| Introduction:Self tolerance is regarded as the anergy condition for the immune system to self antigens. If the self tolerance is broken or blocked by some reasons, autoimmunity and some diseases might occur. Whatever T or B lymphocytes, the tolerance formation include central and peripheral parts. For the T cell education, the developing thymocytes, which expressed the TCRs with high affinity to self antigens, are deleted through a series of thymic selections, like positive selection and negative selection. We call this process as central tolerance. But thymic tolerance is not the only mechanism for our bodies to remove the self reactive T cells since not all the self-proteins can be ectopicly expressed in thymus. Peripheral tolerance also involves in the deletion of autoreactive T cells, which includes all the other means, such as DCs and regulatory T cells. Autoimmune regulator (AIRE) is a transcription factor which mainly expressed in thymic medullary epithelial cells(mTECs). The gene aire was successfully cloned by two separate research groups in 1997. APECED (autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy) is a severe autosomal recessive disease caused by mutations in the Aire gene. Clinically, APECED patients suffer from the autoimmune destruction of different endocrine and non-endocrine target organs giving rise to hypoparathyroidism and adrenocortical failure et al. In addition, they also suffer from chronic mucocutaneous candidiasis and ectodermal dystrophies. Aire deficient mice show similar immune defects with APECED patients. For the Aire function, people wonder how one gene mutation can cause so many different autoimmune features. In 2002, Anderson, MS reported that Aire could regulate the transcription of many tissue specific antigens in mTECs. This is the first time to identify Aire involves in the central tolerance by controlling ectopic expression of peripheral antigen in thymus. In 2003, Liston, A clearly proved Aire was very important for the negative selection process. In TCR/InsHEL Aire-/- mice, due to lack of Aire, self reactive T cells deletion was blocked. So far, the mechanism of Aire regulating transcription is still unknown. Aire might act together with another protein CBP to control self tolerance.IDDM is one of the autoimmune diseases. Recently, its occurrence rate is going up and it also shows a younger tendency. The increase of autoreactive T cells following the imbalance of Th1/Th2 was thought as a key reason for the development of diabetes. In order to better understand the mechanism of autoimmune disease, like diabetes, NOD (nonobese diabetic) mice were often used as an ideal animal model.To find out the role of Aire in self tolerance and autoimmunity, we constructed Aire transgenic NOD mice.Results:Through the phenotype analysis of Aire transgenic NOD mice, we found:Compared with non-transgenic NOD mice, the thymus size of transgenic mice became smaller and this change was not affected by age or sex. This result indicated that Aire might involve in the development of thymus of NOD mice and therefore influence the T cells education.We next took the thymus to see whether the apoptosis process contributed to the thymus anatomical abnormality. Through counting the Annexin V-binding cells and fluorescen tagged dying cells, we verified that more apoptotic cells selectively located in the medulla of transgenic thymus. It was hypothesized that over expressed Aire exacerbated the thymocyte apoptosis, especially cells in medulla of NOD mice, and the thymocyte constitution might be changed.Th1/Th2 balance was thought to be very important to maintain the homeostasis of immune response. By measuring the IFN-γ/IL-4 secretion level of CD4+ T cells under the stimulation of anti-CD3 and anti-CD28 antibodies, we found the ratio of IFN-γ/IL-4 decreased dramatically in Aire transgenic NOD mice. This result suggested that peripheral T cells in transgenic mice were reconstructed and the Th1 dominant paradigm was restored.In order to evaluate the...
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