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Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus


IL-2 and IL-21 are two cytokines with great potential to affect autoimmune infiltration of nonlymphoid tissue, and are contained within the strongest non-MHC-linked locus for type 1 diabetes (T1D) susceptibility on the nonobese diabetic (NOD) mouse (Idd3). IL-21 is necessary for the development of diabetes in the NOD mouse, but a number of important studies argue that decreased expression of IL-2 explains Idd3. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. During our analyses of the IL-2/IL-21 interval, we found that mice segregate into one of two distinct expression profiles. In the first group, which includes the C57BL/6 strain, both Il2 and Il21 were expressed at low levels. In the other group, which includes the NOD strain, Il2 and Il21 were both highly expressed. However, because NOD IL-2 mRNA was relatively unstable, IL-2 production was remarkably similar between strains. The increased production of IL-21 in NOD mice was found to result from two single nucleotide polymorphisms within the distal promoter region that conferred increased binding affinity for the transcription factor Sp1. Our findings indicate that a loss of locus parity after decreased IL-2 mRNA stability ensures that the high-expressing IL-21 allele persists in nature and provides a basis for autoimmunity.

Type Journal
ISBN 1091-6490 (Electronic)
Authors McGuire, H. M.; Vogelzang, A.; Hill, N.; Flodstrom-Tullberg, M.; Sprent, J.; King, C.:
Garvan Authors A/Prof Cecile King
Publisher Name PNAS
Published Date 2009-11-01 00:00:00
Published Volume 106
Published Issue 46
Published Pages 19438-19443
Status Published In-print
OpenAccess Link McGuire PNAS.pdf