@article{2222528a044f44fc954a1e30e5e514b1,
title = "DNA microarray analysis for the identification of innate immune pathways implicated in virus-induced autoimmune diabetes",
abstract = "We have recently demonstrated that upregulation of the innate immune system plays a key role in KRV-induced autoimmune diabetes in the BBDR rat, but the nature of this proinflammatory reaction has not yet been addressed. Using a DNA microarray approach, we identified 569 genes upregulated in pancreatic lymph nodes following virus infection. Among the most highly activated are IL-1 pathways, IFN-γ-induced chemokines, and genes associated with interferon production and signaling. Ex vivo and in vitro studies indicate that KRV upregulates proinflammatory cytokines and chemokines in B lymphocytes and Flt-3L-induced plasmacytoid DCs (pDCs). Finally, in contrast to KRV, infection of BBDR rats with the non-diabetogenic KRV homologue H-1 parvovirus fails to induce a robust proinflammatory response in pancreatic lymph nodes. Our findings provide new insights into KRV-induced innate immune pathways that may play a role in early mechanisms leading to islet inflammation and diabetes.",
keywords = "Autoimmune diabetes, Biobreeding diabetes resistant rat, DNA microarray analysis, Inflammation, Innate immunity, Kilham rat virus, Toll-like receptor",
author = "Wolter, {Travis R.} and Randall Wong and Sarkar, {Suparna A.} and Danny Zipris",
note = "Funding Information: Our data may implicate IFN pathways in KRV-induced inflammation in BBDR rats. This is supported by three lines of evidence. First, we found that virus infection leads to upregulation of transcripts for interferon regulatory factor 7 (IRF7), a transcription factor that plays a crucial role in type I IFN production following virus infection [37–41] . Second, KRV upregulates genes involved in mediating the biological effect of type I IFNs, including signal transducers and activators of transcription (STATs), STAT-1 and STAT-2. This is in accordance with our findings that KRV increases levels of STAT-1 protein as well as the phosphorylated form of these transcription factors in the pancreatic lymph nodes of virally infected animals [42] . The potential role of STAT pathways in disease induction is supported by studies performed in animal models of T1D. Mice transplanted with syngeneic STAT-1 deficient islets are protected from streptozotocin-induced disease [43] and NOD mice deficient of the STAT-1 gene ado not develop insulitis and diabetes [44] . Another observation implicating type I IFN pathways in KRV-induced inflammation is the finding of increased transcript levels for type I IFN-stimulated genes, including protein kinase R, IFN-induced proteins with tetratricopeptides, IFIT1, IFIT2, IFIT3, MX1, MX2, and 2′,5′-oligoadenylate synthetases 1, some of which are implicated in anti-virus activities [41] . Our results are consistent with the possibility that type I IFNs are upregulated in infected BBDR rats, however, they should be interpreted with the caveat that we are currently unable to detect transcripts for IFN-α or IFN-β in pancreatic lymph nodes of KRV-infected animals using quantitative RT-PCR analysis possibly due to their low expression levels. Data from both humans and animal models, however, support a role for type I IFNs in diabetes development [18,19] . ",
year = "2009",
month = jul,
doi = "10.1016/j.clim.2009.02.007",
language = "English",
volume = "132",
pages = "103--115",
journal = "Clinical Immunology",
issn = "1521-6616",
publisher = "Academic Press Inc.",
number = "1",
}