Étude des environnements de microsimulation économique avec agents partiellement rationnels

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

A unifying model of self-tolerance and autoimmunity to the neuroendocrine system

THYDI

Modulation of IGF2 expression in the murine thymus and thymic epithelial cells following coxsackie-B4 infection

Coxsackievirus B4 (CV-B4) can infect human and murine thymic epithelial cells (TECs). In a murine TEC cell line, CV-B4 can downregulate the transcription of the insulin-like growth factor 2 (Igf2) gene coding for the self-peptide of the insulin family. In this study, we show that CV-B4 infections of a murine TEC cell line decreased Igf2 P3 promoter activity by targeting a region near the transcription start site; however, the stability of Igf2 transcripts remained unchanged, indicating a regulation of Igf2 transcription. Furthermore, CV-B4 infections decreased STAT3 phosphorylation in vitro. We also showed that mice infected with CV-B4 had an altered expression of Igf2 isoforms as detected in TECs, followed by a decrease in the pro-IGF2 precursor in the thymus. Our study sheds new light on the intrathymic regulation of Igf2 transcription during CV-B4 infections and supports the hypothesis that a viral infection can disrupt central self-tolerance to insulin by decreasing Igf2 transcription in the thymic epithelium

The presentation of neuroendocrine self-peptides in the thymus: An essential event for individual life and vertebrate survival

Confirming Burnet’s early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 80’s and an important question immediately arose about the nature of the immune self expressed in the thymus. Many genes encoding neuroendocrine-related and tissue-restricted antigens (TRAs) are transcribed in thymic epithelial cells (TECs). They are then processed for presentation by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells (DCs). MHC presentation of self-peptides in the thymus programs self-tolerance by two complementary mechanisms: 1° Negative selection of self-reactive ‘forbidden’ T-cell clones starting already in fetal life, and 2° generation of self-specific thymic T regulatory (tTreg) cells, mainly after birth. Many studies, including the discovery of the AutoImmune REgulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2) proteins, have shown that a defect in thymus central self-tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self-peptides and TRAs in thymic epithelium. Furthermore, Aire and Fezf2 mutations are associated with development of autoimmunity in peripheral organs. The discovery of the intrathymic presentation of self-peptides has revolutionized our knowledge of immunology and is opening novel avenues for prevention/treatment of autoimmunity.THYDI

Coxackievirus B4 transplacental infection severely disturbs central tolerogenic mechanisms in the fetal thymus

Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset