Down syndrome and Diabetes - Insights into rapid progression to Type 1 Diabetes

Abstract

People with Down syndrome (DS) are more likely to develop autoimmune conditions, including type 1 diabetes (T1D), compared to the general population. Type 1 diabetes can be accurately predicted by the presence of two or more islet autoantibodies in the blood. We hypothesised that, risk factors which can lead to the development of islet autoantibodies such as increased genetic risk and atypical pancreas function are present in individuals with DS and underlie the susceptibility to autoimmunity. By using a genetic risk score we found individuals with DS who developed T1D had increased genetic risk in comparison with those
with DS alone. This increased genetic risk was not associated with age at diagnosis of T1D. A biomarker of pancreas function, the enzyme Trypsin(ogen), was reduced in those with DS who had T1D but not DS alone. This suggests that similar to T1D, pancreas function, is reduced in DS with T1D but is not a unique feature of DS alone.

To measure autoantibodies linked to gut and thyroid autoimmunity, new Luciferase Immunoprecipitation system (LIPS) tests were optimised. Thresholds were set using general population controls and methods were tested using clinical cohorts including a birth cohort of children with DS. Feeding and Autoimmunity evaluation in children with Down’s Syndrome Evaluation Study (FADES) recruited 116 children from birth with sampling and questionnaire follow-up to seven years of age or the end of the study. Screening showed
that autoantibodies appeared in early life with some having Thyroid autoimmunity at three months of age and Coeliac autoimmunity at two years of age. Islet autoantibodies were found at high frequency, 9/71 (12.7%) of children with available blood samples, multiple autoantibodies in one child (1.4%) prior to two years of age higher than observed in children from the general population (0.31%). These children were all under five years of age, confirming that islet autoimmunity and non-islet autoimmunity is initiated in early life in children with DS. Interestingly, few of these children had the established T1D associated HLA risk genes, with none having high-risk combination of HLA DR3/4. Instead, three children had protective HLA haplotypes.

Lastly, two hypotheses for pathways to developing autoimmunity in DS were explored. We previously reported individuals with DS had raised levels of antibodies against Bovine Serum Albumin (BSA). We hypothesised that increased gut permeability was leading to more translocation of antigen across the intestinal lumen and that in children with DS, presence of these antibodies was linked to a failure of tolerance in early life. In those with DS who developed T1D, there were increased levels of the enterocyte protein Intestinal Fatty
Acid Binding protein (I-FABP), but this was not observed in DS alone compared with controls. We also found that the levels of the antibodies to BSA were increased in children with DS but also present in children who went onto develop T1D and controls in early life.

The experiments described in this thesis demonstrate multiple experimental approaches and provide strong evidence for the early development of autoimmunity in children with DS. These children need to be considered in population screening efforts and emerging treatments to delay autoimmune conditions.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kathleen M Gillespie (Supervisor), Anna E Long (Supervisor) & Julian P Hamilton-Shield (Supervisor)