In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 9 ( 2008-03-04), p. 3533-3538
Abstract:
Although many autoimmune diseases are associated with particular HLA/H-2 haplotypes, the mechanisms through which specific HLA/H-2 haplotypes afford autoimmune susceptibility remain enigmatic. Here, we analyzed the effects of the diabetes-associated (H-2 g7 ) and an antidiabetogenic (H-2 b ) H-2 haplotypes in NOD mice deficient for programmed cell death-1 (PD-1, Pdcd1 ), a unique model of type 1 diabetes that confers complete penetrance and rapid onset of the disease. NOD- H2 b/b Pdcd1 −/− mice were completely protected from diabetes, confirming that H-2 g7 is indispensable for diabetes even in the absence of PD-1. However, NOD- H2 b/b Pdcd1 −/− mice developed autoimmune inflammation in multiple tissues including peripheral nerves, stomachs, and exocrine tissues, demonstrating that autoreactive T cells are generated in the context of H-2 b . These autoreactive T cells damaged target tissues only in the absence of PD-1, confirming that PD-1 deficiency unravels the hidden autoimmune susceptibility of the strain by reducing the threshold of T cell activation. Transfer experiments revealed that CD4 T cells are the effector cells of neuritis, and nerve-infiltrating CD4 T cells are strongly deviated toward Th1. Interestingly, neuritogenic T cells were also generated in the context of H-2 g7 , in sharp contrast to the strict requirement of H-2 g7 for diabetes. In addition, 60% of the NOD- H2 b/g7 Pdcd1 −/− mice developed diabetes, suggesting that H-2 b does not dominantly suppress diabetes and that H-2 g7 induces diabetes in a dose-dependent fashion.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0710951105
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2008
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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