Insulin transactivator MafA regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes.
OBJECTIVE
Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes.


METHODS
The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms.


RESULTS
Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease.


CONCLUSIONS
These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes.
Noso
Shinsuke
S
Department of Endocrinology, Metabolism, and Diabetes, Kinki University School of Medicine, Osaka, Japan.
Kataoka
Kohsuke
K
Kawabata
Yumiko
Y
Babaya
Naru
N
Hiromine
Yoshihisa
Y
Yamaji
Kaori
K
Fujisawa
Tomomi
T
Aramata
Shinsaku
S
Kudo
Takashi
T
Takahashi
Satoru
S
Ikegami
Hiroshi
H
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology; D051473:Maf Transcription Factors, Large / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D000096927:AIRE Protein
D004268:DNA-Binding Proteins; D007328:Insulin; D051473:Maf Transcription Factors, Large; D014157:Transcription Factors; D000096927:AIRE Protein; C485160:Mafa protein, mouse