Abstract
Enterovirus (EV) infection of insulin-producing pancreatic beta cells is associated with type 1 diabetes (T1D), but little is known about the mechanisms that lead the virus to cause a persistent infection and, possibly, to induce beta cell autoimmunity. A cell line susceptible to most enterovirus types was infected with EV isolates from cases of T1D and, for comparison, with a replication-competent strain of coxsackievirus B3. The transcription of immune-related genes and secretion of cytokines was evaluated in infected vs. uninfected cells. Acutely infected cells showed the preserved transcription of type I interferon (IFN) pathways and the enhanced transcription/secretion of IL6, IL8, LIF, MCP1, and TGFB1. On the other hand, infection by defective EV strains obtained from diabetic subjects suppressed IFN pathways and the transcription of most cytokines, while enhancing the expression of IL8, IL18, IL32, and MCP1. IL18 and IL32 are known for their pathogenic role in autoimmune diabetes. Thus, the cytokine profile of AV3 cells infected by diabetes-derived EV strains closely matches that observed in patients at the early stages of T1D. The concordance of our results with clinically verified information reinforces the hypothesis that the immune changes observed in type 1 diabetic patients are due to a hardly noticeable virus infection.
Highlights
Type 1 diabetes (T1D) is characterized by an irreversible impairment of glucose homeostasis due to the loss of insulin-producing pancreatic beta cells
At the time of clinical onset, interferon (IFN)-stimulated genes are expressed in the islets and human leukocyte antigen (HLA) class-I antigens are hyperexpressed [3]; memory CD8 T lymphocytes are among the infiltrating cells
AV3 cells and the RD, 1.1B4, VC3, and HEK-293 cell lines were obtained from The European Collection of Authenticated Cell Cultures (ECACC) and cultured at 37 ◦C in air with 5% CO2 using Dulbecco’s Modified Eagle Medium (DMEM)/F12 medium supplemented with L-glutamine, heat-inactivated 10% fetal bovine serum (FBS), and penicillin/streptomycin
Summary
Type 1 diabetes (T1D) is characterized by an irreversible impairment of glucose homeostasis due to the loss of insulin-producing pancreatic beta cells. In the early phase of infection, innate immunity is activated by the recognition of pathogen-associated molecular patterns. This leads to the secretion of type-I interferons (IFNs) and pro-inflammatory cytokines. Virus replication is accompanied by more or less pronounced cell damage, possibly accompanied by the release of self-antigens. These are taken up by antigen-presenting cells that, after processing, deliver self-peptides to lymphocytes. HLA-I molecules present antigens to immune cells and play a role in antiviral defense [3]. The presentation of autoantigens may initiate an autoimmune response [17,18]
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