Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes

Abstract

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.

Keywords: autoantibodies; autoimmune disease; autoimmunity; immunity; type 1 diabetes mellitus; virus etiology.

Figure 1.

Timeline of events from the exposure of a trigger such as virus and the subsequent series of events that results in the appearance of a first islet autoantibody. Created with Biorender^®.

Figure 2.

Incidence rate (new autoantibody/1000 person years) of IAA first (red), GADA first (blue) and IAA-GADA simultaneous (green).

Figure 3.

Enterovirus B infection at 3–6 months of age and the risk for developing either GADA, IAA, or both, as the first appearing autoantibody referred to as islet autoimmunity (IA). EV-B is Enterovirus B. The data in the illustration is from reference [88].