencing LpxD of Yersiniaenterocolitica (a distant relative of E. coli and S. typhimurium within Enterobacteriaceae) as well as LpxA of S. typhimurium and Y. enterocolitica, and by analyzing the existing data on these enzymes of Ricketsiarickettsii, it was now shown that the hexapeptide repeat pattern is a very conservative property of these enzymes. Even though the overall homology (allowing equivalent amino acids) between the four proteins was only 59% in LpxA and 58% in LpxD, the homology in the first residue of each hexapeptide was 87% in LpxA and 100% in LpxD. Secondary structure prediction by PredictProtein server suggested a very strong beta strand dominance in all the hexad regions. Accordingly, LpxA and LpxD of various bacterial origins can now be regarded as structurally very unusual enzymes, largely consisting of hexad repeats

Increased HLA class II risk is associated with a more aggressive presentation of clinical type 1 diabetes

Peer reviewe

Probiotic intervention in infancy is not associated with development of beta cell autoimmunity and type 1 diabetes

Non peer reviewe

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes

Aims/hypothesis Shared aetiopathogenetic factors have been proposed in type 1 diabetes and type 2 diabetes and both diseases have been shown to cluster in families. Characteristics related to type 2 diabetes have been described in patients with type 1 diabetes with a positive family history of type 2 diabetes. We wanted to characterise the family history of type 2 diabetes and its possible effects on the phenotype and genotype of type 1 diabetes in affected children at diagnosis. Methods A total of 4993 children under the age of 15 years with newly diagnosed type 1 diabetes from the Finnish Pediatric Diabetes Register were recruited (56.6% boys, median age of 8.2 years) for a cross-sectional, observational, population-based investigation. The family history of diabetes at diagnosis was determined by a structured questionnaire, and markers of metabolic derangement, autoantibodies and HLA class II genetics at diagnosis were analysed. Results Two per cent of the children had an immediate family member and 36% had grandparents with type 2 diabetes. Fathers and grandfathers were affected by type 2 diabetes more often than mothers and grandmothers. The children with a positive family history for type 2 diabetes were older at the diagnosis of type 1 diabetes (p <0.001), had higher BMI-for-age (p = 0.01) and more often tested negative for all diabetes-related autoantibodies (p = 0.02). Conclusions/interpretation Features associated with type 2 diabetes, such as higher body weight, older age at diagnosis and autoantibody negativity, are more frequently already present at the diagnosis of type 1 diabetes in children with a positive family history of type 2 diabetes.Peer reviewe

Seasonality in the manifestation of type 1 diabetes varies according to age at diagnosis in Finnish children

Aim We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during fall and winter, the colder seasons with consistently observed higher incidence of type 1 diabetes. Methods Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents. Metabolic characteristics, beta-cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis. Results Significant seasonality was observed with higher number of new cases during fall and winter (n = 1353/27.1% and n = 1286/25.8%) compared with spring and summer (n = 1135/22.7% and n = 219/24.4%) (p < 0.001). The youngest children (aged 0.5-4 years) differed from the older ones (aged 5-14 years) as a minority of them were diagnosed in winter (p = 0.019) while the older children followed the same pattern as that seen in the total series. Poorer metabolic decompensation was observed during seasons with lower number of new diagnoses. Conclusion The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.Peer reviewe

Autoantibodies to N-terminally Truncated GAD(65)(96-585) : HLA Associations and Predictive Value for Type 1 Diabetes

Objective To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD(65)(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. Design In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD(65) (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). Conclusions Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.Peer reviewe

T Cell Epitopes in Coxsackievirus B4 Structural Proteins Concentrate in Regions Conserved between Enteroviruses

AbstractThe present study aimed to characterize systematically the target epitopes of T cell responses in CBV4 structural proteins. These were studied by synthesizing 86 overlapping 20-aa-long peptides covering the known sequence of CBV4 structural proteins and analyzing the proliferation responses of 18 CBV4-specific T cell lines against these peptides. Recognized peptides differed depending on the HLA-DR genotype of the T cell donor. They were concentrated to the VP4 and VP2 regions as six of seven common peptide epitopes located in this region, whereas there was only one in the VP3 region and none in the VP1 region. Peptides from conserved areas were recognized more often (on average, 15% of them stimulated each T cell line) than those derived from variable areas (3%) (P < 0.0001, Fisher's exact test). Some conserved peptides inducing T cell responsiveness in most subjects were identified, a knowledge which can be useful in the development of new synthetic vaccines

Seasonality in the manifestation of type 1 diabetes varies according to age at diagnosis in Finnish children

Aim: We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during fall and winter, the colder seasons with consistently observed higher incidence of type 1 diabetes.Methods: Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents. Metabolic characteristics, beta-cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis.Results: Significant seasonality was observed with higher number of new cases during fall and winter (n = 1353/27.1% and n = 1286/25.8%) compared with spring and summer (n = 1135/22.7% and n = 219/24.4%) (p Conclusion: The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.</p

Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

Objectives We aimed to further characterize demography and genetic associations of type 1 diabetes "endotypes" defined by the first appearing islet specific autoantibodies. Research Design and Methods We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity.Peer reviewe