Abstract
Context: Congenic NOD. ABHD(18Mit8-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 beta-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. ABH(D18Mit8-D18Mit214) mice receiving splenocytes from NOD and NOD. ABH(D18Mit8-D18Mit214) were similar to that previously observed in NOD. scid recipients, suggesting that the diabetes resistance in NOD. ABH(D18Mit8-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-beta signaling pathway, in activated dendritic cells.
Conclusions: These results implicate Smad2 as an Idd21.1 candidate and Smad2 and the TGF-beta 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.