Antigen targets of type 1 diabetes autoimmunity

Abstract

Type 1 diabetes is characterized by recognition of one or more β-cell proteins by the immune system. The list of target antigens in this disease is ever increasing and it is conceivable that additional islet autoantigens, possibly including pivotal β-cell targets, remain to be discovered. Many knowledge gaps remain with respect to the disorder's pathogenesis, including the cause of loss of tolerance to islet autoantigens and an explanation as to why targeting of proteins with a distribution of expression beyond β cells may result in selective β-cell destruction and type 1 diabetes. Yet, our knowledge of β-cell autoantigens has already led to translation into tissue-specific immune intervention strategies that are currently being assessed in clinical trials for their efficacy to halt or delay disease progression to type 1 diabetes, as well as to reverse type 1 diabetes. Here we will discuss recently gained insights into the identity, biology, structure, and presentation of islet antigens in relation to disease heterogeneity and β-cell destruction.

Figure 1.

Representation of the role of β-cell autoantigens in the development of type 1 diabetes. Thymic events that predispose to impaired tolerance to β-cell proteins include low-level expression or presentation, crypticity, and low affinity. In the periphery, thymic escapee T cells with autoreactive potential are more likely to be primed when expression of the antigen is high, presentation is enhanced, and there is inflammation, perhaps concomitant with the presence of neo- or altered epitopes. Peripheral regulation is fostered by controlled expression of the autoantigen, in the absence of inflammation, using low-frequency exposure to native sequences.

Figure 2.

Loss of immunological tolerance to islet autoantigens. Islet proteins are taken up, processed, and presented by antigen-presenting cells (APC) to islet autoreactive T cells, leading to loss of tolerance. Additional islet autoreactive T cells may become activated (epitope spreading), which may contribute to β-cell destruction or represent nondestructive islet autoimmunity (bystander activation). Activation of islet autoreactive CD8 T cells may lead to direct recognition and destruction of pancreatic β cells. CD4 T cells activate B cells to produce islet autoantibodies. Presentation of islet autoantigen to the immune system may also lead to activation of regulatory T cells (Tregs) leading to inhibition of proinflammtory islet autoimmunity.