Immunology in the clinic review series: focus on type 1 diabetes and viruses: the role of viruses in type 1 diabetes: a difficult dilemma.

Convincing evidence now indicates that viruses are associated with type 1 diabetes (T1D) development and progression. Human enteroviruses (HEV) have emerged as prime suspects, based on detection frequencies around clinical onset in patients and their ability to rapidly hyperglycaemia trigger in the non-obese diabetic (NOD) mouse. Whether or not HEV can truly cause islet autoimmunity or, rather, act by accelerating ongoing insulitis remains a matter of debate. In view of the disease's globally rising incidence it is hypothesized that improved hygiene standards may reduce the immune system's ability to appropriately respond to viral infections. Arguments in favour of and against viral infections as major aetiological factors in T1D will be discussed in conjunction with potential pathological scenarios. More profound insights into the intricate relationship between viruses and their autoimmunity-prone host may lead ultimately to opportunities for early intervention through immune modulation or vaccination.

Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice.

Apoptosis is known as a major mechanism which contributes to beta cell decay in type 1 diabetes. Commitment to this pathway generally involves caspase-mediated protein cleavage and was found to induce cross-presentation of a specific antigen repertoire under certain inflammatory conditions. We aimed to assess the significance of the CD8 T cell population reactive against such caspase-cleaved apoptotic self-antigens in pancreatic islets of prediabetic human leucocyte antigen (HLA)-A2 transgenic non-obese diabetic chimeric monochain transgene construct (NOD.HHD) mice. We have reproduced a unique peptide library consisting of human CD8 T cell-derived apoptosis-specific antigens, all of which belong to structural proteins expressed ubiquitously in human islets. Pancreatic islets from prediabetic NOD.HHD mice, harbouring humanized major histocompatibilty complex (MHC) class I, were isolated and handpicked at various ages, and islet-infiltrating CD8 T cells were expanded in vitro and used as responders in an interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay. Human T2 cells were used as antigen-presenting cells (APC) to avoid endogenous antigen presentation. Analogous to the interindividual variability found with peptides from known islet autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) and insulin, some mice showed variable, low-degree CD8 T cell reactivity against caspase-cleaved self-antigens. Because reactivity was predominantly minor and often undetectable, we conclude that beta cell apoptosis does not routinely provoke the development of dominant cytotoxic T lymphocyte (CTL) reactive against caspase-cleaved self-antigens in the NOD.HHD model.