All authors contributed to the article and approved the submitted version

All authors contributed to the article and approved the submitted version. Funding No direct funding has been received for this review article. the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment. Keywords: CD3, CXCR3, CXCL10, combination therapy, migration, insulitis Type 1 Diabetes It has become clear in the last decades that the predominant destructive force responsible for -cell death in type 1 diabetes (T1D) are KL1333 autoaggressive CD8 T cells. Although there is still debate on how the autoimmune response against islet autoantigens is initiated, it seems clear that local inflammation in the islets participates in drawing KL1333 a broad variety of leukocytes to the islet microenvironment (1). Of course, virus infection has been associated with the etiology of T1D and there is ample evidence to support this hypothesis (2). For KL1333 example, enterovirus proteins and RNA have been found in islets of T1D patients (3). A large meta-analysis confirmed a significant clinical association between enterovirus infection and T1D (4). However, there is yet no firm, causative proof that would directly demonstrate that virus infection results in immunopathogenic events that would result in the destruction of -cells and the development of T1D. One problem is the temporal relation between infection and disease onset. Environmental triggers such as virus infection might have occurred long before clinical diagnosis. Further, it is also feasible that more than one triggering event might be required to finally precipitate the disease (5). Thereby, enterovirus infection might as well accelerate a pre-existing autoimmune condition rather than initiate it. Further investigations with more pancreas material, as available from the network for Pancreatic Organ Donors with Diabetes (nPOD), will hopefully shed some more light on the role of virus infection in the etiology of T1D in the KL1333 future. For many autoimmune diseases, including T1D, a mechanism termed molecular mimicry has been suggested to play a critical role. Molecular mimicry describes a sequential and/or Goat polyclonal to IgG (H+L) conformational similarity between components of an invading pathogen and the host (6). Cross-reactive antibodies and/or T cells that have been generated during the KL1333 anti-pathogen defense would thereby also target the similar self-structures of the host and may cause autoimmune damage resulting in clinical disease. Thereby, depending on the strength of the immune tolerance, molecular similarity between pathogen and natural occurring structures of the host is more likely to break tolerance than molecular identity. Many host proteins are expressed in the thymus and central tolerance established to identical molecules might be too strong to be broken. Indeed, in a mouse model for autoimmune hepatitis (7), an infection with a triggering antigen that is similar but not identical to the host target autoantigen was more effective in breaking tolerance and inducing disease as infection of.