Do post-translational beta cell protein modifications trigger type 1 diabetes?

Abstract

Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate.

Antibodies to post-translationally modified insulin in type 1 diabetes

“…High levels of ROS may lead to oxidative post-translational modification (oxPTM) of beta cell self-proteins and the formation of neoepitopes. Neoepitopes are epitopes that have not been previously presented to the immune system [3,4] and therefore escape immune tolerance and generate autoimmunity. Other intracellular events, such as increases in ROS and endoplasmic reticulum stress, impair beta cell autophagic activity [5].…”

Is there evidence for post-translational modification of beta cell autoantigens in the aetiology and pathogenesis of type 1 diabetes?

“…The final stage would be caused by a combination of a deficiency in insulin production and variable insulin sensitivity. In the accompanying For Debate article it is hypothesised that post-translational modification (PTM) of autoantigens might create tissue-specific neo-epitopes that could trigger type 1 diabetes [2]. It should be noted that the contribution by Størling et al [2] truly fulfils the criterion for a 'For Debate' article in that the authors do not provide strong experimental evidence for PTM.…”

“…In the accompanying For Debate article it is hypothesised that post-translational modification (PTM) of autoantigens might create tissue-specific neo-epitopes that could trigger type 1 diabetes [2]. It should be noted that the contribution by Størling et al [2] truly fulfils the criterion for a 'For Debate' article in that the authors do not provide strong experimental evidence for PTM. Before discussing whether this hypothesis is testable or not, it will first be important to briefly examine the multi-stage character of autoimmune (type 1) diabetes.…”

“…Størling et al [2] propose that increased expression levels (mRNA, not the enzymes themselves) of enzymes with potential PTM activity after in vitro exposure of human islets to certain cytokines indicates that PTM of autoantigens might take place. Regrettably, there are quite a number of candidate PTM enzymes to sort through.…”

“…Autoantibodies to IA-2 and ZnT8 were negatively associated with DQ2 [18,19]. A major question not asked by Størling et al is whether the loading of peptides in the binding cleft of the HLA Class II heterodimer is affected by PTMs [2]. Are post-translationally modified peptides loaded at all?…”