The final pathway of β cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill β cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8 + T cells from HLA-A2 + patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8 + T cells killed human β cells in vitro. Critically, at high glucose concentration, β cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human β cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing β cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining β cells.

Inherited human cPLA 2α deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction

No abstract

The development of type 1 diabetes mellitus (T1DM) has been linked to exposure to environmental triggers, with Enteroviruses (EV) historically considered the prime suspects. Early serological studies suggested a link between EV infections and the development of T1DM and, though controversial, have been bolstered by more recent studies using more sensitive techniques such as direct detection of the EV genome by RT-PCR in peripheral blood. In this review, we consider the weight of evidence that EV can be considered a candidate trigger of T1DM, using three major criteria: (1) is EV infection associated with clinical T1DM, (2) can EV trigger the development of autoimmunity and (3) what would explain the putative association?