How environmental chemicals impair immunity

环境化学物质如何损害免疫力

• 批准号: 7909634
• 负责人: David H Sherr
• 金额: $ 14.35万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909634
• 关键词: Address; Affect; Apoptosis; Apoptotic; Aromatic Polycyclic Hydrocarbons; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Caspase; Cell Death; Cell Line; Cells; Cessation of life; Chemicals; Complex; Development; Down-Regulation; Elements; Event; Family member; Genes; Goals; Hematopoietic; Immune; Immune system; Immunity; In Vitro; Knock-out; Knockout Mice; Lymphopoiesis; MALDI-TOF Mass Spectrometry; MAPK8 gene; Maps; Mediating; Mitochondria; Modeling; Molecular; Mus; Mutant Strains Mice; NF-kappa B; Pathway interactions; Phosphotransferases; Relative (related person); Research Design; Resources; Role; Signal Pathway; Signal Transduction; Stromal Cells; TP53 gene; Techniques; Testing; Work; Xenobiotics; base; caspase-2; caspase-8; environmental chemical; immunotoxicity; in vivo; mutant; programs; receptor

DESCRIPTION (provided by PI): The goal of these studies is to determine the molecular mechanisms by which environmental chemicals impair immune cell development. While many studies demonstrate that environmentally ubiquitous polycyclic aromatic hydrocarbons (PAH) suppress the mature immune system, relatively few have evaluated their effects on the developing immune system. To bridge this gap, we exploited B cell development models to define how PAH affect bone marrow B cells. We demonstrated that PAH suppress B lymphopoiesis by inducing pro-B and pre-B cell apoptosis mediated indirectly through stromal cells constituting the hematopoietic microenvironment. These studies led to the hypothesis that the developing B cell compartment is exquisitely sensitive to environmental chemicals, which inappropriately activate B cell death programs. Our recent studies have begun to elucidate the cascade of signals that executes the B cell death program. The working model built on these studies proposes at least two potentially overlapping pathways, one involving caspase-8 and another involving mitochondrial activation. A combination of unique resources, including apoptosis gene-defective, nontransformed early B cell lines and a stable of knockout mice will be exploited to test and to refine this model. Three specific aims are proposed: 1) Define PAH-induced, caspase-8-dependent, apoptosis signaling pathways in bone marrow B cells (D. 1): We will: a) determine the role of death receptors in caspase-8 activation, b) evaluate the contribution of JNK, PKR, and ASK1 kinases to caspase-8-dependent apoptosis, and c) identify components of activated caspase-8 complexes by mass spectrometry (MALDI-TOF). 2) Evaluate factors contributing to mitochondria-dependent apoptosis signaling. (D.2): The elements of a PAH-induced mitochondrial apoptosis amplification pathway will be mapped out. Specifically, we will: a) determine the roles of caspases-2 and -8 in mitochondrial activation mediated by Bid, b) assess the contribution of JNK, PKR and p53 in caspase-independent mitochondrial activation, and c) define where NF-kappaB down-regulation, a prerequisite to PAH-induced pro/pre-B cell death, interfaces with caspase signaling. 3) Investigate in vivo correlates of the apoptosis pathway mapped out in vitro. (D.3): To build on results obtained in vitro, we will use gene-knockout mice: a) to determine the relative sensitivities of bone marrow B cell subsets to AhR-dependent apoptosis signaling in vivo and b) to investigate PAH-induced, caspase-dependent death signaling in bone marrow B cell subsets in vivo. These studies will not only contribute greatly to our understanding of the molecular effects of PAH on developing B cells, but they also will validate a platform that is easily applicable to the study of other immunotoxic environmental chemicals and other hematopoietic cell subsets on the molecular level.

描述（PI提供）：这些研究的目的是确定环境化学物质损害免疫细胞发育的分子机制。 虽然许多研究表明，环境中普遍存在的多环芳烃（PAH）抑制成熟的免疫系统，但相对较少评估其对发育中的免疫系统的影响。 为了弥补这一差距，我们利用B细胞发育模型来确定PAH如何影响骨髓B细胞。 我们证明PAH通过诱导前B和前B细胞凋亡间接介导构成造血微环境的基质细胞来抑制B淋巴细胞生成。 这些研究导致了这样的假设，即发育中的B细胞区室对环境化学物质非常敏感，这些化学物质不适当地激活了B细胞死亡程序。 我们最近的研究已经开始阐明执行B细胞死亡程序的信号级联。 建立在这些研究基础上的工作模型提出了至少两个潜在的重叠途径，一个涉及caspase-8，另一个涉及线粒体激活。 一个独特的资源组合，包括凋亡基因缺陷，非转化的早期B细胞系和一个稳定的敲除小鼠将被利用来测试和完善这个模型。 提出了三个具体的目标：1）确定PAH诱导的，caspase-8依赖的，骨髓B细胞凋亡的信号通路（D。1）、我们将：a）确定死亡受体在caspase-8活化中的作用，B）评估JNK、PKR和ASK 1激酶对caspase-8依赖性细胞凋亡的贡献，以及c）通过质谱法（MALDI-TOF）鉴定活化的caspase-8复合物的组分。 2)评估促进细胞凋亡信号传导的因素。 (D.2)：将绘制出PAH诱导的线粒体凋亡放大途径的要素。 具体而言，我们将：a）确定半胱天冬酶-2和-8在Bid介导的线粒体活化中的作用，B）评估JNK、PKR和p53在半胱天冬酶非依赖性线粒体活化中的作用，和c）确定NF-κ B下调（PAH诱导的前/前B细胞死亡的先决条件）与半胱天冬酶信号传导的相互作用。3)研究体外绘制的凋亡途径的体内相关性。 (D.3)为了建立在体外获得的结果，我们将使用基因敲除小鼠：a）确定骨髓B细胞亚群对体内AhR依赖性凋亡信号的相对敏感性和B）研究体内骨髓B细胞亚群中PAH诱导的半胱天冬酶依赖性死亡信号。 这些研究不仅将大大有助于我们了解PAH对发育中的B细胞的分子效应，而且还将验证一个易于适用于在分子水平上研究其他免疫毒性环境化学品和其他造血细胞亚群的平台。

项目成果

Induction of PreB cell apoptosis by 7,12-dimethylbenz[a]anthracene in long-term primary murine bone marrow cultures.

• DOI: 10.1006/taap.1997.8263
• 发表时间: 1997-12
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Koichi Yamaguchi;Raymond A. Matulka;Alexander M. Shneider;Paul Toselli;A. Trombino;Shi Yang

Disruption of human plasma cell differentiation by an environmental polycyclic aromatic hydrocarbon: a mechanistic immunotoxicological study.

• DOI: 10.1186/1476-069x-9-15
• 发表时间: 2010-03-24
• 期刊: Environmental health : a global access science source
• 作者: Allan LL;Sherr DH
• 通讯作者: Sherr DH

The role of peritoneal stromal cells in the survival of sIgM+ peritoneal B lymphocyte populations.

腹膜基质细胞在 sIgM 腹膜 B 淋巴细胞群存活中的作用。

• DOI: 10.1006/cimm.1995.1008
• 发表时间: 1995
• 期刊: Cellular immunology
• 影响因子: 4.3
• 作者: Hardin,JA;Yamaguchi,K;Sherr,DH
• 通讯作者: Sherr,DH

Immunoglobulin light chain, Blimp-1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis.

免疫球蛋白轻链、Blimp-1 和细胞色素 P4501B1 肽作为 AL 淀粉样变性的潜在疫苗。

• DOI: 10.1038/icb.2011.73
• 发表时间: 2012
• 期刊: Immunology and cell biology
• 影响因子: 4
• 作者: Flies,Amanda;Ahmadi,Tahamtan;Parks,AshleyJ;Prokaeva,Tatiana;Weng,Liangping;Rolfe,SandraSolomon;Seldin,DavidC;Sherr,DavidH
• 通讯作者: Sherr,DavidH

Environmental chemical-induced pro/pre-B cell apoptosis: analysis of c-Myc, p27Kip1, and p21WAF1 reveals a death pathway distinct from clonal deletion.

环境化学物质诱导的 pro/pre-B 细胞凋亡：对 c-Myc、p27Kip1 和 p21WAF1 的分析揭示了与克隆删除不同的死亡途径。

• DOI: 10.4049/jimmunol.170.10.4897
• 发表时间: 2003
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ryu,Heui-Young;Mann,KorenK;Schlezinger,JenniferJ;Jensen,Brenda;Sherr,DavidH
• 通讯作者: Sherr,DavidH