Abstract

Objective: Fulminant type 1 diabetes is characterized by rapid-onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. Causative mechanisms for accelerated beta-cell failure are unclear.

Research Design and Methods: Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet-cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility-complex (MHC) expressions in the pancreata using immunohistochemical analyses and reverse-transcription-polymerase chain reaction.

Results: Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3-receptor-bearing T cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly co-expressed in all subtypes of islet-cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyper-expression of MHC class I was observed in some islet-cells.

Conclusions: These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates co-expression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells, but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.