DETERMINING THE ROLE OF THE AhR IN IMMUNOGLOBULIN EXPRESSION AND CLASS SWITCH RECOMBINATION A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By BASSAM F. KASHGARI B.S., King Abdul-Aziz University 2015 WRIGHT STATE UNIVERSITY
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DETERMINING THE ROLE OF THE AhR IN IMMUNOGLOBULIN
EXPRESSION AND CLASS SWITCH RECOMBINATION
A thesis submitted in partial fulfillment
of the requirements for the degree of
Master of Science
By
BASSAM F. KASHGARI
B.S., King Abdul-Aziz University
2015
WRIGHT STATE UNIVERSITY
WRIGHT STATE UNIVERSITY
GRADUATE SCHOOL
August 31st, 2015
I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Bassam Kashgari ENTITLED Determining the Role of the AhR in Immunoglobulin Expression and Class Switch Recombination BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science.
Courtney E.W. Sulentic, Ph.D. Thesis Director
Barbara E. Hull, Ph.D. Director of Microbiology and Immunology Program
College of Science and Mathematics
Committee on Final Examination
Courtney E. W. Sulentic, Ph.D.
Barbara E. Hull, Ph.D.
Nancy J. Bigley, Ph.D.
Katherine Excoffon, Ph.D.
Robert E. W. Fyffe, Ph.D.
Vice President for Research and Dean of the Graduate
School
iii
ABSTRACT
Kashgari, Bassam. M.S., Microbiology and Immunology Graduate Program, Wright State University, 2015. Determining the Role of the AhR in Immunoglobulin Expression and Class Switch Recombination.
The aryl hydrocarbon receptor (AhR) is a ligand-activated cytosolic transcription factor
that regulates xenobiotic-metabolizing enzymes. It mediates the toxicity of various
environmental chemicals such as 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). TCDD
inhibits the differentiation of B cells into antibody-secreting cells and inhibits
immunoglobulin (Ig) expression in various animal models. We have previously
determined that TCDD-induced inhibition of the mouse Ig heavy chain gene (mo-Igh) is
AhR-dependent. This inhibition may be mediated by binding of the AhR to dioxin
response elements (DREs) within the 3’Igh regulatory region (3’IghRR) and inhibition of
3’IghRR activity, a significant transcriptional regulator of Ig expression. However, there
are structural differences between the mouse and human 3’IghRR. The mouse contains
four enhancers (hs3A; hs1,2; hs3B; and hs4), whereas the human contains three (hs3;
hs1,2; and hs4). In addition, the human hs1,2 is known to be highly polymorphic and has
been associated with several autoimmune diseases. The current study focuses on
elucidating the role of the AhR in human Ig expression and class switch recombination
(CSR). We disrupted the AhR signaling pathway in a human B-cell line (CL-01) using
two different shRNA constructs or with the chemical AhR antagonist (CH-223191).
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Although the CL-01 AhR has three heterozygous single nucleotide polymorphisms
(SNPs) that results in loss of CYP1A1 gene induction, TCDD significantly inhibits IgG
expression, whereas IgM expression has very low sensitivity to TCDD. Interestingly,
decreased AhR protein levels results in low IgG expression, while there was no change in
IgM expression. In contrast, the AhR antagonist induced greater IgG secretion in
stimulated B cells, which was not replicated by the AhR knockdown suggesting a
mechanistic difference between the chemical antagonist and AhR knockdown. Reduced
AhR levels caused an isotype-specific inhibition of the CSR to IgG1, but not to IgG2,
IgA or IgE. These results demonstrate that there are different mechanisms regulating
different Ig isotypes. With the growing number of human immune-related disorders
correlating with the polymorphic hs1,2 enhancer, understanding the role of the AhR in
3’IGHRR activity and Ig expression could provide insight into potential therapeutic
interventions.
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TABLE OF CONTENTS
Page
I. INTRODUCTION…………………………………......………………………….1
The Aryl Hydrocarbon Receptor (AhR)……....…………………………..1
“V” donates vehicle control, and “T” donates TCDD. Cells were incubated for 96 hours,
then total RNA was extracted, 1 μg was reverse transcribed to cDNA, and 200 ng of
cDNA was used to amplify Cε germline transcripts and β-actin via PCR SYBR Green
real-time PCR (n=3 for each treatment group).
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IV. DISCUSSION
The AhR is a transcription factor that mediates the toxicity of various
environmental chemicals and regulates xenobiotic-metabolizing enzymes (Abel &
Haarmann-Stemmann, 2010). It has been shown in vitro in animal models that the AhR
mediates TCDD-induced inhibition of Ig expression by inhibiting the capacity of the
3’IghRR to increase Ig transcription (Wourms & Sulentic, 2015). However, the role of
AhR with TCDD on Ig expression remains elusive in humans. A study using primary B
cells isolated from human peripheral blood demonstrated reduced Ig expression in nine of
twelve human donor primary B cells when treated with TCDD, while cells from two
donors showed no response and one demonstrated enhanced Ig expression (Lu et al.,
2010). Additionally, IgE expression was enhanced by TCDD in tonsillar B lymphocytes
from atopic patients who are predisposed to type I hypersensitivity reactions (Kimata,
2003). Moreover, it has been shown that TCDD has no effect on IgM secretion but
induces the inhibition of IgG expression in a concentration-dependent manner in a human
B cell line CL-01 (Brooke Johnson, personal communication). Thus, we hypothesized
that the AhR mediates the effects of TCDD in human. However, it was not clear from our
experiments if TCDD's effects are mediated by the AhR because IgM expression was
refractory to TCDD in both AhR wild type (CL-01 WT) and AhR knockdown (shAhR)
cell lines (Figs. 14 and 15); and interestingly, we found a significant decrease in overall
IgG in shAhR cell lines (Figs. 11 and 13), which prevented analysis of TCDD's effects on
IgG. Expression of γ1 germline and functional transcripts were also dramatically inhibited
in the shAhR cells, but ε, α1, and γ2 transcripts were refractory to AhR knockdown (Figs.
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12, 13, 16, data not shown). However, decreased IgG expression with decreased AhR
expression contrasts with the increase in IgG expression following treatment with the
chemical AhR antagonist (AhRA) (Fig. 11). Differing effects between the AhRA and
AhR knockdown suggests an indirect effect through the involvement of other signaling
pathways. Alternatively, the effects of AhRA could be off-target effects. Additionally,
our sequencing results and lack of CYP1A1 induction (Figs. 8, 9, 10) demonstrate that
the AhR expressed in the CL-01 cells is likely incapable of directly transactivating genes
and suggests that our studies are evaluating the effects of protein-protein interaction
between the AhR and other transcription factors in the effect of IgG1 expression. These
results suggest the need of a functional AhR in order to mediate the effect of TCDD on
IgM expression. It also suggests a potential physiological role of the AhR in the
expression of and class switching to IgG1. Therefore, based on these studies we
hypothesize that different mechanisms are involved in regulating the expression of
different Ig isotypes
In our study we used the CL-01 cell line, which is an IgM and IgD expressing cell
line indicating a naive B-cell phenotype. However, low expression of IgG1 was detected
in unstimulated CL-01 cells, which suggests a spontaneous class switch. Since TCDD’s
effect on IgM was not reproducible and IgG was not detectable in AhR knockdown cells,
it is not clear whether the AhR or TCDD are affecting only Ig expression in post-
switched cells as opposed to some effect on CSR to IgG1 as well. Knocking down the
AhR results in a significant decrease in IgG. We can say that this decrease is at the
transcriptional level since we found no detectable γ1 IGH FT mRNA expression in the
shAhR cell lines (Fig. 12). Although TCDD significantly inhibited IgG expression in CL-
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01 WT cells we found no change in the protein and mRNA expression for IgM when
treated with TCDD, and decreased levels of the AhR also had no change on IgM
expression as well (Figs. 14 and 15). In addition, decreased levels of the AhR has no
effect on γ2, α1, and ε transcripts (Fig. 16, data not shown); however, γ1 germline and
functional transcripts were significantly inhibited in the shAhR cell lines (Figs. 12 and
13) suggesting an isotype-specific inhibition in CSR to IgG1 when knocking down the
AhR. Taken together these data support our hypothesis that different mechanisms are
involved in regulating the expression of different Ig isotypes.
Both the shAhR and the AhRA lower the AhR activity but through different
mechanisms, and they have an opposite effect on IgG expression. The AhRA inhibits the
AhR by blocking and keeping the AhR in the cytosol, and shAhR targets the AhR mRNA
for cleavage. Since the AhRA keeps AhR in the cytosol, the AhR is likely not directly
mediating the increase in IgG, but AhRA may increase IgG secretion through the
activation of signaling proteins associated with the cytosolic AhR, such as c-Src.
Alternatively, the increased IgG levels might due to off-target effects of the AhRA. The
inactive AhR is found as a cytosolic complex associated with different proteins, such as
p23, Hsp90, and XAP2 (Feltz et al., 2003; Meyer et al.,1999). Knocking down the AhR
may result in more AhR-associated proteins that can be free in the cytosol or bound to
other molecules. The AhR-associated proteins play roles in cell signaling and gene
expression, that can affect Ig expression and/or CSR, and these roles are not fully
understood (Cai, et al., 2011; Felts & Toft, 2003; Pearl & Prodromou, 2006).
We hypothesized a mechanism by which that the AhR-associated proteins might
lead to an isotype-specific inhibition of class switching to IgG1. Several studies human
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cell lines have shown that the AhR-associated proteins: p23, XAP2, and Hsp90, inhibit
the activation of the glucocorticoid receptor (GR), its transcriptional activity, its
occupancy of DNA, and the recruitment of its co-activators (Dalman et al., 1991;
Hutchison et. al., 1995; Freeman & Yamamoto, 2002; Wochnik et al., 2004; Laenger et
al., 2009). In addition, the GR pathway was shown to inhibit NF-κB activity in humans
(Nelson et al., 2003; Scheinman et al., 1995). Additionally, a study on a mouse cell-line
showed that NF-κB inhibits class switching to IgG1 (Bhattacharya et al., 2002).
Therefore, knocking down the AhR could release more AhR-associated proteins that can
be free in the cytosol that may inhibit GR, leaving GR more readily available to inhibit
NFkB whereas. In addition, the AhRA is known to inhibit the TCDD binding to the AhR
and the AhR translocation into the nucleus (Choi et al., 2012), but it is not known
whether it allows the activation of c-Src, a protein associated with the AhR. Activating c-
Src could activate a signaling cascade that activates the cell and increases Ig expression
(Enan & Matsumura, 1996). Moreover, there are several pathways that cross-talk with the
AhR that could be affected differently when knocking down (i.e. decreased AhR) versus
inhibiting the AhR (retained in cytosol), such as nuclear receptors, i.e. androgen,
estrogen, and progesterone (Ohtake et al., 2008) and NF-κB pathway (Vogel et al., 2013;
Sulentic et al., 2004a; Sulentic et al., 2004b), which inhibits the CSR to IgG1 in mice
(Bhattacharya et al., 2002).
Preliminary studies using a cytokine protein multiplex assay demonstrated some
differences in cytokine expression between the WT and the shAhR cell lines (data not
shown). For example, interleukin 7 (IL-7) was found in the WT cells but not the shAhR
cell lines. The role of IL-7 is well studied in the development of B cells, where it is
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required as an extrinsic signal for somatic recombination (Biuips et al., 1995; Corcoran
et al., 1998). However, mature B cells lack the IL-7 receptor (Oldham, 2012), and there
are no studies on mature B cells. In addition, Eotaxins, which are a CC chemokine
subfamily of eosinophil chemotactic proteins, were not found in the AhR WT B cells, but
were expressed in the shAhR B-cell lines (data not shown). They are known as
chemotactic, but they are not fully understood. In addition, recent studies on AhR-/-
knockout mice demonstrated significantly higher expression of IL-1β and IL-6 in AhR-/-
mice compared to WT in the liver and lung (Wu at el., 2011). Interestingly, our data do
not show a significant difference in IL-1β or IL-6 expression between the CL-01 WT and
shAhR cell lines. Another study showed an AhR-dependent regulation of IL-8 in
response to benzo(a)pyrene in macrophages (Podechard at el., 2008). These data
demonstrate the involvement of the AhR in cytokine expression, which may affect cell
signaling directly and/or indirectly, and potentially could affect the Ig expression.
Clearly, the AhR has distinct roles in B cells other than mediating the xenobiotic
metabolism. It is also showing a potential species differences in the way the AhR affects
the cytokine expression between human and mouse.
Although TCDD induces inhibition of IgM expression in a concentration-
dependent manner in mouse (Sulentic et.al., 1998; North et al., 2009), we could not see a
reproducible TCDD-induced effect on human IgM expression in the CL-01 B cells. In
total IgM protein expression was slightly inhibited by TCDD six times and had no effect
11 times (data not shown). Moreover, Cμ GLT mRNA expression was refractory to
TCDD. These data demonstrate that IgM expression in the CL-01 cell line is less
sensitive to TCDD. These different responses to TCDD could be a result of AhR
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polymorphisms, where some AhR isoforms show significantly less function in inducting
its marker gene (CYP1A1) compared to other isoforms. The CL-01 AhR has three SNPs
on exon 10 that abolished its ability to induce CYP1A1 promoter activity, which may
suggest that a functional AhR is needed to mediate TCDD-induced inhibition on IgM
expression. Additionally, the hs1,2 enhancer is polymorphic, where there is a 53 bp
invariant sequence (IS) within that enhancer that can exist one, two, three, or four times
(Fig. 5). There are several transcription factor binding sites in the IS including a DRE-
like motif, and the increase in the number of IS leads to an increase in the number of
binding sites, which may sensitivity. Our results demonstrate a reproducible inhibition of
IgG, which may be a result of an inhibition of CSR to IgG or perhaps the transcriptional
enhancers controlling Cμ versus Cγ expression have differential sensitivity to TCDD.
We used two different shAhR constructs for knocking down the AhR to avoid off-
target gene effects; however, this does not exclude possible indirect effects on the cellular
signaling pathways. Additionally, knocking down the AhR using shRNA requires a
continuous expression of shRNA, which brings the possibility of variability in
knockdown over time and the potential of off-target effects. Another limitation for this
study is that it has been conducted on only one cell line, which is a cancer cell line
bearing an abnormal chromosomal translocation. It is uncertain how definitive it is since
there are no other studies evaluating a physiological role of the AhR on human Ig
expression, and studies with AhR-/- knockout mice did not show a decrease in IgG levels
(Lawrence & Vorderstrasse, 2004). However, there are significant species differences
regarding the human and mouse AhR, Igh, and the 3’IghRR in gene sequence and likely
cellular signaling (Fernando et al., 2012; Sulentic & Kaminski, 2011; Sulentic et al.,
59
2004a). Moreover, to the best of our knowledge, this is the first human AhR inactivation
study evaluating Ig expression and CSR with TCDD. For future studies, we can further
investigate the ligand-independent role of the AhR in the expression of and CSR to IgG1.
This study showed a ligand-independent role of the AhR in IgG1 expression and CSR to
IgG1, but the mechanisms behind this effect is unclear. The AhR pathway cross-talks
with many other signaling pathways and can change cytokines expression (Wu at el.,
2011; Biuips et al., 1995; Corcoran et al., 1998; Vogel et al., 2013; Sulentic et al., 2004a;
Sulentic et al., 2004b; Ohtake et al., 2008), which may affect Ig expression and/or CSR
directly and/or indirectly. For example, the NF-κB pathway cross-talks with the AhR
pathway and can inhibit CSR to IgG1 in mouse B-cell lines (Vogel et al., 2013; Sulentic
et al., 2004a; Sulentic et al., 2004b). Thus, a future study could determine if NF-κB cross-
talks with the AhR and affects CSR in human B-cell lines. By using co-
immunoprecipitation and electrophoretic shift assays (EMSA), we can determine if the
AhR and NF-κB physically interact and associate with each other when AhR and NF-κB
are activated by TCDD and R848 respectively. Additionally, by knocking out NF-κB and
inducing CSR to different isotypes, using different B-cell stimuli, we can determine if
NF-κB plays a role in CSR to IgG1, as seen in mouse, or to any other isotype. In addition,
there are ongoing efforts in our laboratory to knockout the AhR using the genome-editing
system CRISPR, which should provide a more direct and permanent AhR knockout with
hopefully limited chances of off-target effects particularly those associated with
continuous expression foreign gene. We can also determine if the increase of IgG
expression by the AhRA is due to a completely off-target effect. Since there is no residual
AhR in the AhR-/- cell line, an increase in IgG expression could indicate a complete off-
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target effect. Our CL-01 B-cell line showed an increase in IgG expression by the AhRA
that may be a result of residual AhR (Fig 11). Moreover, to our knowledge, all of the
AhR polymorphism studies test for AhR functionality using upregulation of CYP1A1,
and the studies that showed variation in human Ig expression with TCDD did not test the
functionality of the AhR. Thus, developing human B-cell models expressing different
AhR polymorphisms would allow us to directly test if AhR polymorphisms impact Ig
expression and/or sensitivity of Ig expression to TCDD.
This study revealed for the first time a significant physiological, TCDD-
independent, role of the AhR and/or its associated proteins on the regulation of the
expression of and CSR to IgG1, but not to IgG2 or IgE. Inhibition of IgG1 was not seen
in AhR knockout mice, which indicated a species difference (Lawrence & Vorderstrasse,
2004). IgM expression was not affected by TCDD in CL-01 WT and shAhR cell lines.
These results support our hypothesis that different mechanisms are involved in regulating
the expression of different Ig isotypes. These results also support the limitation in
translating mouse AhR studies into human, which increases the need for more human
AhR studies, especially since the AhR cross-talks with other pathways and molecules. In
addition, understanding how the AhR-ligands modulate Ig expression and CSR and its
relation to the 3’IGHRR will provide insight into how chemically-induced immunotoxic
effects are mediated. The human hs1,2 enhancer in the 3’IGHRR is sensitive to chemical-
induced modulation and associated with a number of lymphomas and Ig-secreting
diseases (Fernando et al., 2012; Cianci et al., 2008; Heckman et al., 2003; Yan et al.,
2007; Aupetit et al., 2000; Tolusso et al., 2009; Pinaud et al., 2011). Understanding the
role of the AhR in mediating TCDD and Ig expression and class switching may provide
61
insight into the etiology of certain disease states and how they can be altered along with
how these diseases could be influenced by environmental exposures. Thus, further
elucidation of the AhR may also provide valuable insight into the identification and
quantification of humans health risks and opportunities for therapeutic intervention in
many immune-related disorders. Although human cell seem less sensitive to TCDD,
maybe due to the lower affinity of human AhR to TCDD, the AhR has a large number of
dietary, pharmaceutical and endogenous ligands that differ in affinity for human versus
mouse AhR and therefore may produce species-specific effects (Denison et al., 2011;
Flaveny et al., 2009). Finally, this study suggests potential off-target effects of the AhRA
on IgG expression and underscores the need for further studies to determine whether the
effects of the commonly used AhRA is truly an off-target effect or a novel alternative
signaling mechanism initiated through the inhibition of AhR nuclear translocation.
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