Heterogeneity of Type 1 diabetes in children

Ahmad Gazali PhD candidate, University of Eastern Finland

Type 1 diabetes (T1D) is an autoimmune disease where the pancreatic β cells that produce insulin, a key hormone involved in the regulation of carbohydrate metabolism, are destroyed through dysregulated immune responses.

Clinical manifestations of T1D

In humans, the clinical manifestation of T1D is typically preceded by a preclinical phase in which diabetes-associated autoantibodies (DAAs) can be detected in the circulation (1), also known as early pre-diabetic stage. Shortly before the manifestation of clinical diabetes, children with circulating DAA exhibit impaired glucose tolerance (IGT) in oral glucose test (OGT) and this stage is known as late pre-diabetic stage (2). Eventually, patients become wholly dependent on exogenous insulin administration to regulate carbohydrate metabolism, a palliative treatment that bears an important social and economic impact.

Unravelling T1D

Despite advances in biomedical research, no cure has been found so far to prevent, slow down or treat T1D, partly because the exact immune pathways that lead to the destruction of pancreatic insulin-producing β-cells still remain elusive. Importantly, unraveling the autoimmune mechanisms involved in the onset of T1D is hampered by the inter-individual heterogeneity of those processes: although patients exhibit similar symptoms and disease progression, varied pathways of β-cell destruction can be at work.

Inter-individual heterogeneity

The most striking evidence of inter-individual heterogeneity relies on the disease progression rate from pre-diabetic to clinical diabetes which allows clinicians to divide patients into two categories: rapid progressors (< 6 months from pre-diabetes to clinical diabetes) versus slow progressors (up to several years from pre-diabetes to clinical diabetes) (3). Furthermore, heterogeneity can be observed at all stages of T1D. For instance, in the early pre-diabetic stage, both the antigen-specificity of disease-associated primary autoantibodies (insulin or glutamic acid decarboxylase) (4) and the affinity of those antibodies influence the progression rate of T1D (5).

Similarly, in the late pre-diabetic stage, follicular T helper cells (TfH), a subset of T cells crucial to B lymphocytes activation, have been shown to be preferentially expanded in the blood of patients with IGT exhibiting two or more DAA, but not in IGT individuals with only one DAA (6).

Even local immune responses appear to be heterogeneous, as the analyses of pancreatic samples obtained from deceased patients have shown that subject with high CD20 expression display more immune cells infiltration in the pancreas compared to low CD20-expressing ones (7).

Mucosal associated invariant T cells (MAIT) in the development of T1D in humans.

Our study aims to investigate circulating mucosal associated invariant T cells (MAIT) in the development of T1D in humans. MAIT are unconventional T cells that express invariant T-cell receptors and recognize riboflavin metabolites from bacteria presented by MR1 molecules. Alterations in gut microbiota have been reported in patients with T1D even before the onset of the disease (8,9). These in turn can potentially lead to alterations in circulating MAIT number and function.

Our data demonstrated that circulating MAIT are reduced in T1D patients compared to controls (DM v HD: 1.3% of T cells v 0.7%), but not in pre-diabetic stage (1% of T cells). This decrease was most evident in children diagnosed at an older age (>5 years old) (DM v HD: 1.4% of T cells v 0.9%). In young children the frequencies of MAIT cells were extremely low (DM v HD: 0.3% of T cells v 0.4%). The frequency of MAIT cells producing pro-inflammatorycytokines IFN gamma and IL-17A was similar between the study groups. Moreover, the activation of MAIT cells by in vitro stimulation with fixed E.coli bacteria through MR1 was comparable between the study groups.

However, T1D patients of younger age (< 5 years old) activated by E.coli exhibited more cytotoxic capability measured by CD107a expression compared to healthy controls (DM v HD: 34% of MAIT v 9%), but not evident in older diabetic patients. Henceforth, our data bring additional evidence to the notion of heterogeneity of the disease process in T1D.

In conclusion, the development of new effective treatment to cure T1D is intimately linked with our ability to unravel the different mechanisms of humoral and cellular autoimmune responses involved in the disease progression.

References

1) Bluestone, J. A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010).

2) Insel, R.A. et al. Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38, 1964-1974 (2015).

3) Pöllänen, P.M. et al. Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility. Diabetologia 60(7), 1284-1293 (2017).

4) Ilonen, J. et al. Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity. Pediatric Diabetes DOI: 10.1111/pedi.12545 (2017).

5) Giannopoulou, E.Z. et al. Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes. Diabetologia 58, 2317-2323 (2015).

6) Viisanen, T. et al. Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies. Diabetes 66, 437-447 (2017).

7) Arif, S. et al. Blood and Islet Phenotype Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 63, 3835-3845 (2014).

8) Davis-Richardson, A.G. et al. Bacteroidetes dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Frontiers in Microbiology 5, 678 (2014).

9) Brown, C.T. et al. Gut Microbiome Metagenomics Analysis Suggest a Functional Model for the Development of Autoimmunity for Type 1 Diabetes. PLoS One 6(10), e25792 (2011).