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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

A 20-Mb Region of Chromosome 4 Controls TNF-{alpha}-Mediated CD8+ T Cell Aggression Toward beta Cells in Type 1 Diabetes.

Identification of candidate genes and their immunological mechanisms that control autoaggressive T cells in inflamed environments, may lead to novel therapies for autoimmune diseases, like type 1 diabetes (T1D). In this study, we used transgenic NOD mice that constitutively express TNF-alpha in their islets from neonatal life ( TNF-alpha-NOD) to identify protective alleles that control T1D in the presence of a proinflammatory environment. We show that TNF-alpha-mediated breakdown in T cell tolerance requires recessive NOD alleles. To identify some of these recessive alleles, we crossed TNF-alpha-NOD mice to diabetes-resistant congenic NOD mice having protective alleles at insulin-dependent diabetes (Idd) loci that control spontaneous T1D at either the preinsulitis (Idd3.Idd5) or postinsulitis (Idd9) phases. No protection from TNF-alpha-accelerated T1D was afforded by resistance alleles at Idd3.Idd5. Lack of protection was not at the level of T cell priming, the efficacy of islet-infiltrating APCs to present islet peptides, nor the ability of high levels of CD4(+)Foxp3(+) T cells to accumulate in the islets. In contrast, protective alleles at Idd9 significantly increased the age at which TNF-alpha-NOD mice developed T1D. Disease delay was associated with a decreased ability of CD8(+) T cells to respond to islet Ags presented by islet-infiltrating APCs. Finally, we demonstrate that the protective region on chromosome 4 that controls T1D in TNF-alpha-Idd9 mice is restricted to the Idd9.1 region. These data provide new evidence of the mechanisms by which selective genetic loci control autoimmune diseases in the presence of a strong inflammatory assault.[1]


  1. A 20-Mb Region of Chromosome 4 Controls TNF-{alpha}-Mediated CD8+ T Cell Aggression Toward beta Cells in Type 1 Diabetes. Chamberlain, G., W??llberg, M., Rainbow, D., Hunter, K., Wicker, L.S., Green, E.A. J. Immunol. (2006) [Pubmed]
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