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首页> 外文学位 >Molecular and cellular regulation of the immune system: A study of Ikaros in Th2 cell lineage decisions and of mast cells' contribution to disease progression in a murine model of type 1 diabetes.
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Molecular and cellular regulation of the immune system: A study of Ikaros in Th2 cell lineage decisions and of mast cells' contribution to disease progression in a murine model of type 1 diabetes.

机译：免疫系统的分子和细胞调节：在1型糖尿病小鼠模型中，对Ikaros进行Th2细胞谱系决定以及肥大细胞对疾病进展的贡献的研究。

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摘要

This dissertation describes studies that investigate aspects of both branches of the immune system; the immediate nonspecific innate response and the downstream targeted adaptive response. Chapter III of this thesis examines the molecular mechanisms that control differentiation of T helper cells, a critical member of the adaptive immune response. We demonstrate that Ikaros, a hematopoietic cell-specific transcription factor with well defined effects on early lymphocyte development in the bone marrow and thymus, is a positive regulator of Th2 cytokine gene expression in peripheral T cells. CD4+ T cells from naive Ikarosnull mice were found to have decreased ability to express Th2 cytokines corresponding with histone H3 hypoacetylation detected across the Th2 cytokine locus as well as decreased GATA-3 and c-maf expression and increased T-bet and STAT1 expression in Ikarosnull cells. These data support the idea that Ikaros directly activates Th2 gene expression by promoting local chromatin accessibility during CD4+ T cell differentiation and also acts indirectly to regulate expression of Th2- and Th1-specific transcription factors.;A breakdown in adaptive regulatory mechanisms can result in misdirected immune responses against self or innocuous substances leading to pathologic consequences such as chronic inflammation, allergy or autoimmunity. In Chapter IV we investigate whether mast cells, a cell type previously restricted to the realm of allergy, impact the development of type 1 diabetes (T1D), a CD4+- and CD8+- T cell mediated disease. Mutations in c-kit, the receptor for stem cell factor which is necessary for mast cell survival, were backcrossed onto a genetic background susceptible to T1D resulting in a novel mast-cell deficient mouse, NODW/Wv. Characterization of these mice by histology and blood glucose analysis revealed that, although c-kit signaling is not necessary for the initiation of insulitis, without c-kit activity pancreatic islets remain relatively free of profound leukocyte invasion and the mice never progress to overt diabetes. Our data provides the first in vivo evidence that mast cells can significantly influence T1D and suggests that mast cells are crucial for progressive beta cell destruction.
机译：本文描述了研究免疫系统两个分支方面的研究。立即非特异性先天反应和下游靶向适应性反应。本论文的第三章探讨了控制T辅助细胞分化的分子机制，T辅助细胞是适应性免疫应答的关键成员。我们证明，Ikaros，对骨髓和胸腺中的早期淋巴细胞发育具有明确作用的造血细胞特异性转录因子，是外周T细胞中Th2细胞因子基因表达的正调节剂。发现来自幼稚Ikarosnull小鼠的CD4 + T细胞表达Th2细胞因子的能力降低，这与在Th2细胞因子基因位点检测到的组蛋白H3低乙酰化相对应，并且Ikarosnull中的GATA-3和c-maf表达降低，T-bet和STAT1表达升高细胞。这些数据支持Ikaros通过促进CD4 + T细胞分化过程中局部染色质可及性直接激活Th2基因表达的想法，并且还间接起到调节Th2和Th1特异性转录因子表达的作用。;自适应调节机制的破坏可能导致方向错误。对自身或无害物质的免疫反应，导致病理后果，例如慢性炎症，过敏或自身免疫。在第四章中，我们研究了肥大细胞（一种先前仅限于过敏领域的细胞类型）是否影响1型糖尿病（T1D），CD4 +和CD8 +-T细胞介导的疾病的发展。 c-kit（肥大细胞存活所必需的干细胞因子受体）中的突变回交到易患T1D的遗传背景上，从而产生了新型肥大细胞缺陷型小鼠NODW / Wv。通过组织学和血糖分析对这些小鼠进行表征显示，尽管c-kit信号对于引发炎性炎并不是必需的，但如果没有c-kit活性，胰岛仍然相对没有严重的白细胞侵袭，并且小鼠从未发展为明显的糖尿病。我们的数据提供了第一个体内证据，肥大细胞可以显着影响T1D，并表明肥大细胞对于进行性β细胞破坏至关重要。

著录项

  • 作者

    Quirion, Mary Ryan.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Molecular.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 180 p.
  • 总页数 180
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:29

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