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.

Public Health Relevance

Dioxin and dioxin-like compounds are ubiquitous environmental contaminants present in soil and at all levels of the food chain. Dioxins produce a variety of toxic responses in mammals including wasting syndrome disease, liver toxicity, birth defects, metabolic syndrome, an increased risk of diabetes and cancer, and especially relevant to this application, immune suppression. This project uses white blood cells as a model to elucidate the mechanisms responsible for toxicity produced by dioxins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002520-26
Application #
8531930
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Humble, Michael C
Project Start
1981-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
26
Fiscal Year
2013
Total Cost
$327,599
Indirect Cost
$107,099
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
De Abrew, K Nadira; Phadnis, Ashwini S; Crawford, Robert B et al. (2011) Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 252:150-8
Sulentic, Courtney E W; Kaminski, Norbert E (2011) The long winding road toward understanding the molecular mechanisms for B-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 120 Suppl 1:S171-91
Lu, Haitian; Crawford, Robert B; Kaplan, Barbara L F et al. (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells. Toxicol Appl Pharmacol 255:251-60
North, Colin M; Crawford, Robert B; Lu, Haitian et al. (2010) 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated suppression of toll-like receptor stimulated B-lymphocyte activation and initiation of plasmacytic differentiation. Toxicol Sci 116:99-112
De Abrew, K Nadira; Kaminski, Norbert E; Thomas, Russell S (2010) An integrated genomic analysis of aryl hydrocarbon receptor-mediated inhibition of B-cell differentiation. Toxicol Sci 118:454-69
Lu, Haitian; Crawford, Robert B; Suarez-Martinez, Jose E et al. (2010) Induction of the aryl hydrocarbon receptor-responsive genes and modulation of the immunoglobulin M response by 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary human B cells. Toxicol Sci 118:86-97
Lu, Haitian; Crawford, Robert B; North, Colin M et al. (2009) Establishment of an immunoglobulin m antibody-forming cell response model for characterizing immunotoxicity in primary human B cells. Toxicol Sci 112:363-73
North, Colin M; Crawford, Robert B; Lu, Haitian et al. (2009) Simultaneous in vivo time course and dose response evaluation for TCDD-induced impairment of the LPS-stimulated primary IgM response. Toxicol Sci 112:123-32
Schneider, Dina; Manzan, Maria A; Crawford, Robert B et al. (2008) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated impairment of B cell differentiation involves dysregulation of paired box 5 (Pax5) isoform, Pax5a. J Pharmacol Exp Ther 326:463-74
Boverhof, Darrell R; Tam, Elaine; Harney, Allison S et al. (2004) 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells. Mol Pharmacol 66:1662-70

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