Enterovirus Infection, CXC Chemokine Ligand 10 (CXCL10), and CXCR3 Circuit

Abstract

OBJECTIVEFulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated β-cell failure are unclear.RESEARCH DESIGN AND METHODSSubjects 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 RT-PCR.RESULTSImmunohistochemical 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-γ and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including β-cells and α-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells.CONCLUSIONSThese results strongly suggest the presence of a circuit for the destruction of β-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-γ and CXCL10 in β-cells. CXCL10 secreted from β-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-γ in the islets, not only damaging β-cells but also accelerating CXCL10 generation in residual β-cells and thus further activating cell-mediated autoimmunity until all β-cells have been destroyed.

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

“…Cultured human islets have been shown to secrete CXCL10 following enterovirus infection [37]. In a recent report, Tanaka et al examined sections of pancreas from autopsy material derived from a deceased patient with fulminant type 1 diabetes, an acute subtype of type 1 diabetes identified in the Japanese population, and detected enterovirus capsid protein infiltration of CXCR3-bearing T cells and macrophages [38]. They also observed IFN-γ and CXCL10 in all subtypes of islets.…”

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

“…Although immunohistochemical studies have suggested the expression of type I IFN (10,11) and some ISGs (12,13) in T1D islets, other studies have failed to detect type I IFN in pancreata from subjects with diabetes (14). End point PCR, with no or limited quantitative value, has suggested IFN-a expression to be more prevalent in T1D than in control pancreata (15,16), but this has not been confirmed by quantitative methods.…”

Immune Regulation and Evasion of Mammalian Host Cell Immunity During Viral Infection

“…Enterovirus infection of the pancreas induces the co-expression of IFN-c and CXCL10 (CXC chemokine ligand 10) in betacells along with MHC-II expression. Hyperexpression of MHC-I in some islet cells of the pancreas and subsequent activation followed by attraction of autoreactive T cells and macrophages to the islets have also been reported [137].…”