Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes. Genes Immun 2013 Sep;14(6):387-400
Date
06/07/2013Pubmed ID
23739610Pubmed Central ID
PMC4027975DOI
10.1038/gene.2013.31Scopus ID
2-s2.0-84883880468 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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-β-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.
Author List
Chen YG, Mordes JP, Blankenhorn EP, Kashmiri H, Kaldunski ML, Jia S, Geoffrey R, Wang X, Hessner MJAuthors
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinMartin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Age FactorsAnimals
Diabetes Mellitus, Type 1
Disease Resistance
Humans
Interleukin-10
Parvovirus
Rats
Rats, Inbred Strains
Transcriptome
Transforming Growth Factor beta