Potential viral pathogenic mechanism in human type 1 diabetes

Abstract

In type 1 diabetes, as a result of as yet unknown triggering events, auto-aggressive CD8(+) T cells, together with a significant number of other inflammatory cells, including CD8(+) T lymphocytes with unknown specificity, infiltrate the pancreas, leading to insulitis and destruction of the insulin-producing beta cells. Type 1 diabetes is a multifactorial disease caused by an interactive combination of genetic and environmental factors. Viruses are major environmental candidates with known potential effects on specific key points in the pathogenesis of type 1 diabetes and recent findings seem to confirm this presumption. However, we still lack well-grounded mechanistic explanations for how exactly viruses may influence type 1 diabetes aetiology. In this review we provide a summary of experimentally defined viral mechanisms potentially involved in the ontology of type 1 diabetes and discuss some novel hypotheses of how viruses may affect the initiation and natural history of the disease.

Fig. 1

Timeline of development of type 1 diabetes. In genetically susceptible individuals, an as yet unknown environmental trigger (1) causes an underlying inflammation of the pancreas that is characterised by a rather discrete lymphocytic infiltrate and the upregulation of MHC I on some beta cells (insulitis). This represents a fertile soil for a complex interplay between T-effector and T-regulatory cells, eventually favouring the CD8⁺ T-effector-mediated attack, causing a scenario of concomitant beta cell destruction and enhanced proliferation (2). The sequential appearance and spreading of antigenic determinants leads to the enhancement of the immune response (3) and feeds a vicious cycle. As soon as the vast majority of beta cells is destroyed, the immune reaction slows down (4), yet some of its features (MHC I upregulation) remain detectable for a long time, probably fuelled by the few remaining beta cells. Pathophysiologically, phases (2) and (3) coincide with the transition from normoinsulinaemia to hypoinsulinaemia and finally to the loss of detectable C-peptide levels