|
||
By
From the Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research
Centre, Faculty of Medicine, Health Sciences Centre, The University of Calgary, Calgary, Alberta
T2N 4N1, Canada
Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta
cell-reactive, I-Ag7-restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic
mice (H-2g7) undergoes thymocyte negative selection in diabetes-resistant H-2g7/b, H-2g7/k,
H-2g7/q, and H-2g7/nb1 NOD mice by engaging antidiabetogenic MHC class II molecules on
thymic bone marrow-derived cells, independently of endogenous superantigens. Thymocyte
deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial
in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules.
Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with
the extent of thymocyte deletion, but are invariably resistant to diabetes development. These
results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype.
This article has been cited by other articles:
| TABLE OF CONTENTS |
|