Transgenic rescue implicates beta 2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice.
Document Type
Article
Publication Date
2001
First Page
11533
Last Page
11538
JAX Source
Proc Natl Acad Sci USA 2001 Sep; 98(20):11533-8.
Abstract
Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic beta cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the beta(2) microglobulin (beta(2)M)(a) allele develop diabetes, whereas NOD mice expressing a murine beta(2)M(b) or human allele are protected. The murine beta(2)M(a) allele differs from the beta(2)M(b) allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD beta(2)M(a) isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.
Recommended Citation
Hamilton WE,
Serreze DV,
Charlton B,
Johnson EA,
Marron MP,
Mullbacher A,
Slattery RM.
Transgenic rescue implicates beta 2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice. Proc Natl Acad Sci USA 2001 Sep; 98(20):11533-8.