Thesis Reference Genetic mechanisms for the expression of endogenous retroviral envelope glycoprotein gp70 implicated in murine systemic lupus erythematosus BAUDINO, Lucie Clementine Abstract The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes as an acute phase protein. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of Xeno, PT or mPT gp70 RNAs in livers in various strains of mice. Our results demonstrated that the expression of different gp70 RNAs was remarkably heterogeneous among mouse strains and that serum gp70 production was regulated by multiple genes in physiological vs. inflammatory conditions. In addition, we observed a contribution of PT and mPT gp70s, in addition of Xeno gp70, to serum gp70. Furthermore, we observed an increased expression of intact mPT env RNA, regulated by the Sgp3 locus, in all lupus-prone mice, as compared with non-autoimmune strains of mice. Finally, we demonstrated that TLR7 played a critical role in the expression of gp70 and in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone mice may possess a unique genetic mechanism responsible for the expression of mPT retroviruses, which could act as a triggering factor through activating [...] BAUDINO, Lucie Clementine. Genetic mechanisms for the expression of endogenous retroviral envelope glycoprotein gp70 implicated in murine systemic lupus erythematosus. Thèse de doctorat : Univ. Genève, 2010, no. Sc. 4234 URN : urn:nbn:ch:unige-107313 DOI : 10.13097/archive-ouverte/unige:10731 Available at: http://archive-ouverte.unige.ch/unige:10731 Disclaimer: layout of this document may differ from the published version. 1 / 1
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Thesis
Reference
Genetic mechanisms for the expression of endogenous retroviral
envelope glycoprotein gp70 implicated in murine systemic lupus
erythematosus
BAUDINO, Lucie Clementine
Abstract
The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is
secreted by hepatocytes as an acute phase protein. To better understand the genetic basis of
the expression of serum gp70, we analyzed the abundance of Xeno, PT or mPT gp70 RNAs
in livers in various strains of mice. Our results demonstrated that the expression of different
gp70 RNAs was remarkably heterogeneous among mouse strains and that serum gp70
production was regulated by multiple genes in physiological vs. inflammatory conditions. In
addition, we observed a contribution of PT and mPT gp70s, in addition of Xeno gp70, to
serum gp70. Furthermore, we observed an increased expression of intact mPT env RNA,
regulated by the Sgp3 locus, in all lupus-prone mice, as compared with non-autoimmune
strains of mice. Finally, we demonstrated that TLR7 played a critical role in the expression of
gp70 and in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone
mice may possess a unique genetic mechanism responsible for the expression of mPT
retroviruses, which could act as a triggering factor through activating [...]
BAUDINO, Lucie Clementine. Genetic mechanisms for the expression of endogenous
retroviral envelope glycoprotein gp70 implicated in murine systemic lupus
__________________________________________________________________________ a Levels of total (WT, D1 and D2), D1 and D2 mPT env RNAs (mean ± SD of 4 mice)
in livers of 2-3 mo-old NZB, BXSB, B6.Sgp3 or B6 female mice 9 h after an i.p.
injection of different stimulators or PBS were quantified relative to a standard curve
generated with serial dilutions of a reference cDNA preparation and normalized using
TBP mRNA. Results are expressed as fold increases of each transcript relative to PBS-
injected NZB, BXSB, B6.Sgp3 or B6 mice. b P value of comparison between LPS- and PBS-injected mice. * P < 0.01;
** P < 0.005; *** P < 0.0005; **** P < 0.0001 c Not detectable.
- 121 -
Figure legends
Figure 1. Semi-quantitative RT-PCR analysis for WT, D1 and D2 mPT env RNAs in
NZB and BXSB mice.
Semi-quantitative RT-PCR analysis for WT, D1 and D2 mPT env RNAs with reverse
primers specific for the three different mPT env genes (mPT1447R, D1-R and D2-R)
and a common forward mPT-specific primer (mPT858F) was carried out with 4-fold
serially diluted cDNAs from 2-3 mo-old female mice. As a control, the abundance of
GAPDH mRNA was assessed in parallel. For the analysis of WT mPT env transcripts in
NZB and BXSB mice, the first dilution of cDNA was 1:40, and four serial dilutions of
cDNAs were examined, while for D1/D2 mPT env RNAs and GAPDH mRNA the first
dilution was 1:10. Representative results of three individual mice analyzed are shown.
Figure 2. Quantitative real-time RT-PCR analysis of D1 mPT env RNA in livers of
NZB mice injected with 1V136, CpG, IL-1β, IL-6, TNFα, IFNβ or PBS.
Levels of D1 mPT env RNA (mean ± SEM of 4 mice) in livers of 2-3 mo-old NZB
female mice 9 h after an i.p. injection of different stimulators or PBS were quantified
relative to a standard curve generated with serial dilutions of a reference cDNA
preparation and normalized using TBP mRNA. Results are expressed as fold increases
of D1 mPT env RNA relative to PBS-injected NZB mice. P value of comparison with
PBS-injected mice. * P < 0.05; ** P < 0.01; *** P < 0.0001
- 122 -
WT
D1
D2
GAPDH
BXSB BXSB + LPS
WT
D1
GAPDH
NZB NZB + LPS
Figure 1
WT
D1
D2
GAPDH
BXSB BXSB + LPS
WT
D1
GAPDH
NZB NZB + LPS
WT
D1
D2
GAPDH
BXSB BXSB + LPS
WT
D1
GAPDH
NZB NZB + LPS
Figure 1
- 123 -
Figure 2
0
5
10
15
LPS CpG1V136 IL-1ββββ IL-6 TNFαααα IFNββββ PBS
Fol
d ch
ange
*** ***
***
**
***
Figure 2
0
5
10
15
LPS CpG1V136 IL-1ββββ IL-6 TNFαααα IFNββββ PBS
Fol
d ch
ange
*** ***
***
**
***
0
5
10
15
LPS CpG1V136 IL-1ββββ IL-6 TNFαααα IFNββββ PBS
Fol
d ch
ange
*** ***
***
**
***
- 124 -
Supporting Information
Figure S1. Levels of serum gp70 and hepatic retroviral gp70 RNAs in B6.Sgp3
homozygous and heterozygous mice.
(A) Serum levels of gp70 in 2-3 mo-old Sgp3 homozygous (NN), Sgp3 heterozygous
(NB) and WT B6 (BB) mice (µg/ml; mean ± SEM of 7-10 mice). Note that
heterozygous mice had intermediate levels of serum gp70 between homozygous and
WT mice. P values of comparison between homozygous and heterozygous mice and
between heterozygous and WT mice: P< 0.0001.
(B) Levels of each gp70 RNA in livers of 2-3 mo-old Sgp3 homozygous (NN), Sgp3
heterozygous (NB) and WT B6 (BB) mice (mean ± SEM of 4 female mice) were
quantified relative to a standard curve generated with serial dilutions of a reference
cDNA preparation and normalized using TBP mRNA. Results are expressed as fold
increases of each transcript relative to B6 mice. P values of comparison for xenotropic
gp70 RNA between homozygous and WT mice and between heterozygous and WT
mice: P <0.001 and P < 0.005, respectively. P values of comparison for PT gp70 RNA
between homozygous and heterozygous mice and between heterozygous and WT mice:
P <0.0001. P values of comparison for mPT gp70 RNA between homozygous and
heterozygous mice and between homozygous and WT mice: P <0.005.
(C) The presence of three different species of mPT env RNAs in livers of 2-3
Sgp3 homozygous (NN), Sgp3 heterozygous (NB) and WT B6 (BB) mice was
determined by RT-PCR with mPT specific gp70 forward and p15E-R reverse primers.
Representative results of three individual animals are shown. As a control (Ctl ), a
mixture of three different plasmids containing WT, D1 and D2 clones obtained from B6
mice was included. Note the predominant expression of WT env transcripts in Sgp3
homozygous (NN) mice, as compared with heterozygous (NB) and WT B6 (BB) mice.
- 125 -
Figure S1
Serum gp70
NN NB BB0
10
20
30
gp70
(µµ µµg
/ml)
A
C
WT
D2D1
Ctl NN NB BB
Xeno RNA
NN NB BB0.0
2.5
5.0
7.5
PT RNA
NN NB BB0.0
2.5
5.0
7.5
mPT RNA
NN NB BB0
10
20
B
Fol
d ch
ange
Figure S1
Serum gp70
NN NB BB0
10
20
30
gp70
(µµ µµg
/ml)
A
C
WT
D2D1
Ctl NN NB BBC
WT
D2D1
Ctl NN NB BB
Xeno RNA
NN NB BB0.0
2.5
5.0
7.5
PT RNA
NN NB BB0.0
2.5
5.0
7.5
mPT RNA
NN NB BB0
10
20
B
Fol
d ch
ange
- 126 -
III.4. The Sgp3 Locus Derived from the 129 Strain is Responsible for Enhanced
Endogenous Retroviral Expression in macroH2A1-deficient Mice
Lucie Baudino, John R. Pehrson and Shozo Izui
Submitted for publication (to the Journal of Virology)
- 127 -
The Sgp3 Locus Derived from the 129 Strain is Responsible for Enhanced
Endogenous Retroviral Expression in macroH2A1-deficient Mice
Lucie Baudino,1 John R. Pehrson,
2 and Shozo Izui
1*
Department of Pathology and Immunology, University of Geneva, Geneva,
Switzerland,1 and Department of Animal Biology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 191042
Running title: Regulation of Endogenous Retroviral Expression
* Corresponding author. Mailing address: Department of Pathology and Immunology,
Centre Médical Universitaire, 1211 Geneva 4, Switzerland.
_____________________________________________________________________________________________________________________ a Serum levels of gp70 (µg/ml; mean ± SEM of 7 female mice at 2-3 months of age).
b Levels of each gp70 RNA and macroH2A1 mRNA (mean ± SEM of 4 female mice at 2-3 months of age) were quantified relative to a
standard curve generated with serial dilutions of a reference cDNA preparation and normalized using TBP mRNA. Results are expressed as
fold increases of each transcript relative to B6 WT mice. c Not tested.
- 145 -
Figure legends
FIG. 1. Genetic map of the chromosome 13 in B6 macroH2A1-/-, B6.NZB-Sgp3 and
B6.NZB.Sgp3a mice. Diagrams indicate the segment of the chromosome 13 derived from
macroH2A1-/- 129 mice in macroH2A1-/- B6 mice (left panel), and from NZB mice in
B6.NZB-Sgp3 (middle panel) and B6.NZB-Sgp3a congenic (right panel) mice. Black sections
indicate the region that is definitely 129 (left panel) or NZB (middle and right panels), and
grey sections the region which cannot be defined as B6 or 129 (left panel) and as B6 or NZB
(middle and right panels). In each panel, the position of selected microsatellite markers from
the centromere is indicated as Mb.
FIG. 2. RT-PCR analysis for WT, D1 and D2 mPT env genes in B6 mice deficient in
macroH2A1 and B6.Sgp3a subcongenic mice.
(A) The presence of three different species of mPT env RNAs in livers of 2-3
mo-old B6 female mice was determined by RT-PCR with mPT specific gp70 forward and
p15E-R reverse primers. Representative results of three individual animals are shown. Note
the predominant expression of WT env transcripts in macroH2A1-/- B6 (KO ) and B6.Sgp3a
subcongenic mice, as compared with WT B6 mice. As a control (Ctl ), a mixture of three
different plasmids containing WT, D1 and D2 clones obtained from B6 mice was included.
(B) Semi-quantitative RT-PCR analysis for WT, D1 and D2 mPT env RNAs with reverse
primers specific for the three different mPT env genes (mPT1447R, D1-R and D2-R) and a
common forward mPT-specific primer (mPT858F) was carried out with 5-fold serially diluted
cDNAs from different B6 mice. As a control, the abundance of GAPDH mRNA was assessed
in parallel. Four 5-fold dilutions of cDNAs were examined for WT mPT env RNA, while
three 5-fold dilutions of cDNAs were examined for D1/D2 mPT env RNAs and GAPDH
mRNA. Representative results of three individual mice analyzed are shown.
FIG. 3. Analysis for PT and mPT RNAs in macroH2A1-/- and WT 129 mice.
(A) Levels of PT and mPT gp70 RNAs from livers of 2-3 mo-old 129 mice (means ± SEM of
5 mice) were quantified relative to a standard curve generated with serial dilutions of a
reference cDNA preparation and normalized using TBP mRNA. Results are expressed as fold
changes of each transcript in macroH2A1-/- mice (KO ) relative to WT mice.
(B) The presence of two different species of mPT env RNAs in livers of macroH2A1-/- and
WT 129 mice was determined by RT-PCR with mPT specific gp70 forward and p15E-R
- 146 -
reverse primers. Representative results of three individual animals are shown. Lane 1,
macrH2A1-/- 129; lane 2, WT 129; lane 3, macroH2A1-/- B6; lane 4, WT B6.
(C) The presence of WT, D1 and D2-specific mPT env proviral sequences in 129 and B6 mice
was analyzed by genomic PCR with reverse primers specific for the three different mPT env
genes and a common forward mPT-specific primer.
- 147 -
Figure 1
D13Mit254
D13Mit13
D13Mit139
macroH2A1
NZB-Sgp3
D13Mit26
Mb
80
70
60
50
D13Mit248
macroH2A1
macroH2A1 KO
D13Mit99
NZB-Sgp3a
macroH2A1
D13Mit26
D13Mit123
D13Mit254
D13Mit283
D13Mit313
80
70
60
50
80
70
60
50
Figure 1
D13Mit254
D13Mit13
D13Mit139
macroH2A1
NZB-Sgp3
D13Mit26
Mb
80
70
60
50
D13Mit248
macroH2A1
macroH2A1 KO
D13Mit99
NZB-Sgp3a
macroH2A1
D13Mit26
D13Mit123
D13Mit254
D13Mit283
D13Mit313
80
70
60
50
80
70
60
50
D13Mit254
D13Mit13
D13Mit139
macroH2A1
NZB-Sgp3
D13Mit26
Mb
80
70
60
50
80
70
60
50
D13Mit248
macroH2A1
macroH2A1 KO
D13Mit99
NZB-Sgp3a
macroH2A1
D13Mit26
D13Mit123
D13Mit254
D13Mit283
D13Mit313
80
70
60
50
80
70
60
50
80
70
60
50
80
70
60
50
- 148 -
WT
D2D1
Ctl B6 KO Sgp3a NZBA
Figure 2
WT
D1
D2
GAPDH
KO Sgp3 B6B
WT
D2D1
Ctl B6 KO Sgp3a NZBA
WT
D2D1
Ctl B6 KO Sgp3a NZBA
Figure 2
WT
D1
D2
GAPDH
KO Sgp3 B6B
WT
D1
D2
GAPDH
KO Sgp3 B6B
- 149 -
129 129 B6B6 129 B6
WT D1 D2C
Figure 3
B1 2 3 4
WTD2D1
KO WT KO WT0.0
0.5
1.0
1.5
Fol
d ch
ange
APT mPT
129 129 B6B6 129 B6
WT D1 D2C
129 129 B6B6 129 B6
WT D1 D2129 129 B6B6 129 B6
WT D1 D2C
Figure 3
B1 2 3 4
WTD2D1
B1 2 3 41 2 3 4
WTD2D1
KO WT KO WT0.0
0.5
1.0
1.5
Fol
d ch
ange
APT mPT
KO WT KO WT0.0
0.5
1.0
1.5
Fol
d ch
ange
APT mPT
- 150 -
- 151 -
IV. GENERAL DISCUSSION
- 152 -
- 153 -
IV. General Discussion
IV.1. Genetic Origin of Serum Retroviral gp70
ERVs are classified as Eco, Xeno or polytropic viruses according their host range
dictated by their respective gp70 proteins. Based on differences in their gp70 nucleotide
sequences, four subgroups of Xeno proviruses (Xeno-I, Xeno-II, Xeno-III and Xeno-IV) as
well as two subgroups of polytropic proviruses termed PT and mPT, are identified in the
C3H, CBA and BALB/c lacks the zinc finger unit of the Zfp759, unlike NZW, MRL, 129,
AKR, B6 and B10. But this polymorphism is not associated with high or low serum levels of
gp70 (Figure 8). On-going RT-PCR analysis revealed an increased expression of Zfp458 and
Zfp455 mRNAs in B6.Sgp3 congenic mice, as compared with WT B6 mice. However, the
observed expression difference is not consistent with the hypothesis of Sgp3 being the loss of
a repressor, as the expression would thus to be expected to be higher in B6 than in B6.Sgp3
mice. Thus, Zfp458 and Zfp455 are unlikely to be a candidate gene for Sgp3. In contrast, we
have observed approximately 5-fold and 2-fold lower levels of Zfp708 and Zfp712 mRNAs,
respectively, in B6.NZB-Sgp3 and B10.BXSB-Sgp3 congenic mice than in WT B6 and B10
mice.
As the Sgp3 locus contains at least four distinc genetic elements which regulate the
expression of ERVs under steady-state and inflammatory conditions, we will not limit our
search for the Sgp candidate genes to those located within the BAC 45-N-22 clone. The
Zfp457 gene presents polymorphism similar to that found in the Zfp759 gene (239). However,
we observed that the strain distribution of the polymorphic allele of the Zfp457 gene is
identical to that of the Rsl1 gene among various strains of mice, arguing against Zfp457 as a
candidate for Sgp3 (Figure 8). Rsl2 and Zfp456 sequences are intermingled in some strains of
mice, resulting in a hybrid gene (239). However, comparison between high-gp70 and low-
gp70 mice showed no association of this mutation with high-gp70 strains of mice, as this
mutation was not present in BXSB, NFS and DBA/2 mice (Figure 8). On-going analysis of
mRNA levels for different Zfp genes revealed that lack of the expression of Zfp595 mRNA in
B6.Sgp3 mice, while it is abundantly present in B6 mice, indicating that Zfp595 is an
additional candidate gene for Sgp3. Clearly, more extensive analysis of other Zfp genes
present in the Sgp3 locus should be able to help identify the additional candidate genes for
Sgp3.
Since Zfp708, Zfp712 and Zfp595 could be so far potential candidates for Sgp3, we
will explore this possibility in vitro and in vivo. Using primary hepatocytes isolated from
B6.Sgp3 and WT B6 mice, we will determine whether the transduction of the WT Zfp708,
Zfp712 or Zfp595 gene could reduce the secretion of gp70 in vitro and the abundance of Xeno,
PT or mPT gp70 RNA in Sgp3-bearing hepatocytes. Finally, the results obtained in vitro can
be confirmed by the generation and analysis of B6.NZB-Sgp3 mice overexpressing the wild-
type allele of the Sgp3 candidate gene in liver.
- 163 -
Figure 8: Polymorphism of Rsl1, Rsl2, Zfp759 and Zfp457 in several strains of mice in
relation with serum levels gp70. a: Mice homozygous for allele identical to NZB; b: Mice
homozygous for allele identical to C57BL/6. ND: not determined.
IV.5. Role of TLR7 and ERVs in Murine SLE
TLR7 is an innate immune receptor specific for single-stranded RNA and plays a
critical role in the development of autoimmune responses against nuclear autoantigens in
murine SLE (243). Our studies demonstrated that the formation of gp70 IC was completely
suppressed in TLR7-deficient B6 mice congenic for the Nba2 locus, an NZB-derived major
lupus susceptibility locus, which contributes to overall production of various lupus antibodies
(73, 100). This indicates the implication of TLR7 in the formation of gp70 IC. Our results
suggest an active role of ERVs through interaction with TLR7 for the development of
autoimmune responses against serum retroviral gp70. This idea is consistent with the finding
that B10.Yaa mice had increased levels of gp70 IC in sera by the presence of the Sgp3 locus,
which promotes the expression of ERVs (235).
NZB mice spontaneously produce a very high titer of replication-competent Xeno
viruses from birth (230), while they fail to express Eco viruses because of the lack of Eco
sequences in their genome (244). In addition, we observed a more than 100-fold increased
levels of mPT env RNA derived from mPT proviruses bearing the intact env gene, but not
Strain
NZB
NZW
MRL
BXSB
NFS
129
AKR
DBA/2
C57BL/6
C57BL/10
C3H/HeJ
CBA
BALB/c
gp70
High
High
High
High
High
High
High
High
Low
Low
Low
Low
Low
Sgp3
a
a
a
a
ND
a
ND
ND
b
b
b
b
b
Rsl1
a
a
a
a
a
a
a
a
b
b
a
a
a
Rsl2
a
a
a
b
b
a
a
b
b
b
b
b
b
Zfp759
a
b
b
a
a
b
b
a
b
b
a
a
a
Zfp457
a
a
a
a
a
a
a
a
b
b
a
a
a
Strain
NZB
NZW
MRL
BXSB
NFS
129
AKR
DBA/2
C57BL/6
C57BL/10
C3H/HeJ
CBA
BALB/c
gp70
High
High
High
High
High
High
High
High
Low
Low
Low
Low
Low
Sgp3
a
a
a
a
ND
a
ND
ND
b
b
b
b
b
Rsl1
a
a
a
a
a
a
a
a
b
b
a
a
a
Rsl2
a
a
a
b
b
a
a
b
b
b
b
b
b
Zfp759
a
b
b
a
a
b
b
a
b
b
a
a
a
Zfp457
a
a
a
a
a
a
a
a
b
b
a
a
a
- 164 -
those bearing the defective env gene, in NZB, BXSB and Sgp3-congenic B6 and B10 mice as
compared with B6 and B10 mice. Such an increase was also observed in two other lupus-
prone NZW and MRL mice, but not in non-autoimmune strains of mice we tested. This
indicates that lupus-prone mice possess a unique genetic mechanism responsible for a very
high-level expression of mPT retroviruses. Consistent with our findings, it has been reported
that an 8.4-kb transcript corresponding to the full-length size mPT retroviruses was expressed
uniquely in thymi of NZB, BXSB and MRL mice, while the expression of full-length
transcripts of Xeno and PT viruses was not limited to lupus-prone mice (234). Although
endogenous mPT viruses are likely to be replication defective, replication-competent and
infectious recombinant viruses containing the mPT gp70 sequence can be generated. These
recombinant viruses utilize the XPR1 cell-surface receptor for infection of mice (XPR1
expressed in the laboratory strains of mice confers susceptibility to PT and mPT retroviruses,
but not to Xeno virus due to the Xpr1 polymorphism). Therefore, one could speculate that
abundant and preferential expression of mPT proviruses possessing an intact env gene in
lupus-prone mice could facilitate the generation of replication-competent mPT-derived
infectious viruses through recombination with Xeno viruses, and these infectious viruses may
act as a triggering factor for the development of murine SLE. In fact, we have attempted to
isolate replication-competent infectious retroviruses containing mPT gp70 sequence from
lupus-prone mice through co-culturing spleen cells from NZB mice with two different target
cell lines, Mus dunni and Fischer rat embryo cells, both of which are devoid of endogenous
Xeno, PT and mPT retroviruses. Significantly, PCR analysis has shown the presence of mPT-
derived proviral sequences in both target cells co-cultivated with spleen cells from 5 mo-old
NZB mice, in addition to Xeno sequences. These data suggest that NZB mice might
spontaneously generate mPT-derived replication-competent infectious retroviruses or
recombinant virus carrying mPT env gene. Obviously, future studies will be to identify the
genetic origin of this infectious virus and determine whether such virus can promote the
development of SLE in mice predisposed to autoimmune diseases.
It has well been established that DC play a pivotal role in the induction and regulation
of the immune response, because immature, non-activated DC that capture autoantigens
induce self tolerance, while the activation of antigen-loaded DC triggers their maturation and
enables them to induce antigen-specific immunity. A particular role of pDC, a subset of DC
which highly express TLR7, in SLE has been proposed, since this DC subset has been
identified as the major source of IFNα (245), a cytokine that plays a substantial role in the
development of SLE (131, 246). Thus, one attractive hypothesis would be that ERVs could
enter in the pDC through endocytosis and gain access to TLR7, leading to the activation of
- 165 -
pDC. Activated pDC rapidly secrete copious amounts of IFNα, and to a lesser extent
proinflammatory cytokines such as IL-6 or TNFα (247). Notably, TNFα is responsible, in
part, for driving the differentiation of immature DC into mature antigen-presenting cells, and
IL-6 and IFNα promote differentiation of plasma cells. Thus, excessive activation of pDC by
ERVs could play an important role in the accelerated development of SLE.
Since TLR7 is not a cell surface receptor but expressed in endosome, the activation of
pDC by ERVs might be dependent on XPR1, which allows their internalization and
subsequent interaction with TLR7 in endosome. Notably, the expression of Xpr1 mRNA in
pDC has been confirmed by RT-PCR. In addition, one cannot exclude the possibility that non-
infectious Xeno viruses internalized through other receptors can activate pDC through
stimulating TLR7 in endosome. For example, Xeno viruses in the form of IC with IgG anti-
gp70 autoantibodies can be internalized through FcγR and subsequently interact with
endosomal TLR7 in pDC (Figure 9A). However, it is unlikely that this is a mechanism to
trigger pDC and initiate autoimmune responses against nuclear and gp70 antigens in SLE,
since the production of IgG anti-gp70 autoantibodies (to form stimulating gp70 IC) is
prerequisite for this process. Instead, this mechanism can sustain the production of IFNα
through IC-mediated activation of pDC, thereby establishing a vicious cycle not only
aggravating the autoimmune process but also promoting the development of autoimmune
responses against a wide array of autoantigens that do not engage TLR. This idea is
supporting by the observation that TLR7 is responsible for enhanced autoimmune responses
against not only DNA- and RNA-related antigens but also several glomerular matrix antigens
(147).
Furthermore, retroviruses can directly activate anti-gp70 autoreactive B cells. ERVs
could be recognized by anti-gp70 BCR, then endocytosed where RNAs of ERVs gain access
to TLR7, inducing TLR signaling cascade and the activation of anti-gp70 autoreactive B cells
(Figure 9B). In this regard, it should be stressed that the activation of anti-gp70 autoreactive
B cells does not necessarily require infectious retroviruses, since ERVs can be internalized
through BCR but not through XPR1. This is also the case for the activation of pDC following
the interaction of ERV-anti-gp70 IC with FcγR. Thus, if high titers of ERVs are produced by
the presence of the Sgp loci, this might be sufficient to trigger anti-gp70 autoimmune
responses in mice predisposed to SLE. These autoimmune responses can be further
accentuated during the course of SLE as a result of activation of pDC and macrophages in
response to IgG IC containing nuclear antigens and ERVs, thereby accelerating the
development of lupus nephritis.
- 166 -
Figure 9: Possible activation by ERVs of pDC and anti-gp70 autoreactive B cells through
TLR7. A. IgG anti-gp70-ERV IC can be internalized through FcγR and subsequently interacts
with endosomal TLR7 in pDC. ERVs bearing PT or mPT gp70 can be also internalized
through the XPR1 entry receptor, leading to the activation of endosomal TLR7. B. Specific
recognition of ERVs by anti-gp70 BCR on autoreactive B cells can lead to their
internalization and to activation of TLR7.
pDC
FcγγγγR
TLR7
TLR7 Signaling
Nucleus
αααα-gp70
Endosome
EndosomeTLR Signaling
Nucleus
TLR7
Anti-gp70 B cell
A
B
.
.
.
.
.
.
.
.
Retrovirus
αααα-gp70BCR
Retrovirus
pDC
FcγγγγR
TLR7
TLR7 Signaling
Nucleus
αααα-gp70
Endosome
EndosomeTLR Signaling
Nucleus
TLR7
Anti-gp70 B cell
A
B
..
..
..
..
..
..
...
...
Retrovirus
αααα-gp70BCR
Retrovirus
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It has been shown that neonatal infection with a murine leukemia virus isolated from
NZB mice induced a lupus-like autoimmune syndrome in (BALB/c x NZB)F1 mice, although
the genetic origin of this virus was not studied (232). In addition, the possible importance of
ERVs as a triggering factor for autoimmune responses in SLE has also been suggested by the
production of anti-nuclear autoantibodies in Sgp3 and GIX congenic mice (248-250).
Furthermore, a more recent study has shown that Raltegravir, a drug which inhibits retroviral
integrase, induced accumulation of pre-integration cDNA of ERVs, which may increase type I
IFN responses, thereby accelerating the development of kidney disease in lupus-prone (NZB x
NZW)F1 mice (251). This finding is consistent with the demonstration that the absence of 3’
repair exonuclease 1 (Trex1) contributes to the development of lupus-like autoimmune
syndrome (252). Collectively, all theses results further support the implication of ERVs in
SLE.
In addition to the contribution of TLR7 and TLR9 to the development of autoimmune
responses against nuclear antigens as well as retroviral gp70, we observed that the stimulation
of TLR7 and TLR9 induced high levels of serum gp70 in NZB mice in kinetics identical to
those induced by LPS or inflammatory cytokines. Notably, activation of TLR7 and TLR9 in
monocytes/macrophages induced the secretion of IL-6 and TNFα (253, 254), both of which
are a good inducer of APP. These data indicate that TLR7 and TLR9 are implicated in the
acute phase expression of serum gp70. Thus, we can speculate that DNA- and RNA-
containing IgG IC activate macrophages through interaction with FcγR and then TLR7 and
TLR9, which induce secretion of cytokines such as IL-6 and TNFα, acting as a positive
feedback on the production of serum gp70 and ERVs. Thus, TLR7 and TLR9 display dual
effects on the development of SLE. On one hand, they promote autoimmune responses
against nuclear and retroviral antigens through the activation of autoreactive B cells as well as
pDC, and on the other hand, they enhance the production of serum gp70 in the presence of the
Sgp loci, thereby providing an additional source for antigenic stimulation and for
nephritogenic IC formation.
All these results allow us to propose the following mechanism (Figure 10). The
expression of ERVs depends on their presence in the genome and the site of integration or
transcriptional regulation. Xeno, PT and mPT viruses contribute to steady-state levels of
serum gp70. Sgp3 and Sgp4 are the major genetic loci controlling the expression of serum
gp70 and ERVs. ERVs internalized through XPR1 receptor and/or FcγR stimulate TLR7
signaling cascade in pDC. Activated pDC aggravate autoimmune process, leading to increases
of various autoantigen-autoantibody IC, such as DNA-anti-DNA IC, implicated in lupus
nephritis. Furthermore, retroviral gp70 can be recognized by anti-gp70 BCR resulting in the
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activation of gp70-specific autoreactive B cell through TLR7 signaling. The production of
IgG anti-gp70 autoantibodies and subsequent formation of gp70 IC further contributes to the
development and progression of lupus nephritis. In addition, IgG IC containing nucleic acids
activate macrophages via TLR signaling, resulting in the production of inflammatory
cytokines, which further enhance the production of serum gp70 and ERVs.
Figure 10: Model of the implication of ERVs in murine SLE.
A possible contribution of ERVs to the development of human SLE has long been
suspected. With the use of polyclonal antibodies raised against murine and feline leukemia
viruses, the presence of an antigen related to mammalian retroviral core protein, p30, was
reported in immune deposits of glomerular lesions from human SLE patients (255). In
addition, the presence of free anti-gp70 antibodies of the simian sarcoma virus-simian
sarcoma-associated virus (256) or woolly monkey type C virus has been described in humans
(257). However, the search for the presence of serum retroviral gp70 (or its counterpart) and
for gp70 IC has, until now, not been successful in human SLE patients. One possible
explanation for this failure may be a lack of appropriate antibodies to specifically detect
retroviral gp70 antigens implicated in human SLE.
Nevertheless, a member of human ERVs, called multiple sclerosis (MS)-associated
retroviral agent (MSRV), was isolated in leptomeninges, choroid plexus and monocyte
cultures of MS patients (258-261). The MSRV Env protein was shown to stimulate activation
Retrovirus
Provirus
gp70
Anti-gp70
gp70-αααα-gp70 IC
Lupus Nephritis
Sgp3/4 Sgp3
TLR7
Nba2
Anti-DNA
DNA-αααα-DNA IC
TLR7
Nba2
TLR7TLR7
MacrophagesTLR7/9Retrovirus
Provirus
gp70
Anti-gp70
gp70-αααα-gp70 IC
Lupus Nephritis
Sgp3/4 Sgp3
TLR7
Nba2
Anti-DNA
DNA-αααα-DNA IC
TLR7
Nba2
TLR7TLR7
MacrophagesTLR7/9
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of T lymphocytes (262) and the production of inflammatory cytokines (263-265), suggesting
that MSRV are involved in the pathogenesis of MS. Moreover, the possible role of Xeno
murine leukemia virus-related virus (XMRV) has recently been claimed in the pathogenesis
of human prostate cancer and chronic fatigue syndrome (CFS) (266, 267). XMRVs were
linked to prostate cancer in patients deficient for ribonuclease L (RNase L), which is an
effector of innate anti-viral responses (266). R462Q RNase L variant, showing a decreased
activity compared to wild-type enzyme, was found in 13% of prostate cancer cases, and 40%
of patients homozygous for the R462Q allele harbored the genome of XMRV. Furthermore,
XMRV sequences essentially identical to those isolated from patients with prostate cancer
were found in 67% of CFS patients (267). Infectious XMRVs were detected in activated B
and T cells of CFS patients. CFS patient-derived XMRVs were infectious either by cell-
associated (through co-culture) or cell free (through the plasma) transmission. In contrast to
the prostate cancer study, CFS study did not reveal any link between XMRV infection and
RNase L polymorphism. It is worth noting that the XMRV sequence is not found in human
genome, suggesting that XMRVs must have been acquired exogenously from rodents.
However, transfer of XMRV from rodent to human would require unlikely high levels of
rodent exposure for our society. Therefore, it has been suggested that XMRV may have been
resident in the human population for some time (266). Clearly, further studies are awaited to
define whether XMRVs are indeed a contributing factor in the pathogenesis of prostate cancer,
CFS and possibly other human diseases. Nevertheless, the possible role of MSRV or XMRVs
in the pathogenesis of different human diseases argues in favor of a possible contribution of
either human or murine retroviruses to human SLE. Further research on molecular basis
responsible for the expression of ERVs implicated in murine SLE will enable us to address
the relevance of their human counterparts, thus providing a clue for a potential role of ERVs
in human SLE.
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- 171 -
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