Smad2

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Abstract

Context:

Congenic NOD.ABHD18Mit8-D18Mit214 mice, which contain greater than 12.8 Mb of DNA encompassing Idd21.1 from diabetes-resistant Biozzi/ABH mice, have a lower frequency of diabetes compared with the parental nonobese diabetic (NOD) strain, possibly due to reduced pathogenicity of β-islet-infiltrating immune cells.

Objective:

The objective of the study was to identify an Idd21.1 candidate gene.

Methods:

The methods used in the study were adoptive transfer into scid mice lacking an adaptive immune system; dendritic cell phenotyping and gene expression analysis; and fine-mapping Idd21.1 by congenic mapping.

Results:

Diabetes incidences of NOD.scid.ABHD18Mit8-D18Mit214 mice receiving splenocytes from NOD and NOD.ABHD18Mit8-D18Mit214 were similar to that previously observed in NOD.scid recipients, suggesting that the diabetes resistance in NOD.ABHD18Mit8-D18Mit214 is primarily mediated by the adaptive immune system, findings supported by adoptive transfer of CD4+ T cells. In activated dendritic cells, there were no conclusive differences in cytokine profiles and activation marker expression. However, microarray analysis comparing gene expression between activated dendritic cells from NOD and NOD.ABH D18Mit8-D18Mit214 revealed that Smad2, in a maximal 6.5-Mb region to which Idd21.1 was further resolved by congenic mapping, was differentially expressed (increased in NOD). Quantitative real-time PCR confirmed the differential expression of Smad2, and other genes in the TGF-β signaling pathway, in activated dendritic cells.

Conclusions:

These results implicate Smad2 as an Idd21.1 candidate and Smad2 and the TGF-β signaling pathway in activated dendritic cells in diabetogenesis. With suggestive evidence from human genome-wide association studies supporting a role for SMAD7 in human type 1 diabetes, a comprehensive genetic investigation of the SMAD genes in type 1 diabetes is warranted.

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