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Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice. J Immunol 2012 Aug 01;189(3):1406-17

Date

06/27/2012

Pubmed ID

22732593

Pubmed Central ID

PMC3401322

DOI

10.4049/jimmunol.1200120

Scopus ID

2-s2.0-84864150616   11 Citations

Abstract

Autoimmune type 1 diabetes (T1D) in humans and NOD mice results from interactions between multiple susceptibility genes (termed Idd) located within and outside the MHC. Despite sharing ∼88% of their genome with NOD mice, including the H2(g7) MHC haplotype and other important Idd genes, the closely related nonobese resistant (NOR) strain fails to develop T1D because of resistance alleles in residual genomic regions derived from C57BLKS mice mapping to chromosomes (Chr.) 1, 2, and 4. We previously produced a NOD background strain with a greatly decreased incidence of T1D as the result of a NOR-derived 44.31-Mb congenic region on distal Chr. 4 containing disease-resistance alleles that decrease the pathogenic activity of autoreactive B and CD4 T cells. In this study, a series of subcongenic strains for the NOR-derived Chr. 4 region was used to significantly refine genetic loci regulating diabetogenic B and CD4 T cell activity. Analyses of these subcongenic strains revealed the presence of at least two NOR-origin T1D resistance genes within this region. A 6.22-Mb region between rs13477999 and D4Mit32, not previously known to contain a locus affecting T1D susceptibility and now designated Idd25, was found to contain the main NOR gene(s) dampening diabetogenic B cell activity, with Ephb2 and/or Padi2 being strong candidates as the causal variants. Penetrance of this Idd25 effect was influenced by genes in surrounding regions controlling B cell responsiveness and anergy induction. Conversely, the gene(s) controlling pathogenic CD4 T cell activity was mapped to a more proximal 24.26-Mb region between the rs3674285 and D4Mit203 markers.

Author List

Stolp J, Chen YG, Cox SL, Henck V, Zhang W, Tsaih SW, Chapman H, Stearns T, Serreze DV, Silveira PA

Author

Yi-Guang Chen PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
B-Lymphocyte Subsets
CD4-Positive T-Lymphocytes
Cell Communication
Cells, Cultured
Crosses, Genetic
Diabetes Mellitus, Type 1
Female
Gene Expression Regulation
Genetic Markers
Genetic Predisposition to Disease
Male
Mice
Mice, Congenic
Mice, Inbred NOD
Mice, Knockout
Mice, Transgenic
Radiation Chimera