Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes Journal Article

Authors: Chen, Y. G.; Mordes, J. P.; Blankenhorn, E. P.; Kashmiri, H.; Kaldunski, M. L.; Jia, S.; Geoffrey, R.; Wang, X; Hessner, M. J.
Article Title: Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes
Abstract: The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-beta-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.
Journal Title: Genes and immunity
Volume: 14
Issue: 6
ISSN: 1476-5470; 1466-4879
Publisher: Unknown  
Journal Place: England
Date Published: 2013
Start Page: 387
End Page: 400
Language: eng
Notes: LR: 20140408; GR: 1-UL1-RR031973/RR/NCRR NIH HHS/United States; GR: DP3 DK098161/DK/NIDDK NIH HHS/United States; GR: DP3DK098161/DK/NIDDK NIH HHS/United States; GR: R00DK077443/DK/NIDDK NIH HHS/United States; GR: R01 AI078713/AI/NIAID NIH HHS/United States; GR: R01AI078713/AI/NIAID NIH HHS/United States; GR: R01DK080100/DK/NIDDK NIH HHS/United States; GR: R21AI088480/AI/NIAID NIH HHS/United States; GR: R43DK85910/DK/NIDDK NIH HHS/United States; GR: UL1 RR031973/RR/NCRR NIH HHS/United States; JID: 100953417; 0 (Transforming Growth Factor beta); 130068-27-8 (Interleukin-10); 2013/03/28 [received]; 2013/04/24 [revised]; 2013/04/25 [accepted]; 2013/06/06 [aheadofprint]; ppublish