Riitta Veijola

Background: Daycare attendance and breastfeeding have been associated with asthma risk. However, it remains unclear whether the association between breastfeeding and asthma risk depends on daycare attendance. We investigated whether daycare attendance acts as a modifier in the relationship between breastfeeding and asthma risk. Methods: We included 72,558 children from the MoBa and 3015 children from the DIPP studies. Current asthma at age 7 years in MoBa and time to asthma by the age 5 years in DIPP were analyzed. Results: In both cohorts, approximately 4% of participants were diagnosed with asthma. In MoBa, breastfeeding was associated with lower risk of overall asthma (adjusted risk ratio, aRR 0.99 [95% CI, 0.98–1.00]) and nonatopic asthma (aRR 0.97 [95% CI, 0.96–0.99]) in children who had attended daycare by the age of 18 months, and it was associated with higher overall asthma (aRR 1.01 [95% CI, 1.00–1.02]) and atopic asthma risk (aRR 1.03 [95% CI, 1.01–1.06]) in children who had not attended daycare by that age (all interaction p values ≤.05). In DIPP, the duration of breastfeeding was inversely associated with risk of atopic asthma only in an exploratory analysis in those who had started daycare by the age of 12 months (adjusted hazard ratio, aHR 0.75 [95% CI, 0.59–0.95]) but not in children who had started daycare at the age of 13–24 months (adjusted hazard ratio, aHR 1.03 [95% CI, 0.96–1.10]) or had not started daycare by the age of 24 months (adjusted hazard ratio, aHR 1.00 [95% CI, 0.94–1.06]) (interaction p value .04). Conclusions: While the primary analysis in the MoBa study suggested that age at daycare entry might mildly modify the association of breastfeeding with asthma risk, in the DIPP study an interaction only appeared in an exploratory analysis with limited atopic asthma cases. Consequently, these findings represent inconsistent evidence. image

CTLA-4 is an inhibitory receptor on T cells that limits immune activation by competing with the co-stimulatory receptor CD28 for binding to CD80 and CD86 on antigen-presenting cells. Regulatory T cells (Tregs) employ CTLA-4–mediated transendocytosis as a key suppressive mechanism. Several CTLA4 polymorphisms are associated with autoimmune disease risk and may modulate CTLA-4 expression and function. Here, we analyzed samples from 155 genotyped subjects using flow cytometry and functional assays to determine how haplotypes formed by 3 CTLA4 single-nucleotide polymorphisms shape T-cell phenotype and function ex vivo. The autoimmune-protective CTLA4 rs5742909-rs231775-rs3087243 CAA haplotype was linked to increased intracellular CTLA-4 expression in both Tregs and conventional CD4+ T cells compared with CGG, CAG, and TAG haplotypes, implicating rs3087243 as the likely causal variant. The CAA haplotype was also associated with increased Treg frequencies. In Tregs from CAA/CAA subjects, elevated steady-state CTLA-4 expression promoted enhanced early CTLA-4 surface mobilization following anti-CD3/anti-CD28 stimulation. Moreover, naïve Tregs from CAA/CAA subjects more effectively suppressed naïve CD4+ T-cell proliferation in the presence of CD80/CD86-expressing dendritic cells. Collectively, these findings indicate that the rs3087243-A–linked CAA haplotype is associated with increased CTLA-4 expression and enhanced Treg function, providing a mechanistic explanation for its protective association with autoimmunity.

Background: The external environment, including toxicants, remains largely unexplored in celiac disease (CeD). Some of the per- and polyfluoroalkyl substances (PFAS) have immune-toxic properties and may play a role in the development of autoimmune diseases.Methods: In case-control studies nested in the Norwegian MoBa and the Finnish DIPP cohorts, children with CeD were identified by case-finding (n=349, MoBa) or screening with clinical ascertainment (n=129, DIPP). Cohort controls were randomly selected (n=324, MoBa) or matched by age, sex and place of birth (n=273, DIPP). Blood samples were collected at birth (cord blood, MoBa) or at the age of 6 months (DIPP) and 15 PFAS compounds were measured using liquid chromatography mass spectrometry. The sum of four common PFASs (PFOS + PFOA + PFHxS + PFNA = PFAS4) were the primary exposure in logistic regression models, adjusted for parity, maternal education, breastfeeding (DIPP) and other covariates.Findings: The cord blood PFAS4 concentration in MoBa was similar between cases (mean 8·47 ng/mL; SD 3·60) and controls (8·63; 4·21), and the adjusted odds ratio for CeD per unit increase was 0·99 (95% CI 0·95–1·04). In DIPP, the serum PFAS4 concentration at the age of 6 months was also similar between cases (13·30 ng/mL; SD 10·47) and controls (13·61; SD 10·29), and the adjusted odds ratio per unit increase was 1·00 (0·97–1·03). None of the specific PFASs (PFOS, PFOA, PFHxS, PFNA) were associated with CeD in MoBa or DIPP. The PFAS4 concentrations were significantly lower by increasing birth year and parity.Interpretation: The findings suggest that pre- and postnatal exposure to the environmental toxicant PFAS does not contribute to the risk of CeD in childhood. The findings were robust across cohorts and exposure pathways. Funding Funded by a grant from EU Horizon 2020.

Background: The urbanization of African populations adopting Westernized lifestyles might be connected to changes in microbial exposure and immune system activity that are harmful to health and increase the risk of non-communicable diseases, such as immune-mediated diseases. The study aims to compare microbial exposure, immune system markers, and gut microbiota between rural African and Westernized Northern European children to delineate whether there are differences present in these factors in early childhood. Methods: We compared innate immune cytokines in plasma (IL-10, IL-6, IL-1β, and TNF-α) using Luminex, gut microbiota using 16S rRNA sequencing, and microbial infections using qPCR in early childhood longitudinal sample series of children from rural Africa (participants from the iLINS-DYAD-M study conducted in Malawi) and from Northern Europe (participants from the DIPP study conducted in Finland) to identify differences which could be associated with negative health outcomes in Westernized societies. Results: Here, we show that the levels of plasma cytokines and frequency of stool pathogen positivity are substantially higher in Malawian than in Finnish children and that some of the cytokines differ in their longitudinal pattern between the two groups. Also, the diversity and composition of gut microbiota differ between the groups at the age of 6 months and diverge more with increasing age. Conclusions: These results highlight the early emergence of differences in the immune system and gut microbiota between children living in extremities of the microbial exposure gradient. These differences add to the existing knowledge of possible factors contributing to increasing prevalence of chronic inflammatory diseases in African societies shifting towards more Westernized lifestyle.

Aims/hypothesis: In this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes. Methods: Data on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes. Results: During the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins. Conclusions/interpretation: High intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity. Graphical

Aims/hypothesis: The aetiology of type 1 diabetes remains elusive. Family history of type 1 diabetes increases the disease risk but the role of other autoimmune diseases or type 2 diabetes in the family are unclear. Here, we aimed to analyse the effect of family history of diabetes and autoimmune diseases on development of islet autoimmunity and progression to type 1 diabetes. Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective observational cohort study of children recruited as newborns in 2004–2010 at clinical centres in Finland, Germany, Sweden and the USA. A total of 8676 children with high-risk HLA-DR-DQ genotype for type 1 diabetes fulfilled the eligibility criteria for regular follow-up. Questionnaire-based family history of all types of diabetes and autoimmune diseases among first- and second-degree relatives (FDRs and SDRs; data available for 8558 and 7479 children, respectively) was collected. The main outcomes were development of islet autoimmunity and progression from autoimmunity to type 1 diabetes. Data until 31 January 2016 were analysed. Results: Persistent islet autoantibodies were found in 669 children and type 1 diabetes in 233 children (45% and 46% female sex, respectively). The median follow-up time after seroconversion was 6.5 years (IQR 3.3–8.5). Having an FDR with type 1 diabetes increased the child’s risk of islet autoimmunity (HR 2.2 [95% CI 1.8, 2.8]; p p =0.017). Notably, progression from autoantibody positivity to type 1 diabetes was significantly delayed in children having type 2 diabetes in an SDR (HR 0.61 [95% CI 0.44, 0.86]; p =0.004). Islet autoimmunity or progression to type 1 diabetes were not associated with other types of diabetes or autoimmune diseases in the family. Conclusions/interpretation: Family history of diabetes is differentially associated with development of islet autoimmunity and progression to type 1 diabetes. The contribution made by familial, genetic and environmental factors to the two phases of the disease pathogenesis deserves distinct analyses. Data availability: Data reported here can be obtained by request at the NIDDK Central Repository website, Resources for Research (R4R), https://repository.niddk.nih.gov/ . Graphical

Aims/hypothesis: Islet autoimmunity during presymptomatic type 1 diabetes is heterogeneous. We hypothesised that a positive family history of type 1 diabetes is associated with specific characteristics of the autoimmune process resulting in clinical diabetes. In a prospective birth cohort study, we compared the initiation and evolution of islet autoimmunity and the rate of progression from islet autoimmunity to diabetes between children with and without a first-degree relative (FDR) with type 1 diabetes. Methods: In the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study, we prospectively followed children with HLA-conferred susceptibility from birth for the appearance of islet autoantibodies (IAA, GADA, IA-2A, ZnT8A), further development of islet autoimmunity, and progression to clinical diabetes. The presence of type 1 diabetes among their FDRs was recorded at the time of birth, and the family history data was updated during the follow-up period. Results: Among a total of 1334 children with confirmed positivity for at least one islet autoantibody, 145 (10.9%) had one or more FDRs with type 1 diabetes at the time of birth (FDR+). During a median follow-up period of 8.6 years, FDRs of an additional 87 children developed type 1 diabetes (FDR− FDR+). At seroconversion, both FDR+ and FDR− FDR+ children were significantly more often positive for GADA and multiple autoantibodies than children without affected FDRs (FDR−). The seroconversion age was similar between the three groups (median 2.7 vs 2.1 vs 3.0 years in FDR+, FDR− FDR+ and FDR− children, respectively). During the follow-up period, FDR+ and FDR− FDR+ children more often had IAA, GADA, IA-2A and multiple autoantibodies than FDR− children, and progressed more frequently to diabetes (55.9 vs 57.5 vs 38.9%, respectively). Time from seroconversion to clinical diabetes was significantly shorter in FDR+ children compared with FDR− children (2.7 vs 3.6 years). Children with paternal type 1 diabetes at birth ( n =71; i.e., the father had type 1 diabetes) were twice as often positive for multiple autoantibodies at seroconversion as those with maternal type 1 diabetes ( n =50; i.e. the mother had type 1 diabetes) (39.4% vs 20.0%). Conclusions/interpretation: At seroconversion, genetically susceptible children who had one or more FDRs with type 1 diabetes, especially an affected father, were more often positive for GADA and multiple islet autoantibodies. During the follow-up period, children with an affected FDR were more often positive for IAA, GADA and IA-2A, and progressed to clinical type 1 diabetes more often and faster than children without an affected FDR. These data should be considered when designing intervention and screening studies. Graphical

Context: Autoimmune destruction of β cells and their functional decline precedes the clinical onset of type 1 diabetes. However, altered α-cell function and hyperglucagonemia may contribute to the development of hyperglycemia and ketoacidosis at onset. Objective: In this cross-sectional study, we analyzed glucagon concentrations during an oral glucose tolerance test (OGTT) in individuals at the early stages of type 1 diabetes to understand the role of α-cell function in the disease process. Methods: We recruited 47 participants, aged 4 to 25 years, from the Finnish Diabetes Prediction and Prevention (DIPP) study, and categorized them into the following groups: islet autoantibody (IAb) negative, single IAb positive, and stages 1 to 3 of type 1 diabetes. Glucagon levels were measured during a 6-point OGTT using a conventional radioimmunoassay, alongside insulin, C-peptide, glucose, and glucagon-like peptide-1 (GLP-1). Results: Fasting plasma glucagon levels increased with disease progression. The longitudinal patterns of glucagon concentrations during the OGTT differed significantly between groups, with a paradoxical 15-minute glucagon increase observed only in individuals at early stage 3 of type 1 diabetes. Conclusion: These findings highlight the need for prospective studies to further elucidate the role of α cells in disease progression and support testing pharmacotherapies aimed at improving both α- and β-cell functions during disease development.

Purpose: A randomized clinical trial was conducted to evaluate the impact of a gluten-free diet (GFD) on β-cell function and glucose tolerance in persons with multiple islet autoantibodies. Methods: Individuals (n = 59; median age 11 years) with multiple islet autoantibodies were recruited to a randomized clinical trial between April 2016 and April 2021. The participants were randomized to a GFD (n = 30; female n = 14) or a normal diet (ND) (n = 29; female n = 16). The study was conducted at 6 clinical research centers in Finland and Sweden, with a dietary intervention for 17 months followed by a 6-month washout on a ND. The primary outcomes were (1) the proportion of participants going from normal glucose tolerance at the time of the randomization to abnormal glucose tolerance by 18 months, (2) a change in first-phase insulin response in IV glucose tolerance tests between randomization and 18 months, and (3) a change in C-peptide area under the curve in oral glucose tolerance test between randomization and 18 months. Results: We did not find differences between participants randomized to GFD and ND in any of the glucose tolerance outcomes. No serious adverse events or adverse events related to a GFD were noted. Conclusion: Being on a GFD was not found to differ from being on a ND in preserving β-cell function or maintaining normal glucose tolerance in persons with multiple islet autoantibodies.