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The role of the aryl hydrocarbon receptor in normal and malignant B cell development.

Sherr DH, Monti S - Semin Immunopathol (2013)

Bottom Line: Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease.Here, we focus on AhR expression and function during B cell differentiation.Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, MA, 02118, USA, dsherr@bu.edu.

ABSTRACT
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a "nominally activated" AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.

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Related in: MedlinePlus

AhR interactions with B cell differentiation decisions. A “bi-stable circuit” controls the decision of activated B cells to differentiate into antibody-secreting plasma cells. The consensus “all-or-none” switching pathway involves five interacting transcription factors: Prdm (encoding Blimp-1), AP1, Bach2, Pax5 (BSAP), Bcl6, and XBP1. The AhR has been shown to suppress the transcription of AP1, Prdm1, and IgM while enhancing the transcription of Bach2
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Fig2: AhR interactions with B cell differentiation decisions. A “bi-stable circuit” controls the decision of activated B cells to differentiate into antibody-secreting plasma cells. The consensus “all-or-none” switching pathway involves five interacting transcription factors: Prdm (encoding Blimp-1), AP1, Bach2, Pax5 (BSAP), Bcl6, and XBP1. The AhR has been shown to suppress the transcription of AP1, Prdm1, and IgM while enhancing the transcription of Bach2

Mentions: The contribution of the AhR to antibody secretion was studied extensively in a CD5+ murine B cell lymphoma line (CH12.LX). In early studies, it was shown that hyperactivation of the AhR with TCDD alters the ability of these AhR+ cells to produce antibody in response to LPS by binding to and inhibiting the transcription of the 3′ alpha immunoglobulin heavy chain gene [66–71]. Inhibition of antibody production was not seen in AhR− BCL-1 B cells [72]. AP1 (c-Jun), a component of the LPS-activated TLR-4 signaling pathway [73], also appeared to be targeted since its expression and function were downregulated by TCDD in AhR+ CH12.LX, but not in AhR− BCL-1, cells [72]. Follow-up studies further implicated the AhR in B cell differentiation by demonstrating that hyperactivated AhR decreases Blimp-1 expression and binding to the PAX5 gene promoter [66]. The decrease in Prdm1 (Blimp-1) transcription appears to be tied to the aforementioned decrease in AP1 since TCDD treatment decreased AP1 binding to Prdm1 [66]. Prdm1 transrepression may also be linked to an AhR-dependent transactivation of Bach2, a Prdm1 repressor [74]. That is, TCDD-activated AhR binds to a cognate site in the first intron of Bach2, increasing Bach2 expression and binding to the Maf elements in Prdm1 [74]. This circuit of transcription factors controlling B/plasma cell differentiation is summarized in Fig. 2.Fig. 2


The role of the aryl hydrocarbon receptor in normal and malignant B cell development.

Sherr DH, Monti S - Semin Immunopathol (2013)

AhR interactions with B cell differentiation decisions. A “bi-stable circuit” controls the decision of activated B cells to differentiate into antibody-secreting plasma cells. The consensus “all-or-none” switching pathway involves five interacting transcription factors: Prdm (encoding Blimp-1), AP1, Bach2, Pax5 (BSAP), Bcl6, and XBP1. The AhR has been shown to suppress the transcription of AP1, Prdm1, and IgM while enhancing the transcription of Bach2
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824572&req=5

Fig2: AhR interactions with B cell differentiation decisions. A “bi-stable circuit” controls the decision of activated B cells to differentiate into antibody-secreting plasma cells. The consensus “all-or-none” switching pathway involves five interacting transcription factors: Prdm (encoding Blimp-1), AP1, Bach2, Pax5 (BSAP), Bcl6, and XBP1. The AhR has been shown to suppress the transcription of AP1, Prdm1, and IgM while enhancing the transcription of Bach2
Mentions: The contribution of the AhR to antibody secretion was studied extensively in a CD5+ murine B cell lymphoma line (CH12.LX). In early studies, it was shown that hyperactivation of the AhR with TCDD alters the ability of these AhR+ cells to produce antibody in response to LPS by binding to and inhibiting the transcription of the 3′ alpha immunoglobulin heavy chain gene [66–71]. Inhibition of antibody production was not seen in AhR− BCL-1 B cells [72]. AP1 (c-Jun), a component of the LPS-activated TLR-4 signaling pathway [73], also appeared to be targeted since its expression and function were downregulated by TCDD in AhR+ CH12.LX, but not in AhR− BCL-1, cells [72]. Follow-up studies further implicated the AhR in B cell differentiation by demonstrating that hyperactivated AhR decreases Blimp-1 expression and binding to the PAX5 gene promoter [66]. The decrease in Prdm1 (Blimp-1) transcription appears to be tied to the aforementioned decrease in AP1 since TCDD treatment decreased AP1 binding to Prdm1 [66]. Prdm1 transrepression may also be linked to an AhR-dependent transactivation of Bach2, a Prdm1 repressor [74]. That is, TCDD-activated AhR binds to a cognate site in the first intron of Bach2, increasing Bach2 expression and binding to the Maf elements in Prdm1 [74]. This circuit of transcription factors controlling B/plasma cell differentiation is summarized in Fig. 2.Fig. 2

Bottom Line: Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease.Here, we focus on AhR expression and function during B cell differentiation.Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, MA, 02118, USA, dsherr@bu.edu.

ABSTRACT
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a "nominally activated" AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.

Show MeSH
Related in: MedlinePlus