Autoantibodies against ATP4A are a feature of the abundant autoimmunity that develops in first-degree relatives of patients with type 1 diabetes

Objective: Type 1 diabetes is associated with autoantibodies to different organs that include the gut. The objective of the study was to determine the risk of developing gastric parietal cell autoimmunity in relation to other autoimmunity in individuals with a family history of type 1 diabetes. Methods: Autoantibodies to the parietal cell autoantigen, H+/K+ ATPase subunit A (ATP4A) was measured in 2218 first-degree relatives of patients with type 1 diabetes, who were prospectively followed from birth for a median of 14.5 years. All were also tested regularly for the development of islet autoantibodies, transglutaminase autoantibodies, and thyroid peroxidase autoantibodies. Results: The cumulative risk to develop ATP4A autoantibodies was 8.1% (95% CI, 6.6–9.6) by age 20 years with a maximum incidence observed at age 2 years. Risk was increased in females (HR, 1.9; 95% CI, 1.3–2.8; p = 0.0004), relatives with the HLA DR4-DQ8/DR4-DQ8 genotype (HR, 3.4; 95% CI, 1.9–5.9; p < 0.0001) and in participants who also had thyroid peroxidase autoantibodies (HR, 3.7; 95% CI, 2.5– 5.5; p < 0.0001). Risk for at least one of ATP4A-, islet-, transglutaminase-, or thyroid peroxidase-autoantibodies was 24.7% (95% CI, 22.6–26.7) by age 20 years and was 47.3% (95% CI, 41.3–53.3) in relatives who had an HLA DR3/DR4-DQ8, DR4-DQ8/ DR4-DQ8, or DR3/DR3 genotype (p < 0.0001 vs. other genotypes). Conclusions: Relatives of patients with type 1 diabetes who have risk genotypes are at very high risk for the development of autoimmunity against gastric and other organs

Novel minor HLA DR associated antigens in type 1 diabetes

Type 1 diabetes is an autoimmune disease leading to insulin deficiency. Autoantibodies to beta cell proteins are already present in the asymptomatic phase of type 1 diabetes. Recent findings have suggested a number of additional minor autoantigens in patients with type 1 diabetes. We have established luciferase immunoprecipitation systems (LIPS) for anti-MTIF3, anti-PPIL2, anti-NUP50 and anti-MLH1 and analyzed samples from 500 patients with type 1 diabetes at onset of clinical disease and 200 healthy individuals who had a family history of type 1 diabetes but no evidence of beta cell autoantibodies. We show significantly higher frequencies of anti-MTIF3, anti-PPIL2 and anti-MLH1 in recent onset type 1 diabetes patients in comparison to controls. In addition, antibodies to NUP50 were associated with HLA-DRB1*03 and antibodies to MLH1 were associated with HLA-DRB1*04 genotypes.:1. Introduction 2. Material and methods 2.1 Participants 2.2. Cloning and expression of antigens 2.3. Luciferase ImmunoPrecipitation (LIPS) assays 2.4. Antinuclear antibodies (ANA) 2.5. Statistics 3. Results 4. Discussion 5. Conclusion Declaration of interest Funding Acknowledgements Appendix A Suplementary data Reference

Age, HLA, and Sex Define a Marked Risk of Organ-Specific Autoimmunity in First-Degree Relatives of Patients With Type 1 Diabetes

OBJECTIVE Autoimmune diseases can be diagnosed early through the detection of autoantibodies. The aim of this study was to determine the risk of organ-specific autoimmunity in individuals with a family history of type 1 diabetes. RESEARCH DESIGN AND METHODS The study cohort included 2,441 first-degree relatives of patients with type 1 diabetes who were prospectively followed from birth to a maximum of 29.4 years (median 13.2 years). All were tested regularly for the development of autoantibodies associated with type 1 diabetes (islet), celiac disease (transglutaminase), or thyroid autoimmunity (thyroid peroxidase). The outcome was defined as an autoantibody-positive status on two consecutive samples. RESULTS In total, 394 relatives developed one (n = 353) or more (n = 41) of the three disease-associated autoantibodies during follow-up. The risk by age 20 years was 8.0% (95% CI 6.8–9.2%) for islet autoantibodies, 6.3% (5.1–7.5%) for transglutaminase autoantibodies, 10.7% (8.9–12.5%) for thyroid peroxidase autoantibodies, and 21.5% (19.5–23.5%) for any of these autoantibodies. Each of the three disease-associated autoantibodies was defined by distinct HLA, sex, genetic, and age profiles. The risk of developing any of these autoantibodies was 56.5% (40.8–72.2%) in relatives with HLA DR3/DR3 and 44.4% (36.6–52.2%) in relatives with HLA DR3/DR4-DQ8. CONCLUSIONS Relatives of patients with type 1 diabetes have a very high risk of organ-specific autoimmunity. Appropriate counseling and genetic and autoantibody testing for multiple autoimmune diseases may be warranted for relatives of patients with type 1 diabetes. </jats:sec

Additional file 1: of Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence

Table S1. Performance of the autoantibody assays used in the BABYDIAB and BABYDIET studies in the international Diabetes Autoantibody Standardisation Programme (DASP) and the Islet Autoantibodies Standardisation Programme (IASP). Table S2. Landmark model of cumulative risks of developing islet autoantibodies and type 1 diabetes in children with the DR3/4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes. Table S3. Landmark model of cumulative risks of developing transglutaminase autoantibodies. Figure S1. One-phase exponential decay functions of single and multiple islet autoantibodies for 6-year (black) and 12-year follow-up (blue). The 6-year exponential decay functions are 5.9 × exp.(− 0.267 × age) and 5.3 × exp.(− 0.241 × age) for single and multiple autoantibodies respectively. The 12-year exponential decay functions are 7.8 × exp.(− 0.254 × age) and 6.6 × exp.(− 0.272 × age) for single and multiple autoantibodies respectively. Figure S2. Cumulative Risks of developing transglutaminase autoantibodies (total population (A) and children with DR3/3 genotype (B)) from birth (red), from 3.5 years of age (green), from 6.5 years (blue) and from 12.5 years (grey), and one-phase exponential decay curves for total cohort and the high risk HLA DR3-DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes (C). Figure S3. Cumulative risks of developing type 1 diabetes in multiple islet autoantibody positive children. The cumulative risks were calculated from 1.5 years (red), 3.5 years (green), 6.5 years (blue) and 12.5 years (grey) in children who were multiple islet autoantibody positive at the respective landmark. (DOC 441 kb

Yield of a public health screening of children for islet autoantibodies in Bavaria, Germany

Importance: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. Objective: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. Design, Setting, and Participants: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. Exposures: Measurement of islet autoantibodies. Main Outcomes and Measures: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; &gt;20 indicates severe depression). Results: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P &lt; .001). Conclusions and Relevance: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies