Immune dysregulation by psychosocial distress

描述（由申请人提供）：乳腺癌的诊断以及乳腺癌治疗的负担使妇女面临心理社会困扰的风险。心理社会困扰损害免疫系统，影响自然杀伤细胞和细胞因子的产生。这对乳腺癌患者特别重要，因为乳腺癌可能对自然杀伤细胞和细胞因子有反应。免疫系统的这些组分通过保护免受肿瘤起始、原发性肿瘤生长和肿瘤转移而有助于癌症控制。在过去的十年中，被诊断患有乳腺癌形式的妇女人数显着增加，称为导管原位癌（DCIS）。DCIS患者数量的增加是由于高分辨率筛查乳房X光检查的广泛使用。DCIS是一个重要的临床管理问题，诊断为DCIS的女性面临着困难的治疗选择，不仅必须权衡癌症复发的风险，还要权衡她们的个人价值。我们的初步数据显示，DCIS妇女经历的心理社会困扰，其特征是情绪障碍，焦虑和感知压力升高。伴随着这种心理困扰的是免疫失调，其特征是自然杀伤细胞功能降低和细胞因子干扰素γ的产生减少。这种对免疫系统的影响可能会对乳腺癌患者的整体健康和生活质量产生相当大的影响。然而，令人惊讶的是，我们对所观察到的免疫失调的分子基础知之甚少。本项目的总体目的是在分子水平上确定这种免疫失调的基础。这种鉴定将通过确定是否外周血单核细胞表观遗传修饰，随后的心理社会困扰，介导的免疫失调。该项目的具体目标是：1）确定诊断为DCIS的女性中与心理社会困扰介导的免疫失调相关的外周血单核细胞表观遗传模式。2)评估表观遗传修饰是否与DCIS女性患者的特异性免疫反应基因失调相关。这个为期两年的发展/试点（R21）项目将在2个数据收集时间段评估DCIS女性，一个是乳腺癌诊断后，另一个是癌症治疗完成后2个月。结果将与匹配的妇女对照组进行对比。该项目的设计将提供外周血单核细胞亚群的鉴定，具有可证实的表观遗传模式修饰。一旦确定，这些子集将通过染色质免疫沉淀和聚合酶链反应进行评估，以确定观察到的表观遗传效应是否与这些女性中失调的特定免疫应答基因的调节区域相关。以前没有完成过这样的分析，这项研究将首次调查心理社会痛苦对免疫系统的表观遗传影响。确定这种免疫失调的表观遗传基础将提供新的见解的影响，心理社会困扰，并允许未来的发展的手段来管理这种失调。这种管理不仅可以减少免疫失调的长期不良影响，还可以改善这些患者的整体健康和生活质量。

DESCRIPTION (provided by applicant): Diagnosis of breast cancer as well as the burden of breast cancer treatment put women at risk for psychosocial distress. Psychosocial distress impairs the immune system, impacting both natural killer cells and the production of cytokines. This is of particular importance to breast cancer patients because breast cancer can be responsive to natural killer cells and cytokines. These components of the immune system contribute to cancer control by protection from tumor initiation, primary tumor growth, and tumor metastasis. In the past decade, the number of women diagnosed with the form of breast cancer known as ductal carcinoma in situ (DCIS) has markedly increased. This increase in the number of DCIS patients is due to the widespread use of high- resolution screening mammography. DCIS is a significant clinical management problem and women diagnosed with DCIS face difficult treatment choices that must be weighed against not only the risk of cancer recurrence but also their personal values. Our preliminary data show that women with DCIS experience psychosocial distress that is characterized by elevated mood disturbance, anxiety, and perceived stress. Accompanying this psychosocial distress is immune dysregulation characterized by reduced natural killer cell function and reduced production of the cytokine interferon y. Such effects upon the immune system may have considerable impact upon the overall health and quality of life of breast cancer patients. However, surprisingly little is known about the molecular basis for the observed immune dysregulation. It is the overall purpose of this project to identify, at the molecular level, the basis for this immune dysregulation. This identification will be accomplished by determining whether peripheral blood mononuclear cell epigenetic modifications, subsequent to psychosocial-distress, mediate the immune-dysregulation. The specific aims of the project are to: 1) Identify peripheral blood mononuclear cell epigenetic patterns associated with psychosocial-distress mediated immune-dysregulation in women who are diagnosed with DCIS. 2) Evaluate whether epigenetic modifications are associated with specific dysregulated immune response genes in women with DCIS. This two-year developmental/pilot (R21) project will evaluate women with DCIS at 2 data collection time periods, one following breast cancer diagnosis and one 2 months after completion of cancer treatment. Results will be contrasted with a comparison group of matched women. The design of this project will provide for an identification of the peripheral blood mononuclear cell subsets, with demonstrable epigenetic pattern modification. Once identified, these subsets will be evaluated by chromatin immunoprecipitation and polymerase chain reaction to determine whether the observed epigenetic effects are associated with regulatory regions of specific immune response genes dysregulated in these women. No such analysis has been accomplished previously and this study will provide the first investigation of the epigenetic effects of psychosocial distress upon the immune system. Identification of an epigenetic basis for this immune-dysregulation will provide new insight into the effects of psychosocial-distress and will allow for future development of the means by which to manage this dysregulation. Such management will not only reduce the long-term adverse effects of immune-dysregulation but will also improve the overall health and quality of life of these patients.