93-OR: Expression of Genes Associated with Host Viral Responses in Insulitic Islets

Background: Type 1 diabetes (T1D) is an autoimmune condition long hypothesized to be enhanced or triggered by viral infections. Islet pathology in T1D is characterized by destruction and subsequent loss of insulin producing pancreatic beta cells. In this study we evaluated specific physiological pathways associated with the disorder’s pathogenesis by examining differential expression of host genes within islets, with special emphasis on identifying evidence suggestive of responses to a viral infection. Methods: Pancreatic tissue samples were obtained from nondiabetic donors, autoantibody positive donors, and donors with T1D through the Network for Pancreatic Organ donors with Diabetes (nPOD) program. Laser microdissection was used to isolate individual islets based on immunohistochemical documentation of presence or absence of insulin (INS+) and T-lymphocytes (CD3+). RNA was isolated and microarray used to assess transcriptomes. Results: Increased expression in insulitic islets was seen in a variety of genes including TLR pathway inhibitors: LAIR1 (p=2.77E-8), SIGLEC7 (p=8.33E-6), SIGLEC9 (p=1.59E-4), and C1q (p=6.11E-16); as well as genes downstream of the TLR pathway: CD163 (p=2.34E-11), CTSS (p=9.89E-7) and IFNγ (p=5.9E-8). We also observed variances in the frequency of viral response genes, including those known to be associated with T1D at a GWAS level: STAT1 (p=1.64E-7) and OAS3 (p=1.04E-8). Pathway analysis demonstrated increased representation of antigen processing and presentation genes (p=3.0E-14). Conclusions: In sum, these studies noted an increased expression of multiple host genes associated with anti-viral responses. The demonstration of specific protein involvement in host responses to infections are up-regulated in T1D islets, specifically in those with signs of immune activation and residual insulin positivity (INS+CD3+), supports the potential involvement of host viral response pathways in the development of T1D. Disclosure G. Nelson: None. N.I. Lenchik: None. M. Campbell-Thompson: None. M.A. Atkinson: None. I.C. Gerling: None. Funding National Institutes of Health (UC4DK104155)