Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes.
BACKGROUND
Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet beta-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell self-tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat.


METHODS
The expression of the mammalian insulin-related genes (Ins, Igf1 and Igf2) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes-resistant BB (BBDR) and diabetes-prone BB (BBDP) rats.


RESULTS
RT-PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2-day-old, 5-day-old and 5-week-old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue-specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF-2 protein was significantly lower in BBDP than in BBDR rats (p<0.01).


CONCLUSIONS
The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue-specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T-cell development) and the absence of central T-cell self-tolerance of the insulin hormone family (by defective negative selection of self-reactive T-cells).
Kecha-Kamoun
O
O
University of Liège, Department of Medicine & Center of Immunology, Institute of Pathology CHU-B23, B-4000 Liège 1-Sart Tilman, Belgium.
Achour
I
I
Martens
H
H
Collette
J
J
Lefebvre
P J
PJ
Greiner
D L
DL
Geenen
V
V
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D007113:Immunity, Innate; D015592:Immunoradiometric Assay; D007328:Insulin / Q000032:analysis / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000235:genetics*; D011384:Proinsulin / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000254:growth & development / Q000502:physiology*; D014158:Transcription, Genetic
D007328:Insulin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011384:Proinsulin