Impaired B cell Activation/Differentiation via Sustained BCL6 Expression by TCDD

TCDD 持续表达 BCL6 导致 B 细胞活化/分化受损

• 批准号: 8688243
• 负责人: Norbert E Kaminski
• 金额: $ 33.02万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688243
• 关键词: Address; Affect; Affinity; Animals; Aryl Hydrocarbon Receptor; B-Cell Activation; B-Lymphocytes; BCL6 gene; Binding; CD40 Ligand; CD80 gene; Cell Death; Cell physiology; Cells; ChIP-on-chip; Congenital Abnormality; Cytochrome P450; DNA Binding; Data; Dioxins; Disease; Down-Regulation; Environmental Pollution; Epidemiologic Studies; Exhibits; Food Chain; Funding; Gene Expression Microarray Analysis; Genes; Genome; Goals; Half-Life; Hepatotoxicity; Human; Humoral Immunities; Immune response; Immunobiology; Immunoglobulin M; Immunosuppression; Impairment; Incidence; Individual; Isoenzymes; Knowledge; Leukocytes; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Messenger RNA; Metabolic syndrome; Modeling; Molecular; Mouse Strains; Mus; Non-Hodgkin' s Lymphoma; PTPN6 gene; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Plasma Cells; Population; Proteins; Receptor Signaling; Regulation; Research; Role; STAT5A gene; Soil; Surface; Testing; Tetrachlorodibenzodioxin; Time; Toxic effect; Transcription Factor AP-1; Up-Regulation; Wasting Syndrome; anergy; base; chromatin immunoprecipitation; diabetes risk; human AHR protein; insight; mouse Ahr protein; p65; research study; response

DESCRIPTION (provided by applicant): Epidemiologic studies have established an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and altered B cell function including, suppression of humoral immunity and increased incidence of non-Hodgkin's lymphoma. TCDD is ubiquitous, highly stable, lipophilic environmental contaminants that impair plasma cell formation. The overall goal of this five-year research plan is to test the Hypothesis: Impaired human B cell function by TCDD is mediated through sustained elevation of BCL6 in activated B cells. This sustained elevation in BCL6 promotes anergy and cell death in the majority of TCDD-affected B cells and impaired differentiation in a smaller population of TCDD-affected but surviving B cells. Next to induction of certain cytochrome P-450 drug metabolizing isozymes, suppression of primary humoral immune responses by impairment of plasma cell formation is one of the most sensitive sequela produced by TCDD, and has been demonstrated in virtually every animal species investigated. During the existing project period, one of the most significant advancement has been the demonstration that in the majority of human donors evaluated, human primary B (HPB) cells exhibited similar sensitivity to TCDD as B cells from TCDD "responsive" mouse strains (e.g., C57Bl/6) in spite of the fact that the human aryl hydrocarbon receptor (AHR) has approximately ten-fold lower affinity for TCDD than the mouse AHR. The direct effects of TCDD on HPB cell function represents a longstanding "data gap", which we have begun to address and will continue in this competing renewal application. Moreover our results show, that in addition to decreased numbers of IgM secreting cells, TCDD- treatment caused elevated and sustained levels of BCL6, and decreased levels of CD80, CD69, pERK, p- p65/NF?B, and p-cJun, which are hallmarks of impaired B cell activation. Based on the above findings, a multifaceted cellular and molecular approach will be used to test our hypothesis using human primary B cells with the following specific aims (SA): SA1 is to determine the molecular mechanism responsible for impaired BCL6 down-regulation by TCDD in activated HPB cells; SA2 is to determine the role of TCDD-mediated induction of SHP-1 on suppression of B cell activation and function; SA3 is to establish the role of NFkB, AP-1 and BCL6 in TCDD-mediated impairment of CD80 up-regulation, a hallmark of altered B cell activation; and SA4 is to determine whether TCDD induces B cell anergy or an anergy-like phenotype. The significance of the proposed studies is that they will for the first time provide new and important information concerning the molecular mechanisms by which TCDD impairs human primary B cell function as well as offer new insights on how TCDD might contribute to the increased incidence of non-Hodgkin's lymphoma. Finally, the proposed experiments will provide new knowledge concerning the fundamental role of the AHR in B cell immunobiology.

描述（由申请人提供）：流行病学研究已经确定了2，3，7，8-四氯二苯并-对-二恶英（TCDD）暴露与B细胞功能改变（包括体液免疫抑制和非霍奇金淋巴瘤发病率增加）之间的相关性。TCDD是普遍存在的、高度稳定的亲脂性环境污染物，其损害浆细胞形成。这项为期五年的研究计划的总体目标是验证以下假设：TCDD对人类B细胞功能的损害是通过激活的B细胞中BCL 6的持续升高介导的。BCL-6的这种持续升高促进了大多数受TCDD影响的B细胞的无反应性和细胞死亡，并损害了少数受TCDD影响但存活的B细胞的分化。除了诱导某些细胞色素P-450药物代谢同工酶外，通过损害浆细胞形成抑制原发性体液免疫反应是四氯二苯并对二恶英产生的最敏感的后遗症之一，并且几乎在所有研究的动物物种中均得到证实。在现有项目期间， 显著的进展是证明了在大多数评估的人供体中，人原代B（HPB）细胞表现出与来自TCDD“应答”小鼠品系的B细胞相似的对TCDD的敏感性（例如，C57 B1/6），尽管事实上人芳烃受体（AHR）对TCDD的亲和力比小鼠AHR低大约10倍。TCDD对HPB细胞功能的直接影响代表了一个长期存在的“数据缺口”，我们已经开始解决这个问题，并将继续在这个竞争性的更新申请。结果表明，TCDD处理后，除IgM分泌细胞数量减少外，BCL 6水平升高并持续，CD 80、CD 69、pERK、p-p65/NF水平降低。B和p-cJun，它们是受损的B细胞活化的标志。基于上述发现，本研究将采用多方面的细胞和分子方法，以人原代B细胞为实验对象，以下列特定目标（SA）来验证我们的假设：SA 1是确定TCDD在活化的HPB细胞中导致BCL 6下调受损的分子机制; SA 2是确定TCDD介导的SHP-1对B细胞活化和功能的抑制作用; SA 3旨在确定NF κ B、AP-1和BCL 6在TCDD介导的CD 80上调损伤中的作用，这是B细胞活化改变的标志; SA 4旨在确定TCDD是否诱导B细胞无反应性或无反应样表型。拟议的研究的意义在于，它们将首次提供有关TCDD损害人类原发性B细胞功能的分子机制的新的和重要的信息，并提供有关TCDD如何可能导致非霍奇金淋巴瘤发病率增加的新见解。最后，所提出的实验将提供新的知识有关的基本作用的AHR在B细胞免疫生物学。