Prediction and pathogenesis in type 1 diabetes

Abstract

A combination of genetic and immunological features is useful for prediction of autoimmune diabetes. Patterns of immune response correspond to the progression from a preclinical phase of disease to end-stage islet damage, with biomarkers indicating transition from susceptibility to active autoimmunity, and to a final loss of immune regulation. Here, we review the markers that provide evidence for immunological checkpoint failure and that also provide tools for assessment of individualized disease risk. When viewed in the context of genetic variation that influences immune response thresholds, progression from susceptibility to overt disease displays predictable modalities of clinical presentation resulting from a sequential series of failed homeostatic checkpoints for selection and activation of immunity.

Copyright 2010 Elsevier Inc. All rights reserved.

Figures

Figure 1

Individual stratification for diabetes risk reflects stages of disease progression. (GAD, glutamic acid decarboxylase; IA-2, islet-associated autoantibody 2; ZnT8, zinc transporter 8; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test; HbA1c, hemoglobin A1c).

Figure 2

Type 1 diabetes risk stratification by islet autoantibody properties: Increase in T1D risk is associated with progression of islet autoantibodies from single to multiple autoantibodies. Characteristics of the initial antibody response can help predict disease progression. (IAA, insulin autoantibodies; GAD65, glutamic acid decarboxylase 65; IA-2, islet-associated autoantibody 2; ZnT8, zinc transporter 8;

Figure 3

Incidence of islet autoantibodies (cases with at least one Ab of IAA, GADA, IA2A, or ZnT8A per year, expressed as a % of children with a family history of diabetes ascertained in the BABYDIAB study population); abbreviations as in legend to Figure 2). Two waves of islet autoimmunity with an increased incidence at around one year of age (“neonate” autoimmunity) and at around puberty are observed with distinct characteristics.