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.
McGuire
Helen M
HM
Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
Vogelzang
Alexis
A
Hill
Natasha
N
Flodström-Tullberg
Malin
M
Sprent
Jonathan
J
King
Cecile
C
D000483:Alleles; D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000098546:Interleukin-21
D007376:Interleukin-2; D007378:Interleukins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D000098546:Interleukin-21