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首頁> 外文學(xué)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.

機(jī)譯：免疫系統(tǒng)的分子和細(xì)胞調(diào)節(jié)：在1型糖尿病小鼠模型中，對Ikaros進(jìn)行Th2細(xì)胞譜系決定以及肥大細(xì)胞對疾病進(jìn)展的貢獻(xiàn)的研究。

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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.
機(jī)譯：本文描述了研究免疫系統(tǒng)兩個(gè)分支方面的研究。立即非特異性先天反應(yīng)和下游靶向適應(yīng)性反應(yīng)。本論文的第三章探討了控制T輔助細(xì)胞分化的分子機(jī)制，T輔助細(xì)胞是適應(yīng)性免疫應(yīng)答的關(guān)鍵成員。我們證明，Ikaros，對骨髓和胸腺中的早期淋巴細(xì)胞發(fā)育具有明確作用的造血細(xì)胞特異性轉(zhuǎn)錄因子，是外周T細(xì)胞中Th2細(xì)胞因子基因表達(dá)的正調(diào)節(jié)劑。發(fā)現(xiàn)來自幼稚Ikarosnull小鼠的CD4 + T細(xì)胞表達(dá)Th2細(xì)胞因子的能力降低，這與在Th2細(xì)胞因子基因位點(diǎn)檢測到的組蛋白H3低乙?；鄬?yīng)，并且Ikarosnull中的GATA-3和c-maf表達(dá)降低，T-bet和STAT1表達(dá)升高細(xì)胞。這些數(shù)據(jù)支持Ikaros通過促進(jìn)CD4 + T細(xì)胞分化過程中局部染色質(zhì)可及性直接激活Th2基因表達(dá)的想法，并且還間接起到調(diào)節(jié)Th2和Th1特異性轉(zhuǎn)錄因子表達(dá)的作用。;自適應(yīng)調(diào)節(jié)機(jī)制的破壞可能導(dǎo)致方向錯(cuò)誤。對自身或無害物質(zhì)的免疫反應(yīng)，導(dǎo)致病理后果，例如慢性炎癥，過敏或自身免疫。在第四章中，我們研究了肥大細(xì)胞（一種先前僅限于過敏領(lǐng)域的細(xì)胞類型）是否影響1型糖尿?。═1D），CD4 +和CD8 +-T細(xì)胞介導(dǎo)的疾病的發(fā)展。 c-kit（肥大細(xì)胞存活所必需的干細(xì)胞因子受體）中的突變回交到易患T1D的遺傳背景上，從而產(chǎn)生了新型肥大細(xì)胞缺陷型小鼠NODW / Wv。通過組織學(xué)和血糖分析對這些小鼠進(jìn)行表征顯示，盡管c-kit信號對于引發(fā)炎性炎并不是必需的，但如果沒有c-kit活性，胰島仍然相對沒有嚴(yán)重的白細(xì)胞侵襲，并且小鼠從未發(fā)展為明顯的糖尿病。我們的數(shù)據(jù)提供了第一個(gè)體內(nèi)證據(jù)，肥大細(xì)胞可以顯著影響T1D，并表明肥大細(xì)胞對于進(jìn)行性β細(xì)胞破壞至關(guān)重要。

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  • 作者

    Quirion, Mary Ryan.;

  • 作者單位

    Northwestern University.;

  • 授予單位 Northwestern University.;
  • 學(xué)科 Biology Molecular.;Health Sciences Immunology.
  • 學(xué)位 Ph.D.
  • 年度 2009
  • 頁碼 180 p.
  • 總頁數(shù) 180
  • 原文格式 PDF
  • 正文語種 eng
  • 中圖分類
  • 關(guān)鍵詞

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