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

描述（由申请人提供）：流行病学研究已经建立了2,3,7,8-四氯二苯并-对二恶英（TCDD）暴露与B细胞功能改变之间的关联，包括体液免疫抑制和非霍奇金淋巴瘤发病率增加。TCDD是一种普遍存在的、高度稳定的亲脂性环境污染物，会损害浆细胞的形成。这个五年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B细胞中BCL6的持续升高来介导的。BCL6的持续升高在大多数受tcdd影响的B细胞中促进能量和细胞死亡，在少数受tcdd影响但存活的B细胞中促进分化受损。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来抑制原发性体液免疫反应是TCDD产生的最敏感的后遗症之一，并且在几乎所有被调查的动物物种中都得到了证实。在现有的项目期间，其中最

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.