Presented at the 1777th Meeting of The Keio Medical Society in Tokyo, September 14, 2010.
Reprint requests to: Pierre Youinou, MD, DSc, Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609, Brest, France, E-mail:
Copyright © 2011 by The Keio Journal of Medicine
The sequence of events that leads to autoimmunity re-
mains unknown. Although variations in a number of
genes have been claimed to be associated with suscepti-
bility to anti-self responses,1 there is growing evidence
to indicate that, besides genetics, environmental factors
participate in the development of autoimmunity (e.g.,
drugs, ultraviolet light, infection and diet). The involve-
ment of such factors is reflected by the facts that the fre-
quency of the consequential abnormalities differs from
country to country and that geographic segregation of
patients suffering from a given autoimmune disease has
been identified. The perplexing observation that concor-
dance with respect to systemic lupus erythematosus
(SLE) is never 100% in monozygotic twins (MTs) raises
the question as to what happens to the transcription and
translation machineries between the genotype upstream
and the phenotype downstream. The discordance results,
at least in part, from epigenetics, which has been cited as
a mechanism by which cells with as few as 30,000 genes
differentiate into so many different cell types and vary
so extensively at different developmental and functional
In essence, gene mutations are permanent and affect
all cells when passed through the germline. In contrast,
epigenetics consists of stable (but reversible), and cell
type-specific (but heritable) changes in gene expression
Epigenetics and Autoimmunity,
with Special Emphasis on Methylation
Yves Renaudineau and Pierre Youinou
Epigenetics signifies stable and heritable changes in gene expression without changes in the
genetic code. There is a wealth of emerging evidence for such processes in promoting autoim-
munity. The first clue is that inhibition of DNA methyl transferases (DNMTs) induces systemic
lupus erythematosus (SLE) in animals. Similar immune-mediated disorders have been gener-
ated by injecting normal T cells incubated with DNMT inhibitors into healthy mice. Further,
monozygotic twins display differences in DNA methylation that parallel discordances in SLE.
Moreover, defects in DNA methylation characterize lymphocytes from SLE, synoviocytes from
rheumatoid arthritis, and neural cells from multiple sclerosis patients. It has also been shown
that DNA hypomethylation of T and B cells correlates with reduced DNMT efficacy and his-
tone acetylation in SLE. Once a gene promoter has been demethylated, the gene recovers its
capacity to be transcribed, e.g., genes for cytokines, activation receptors on cells, and endoge-
nous retroviruses. This outcome has been associated with a blockage of the Erk pathway and/
or a growth arrest at the G0/G1 interface of the cell cycle. Of importance is the fact that these
changes can be reversed. For example, blockade of the interleukin-6 autocrine loop in SLE B
cells restores DNA methylation status, thus opening new perspectives for therapy. (Keio J Med
60 (1) : 10－16, March 2011)
Keywords: epigenetics, autoimmune diseases, B cells, T cells
Laboratory of Immunology, Brest University Medical School Hospital,
and European University of Brittany, Brest, France
(Received for publication on October 8, 2010)
(Revised for publication on November 10, 2010)
(Accepted for publication on November 25, 2010)
Keio J Med 2011; 60 (1): 10－16 11
which are unrelated to DNA alterations. Thus, several
mechanisms govern gene expression over the cell cycle,
regulate lineage development throughout its ontogenesis,
and produce the response to environmental stimulations
and to biological modifications.
This series of events supports the notion that the im-
mune system is tightly regulated at the epigenetic level.
Furthermore, ensuing alterations antedate the emergence
of autoimmune traits and render genetically predisposed
individuals at risk of developing overt autoimmune dis-
ease.2 Of critical importance, these disturbances are not
restricted to idiopathic disorders, but have been implicat-
ed in the pathogenesis of autoimmune diseases induced
by chemicals or drugs.
Epigenetic modifications of the kind described above
are associated not only with autoimmune disorders but
also with various pathological conditions, including can-
cer, heart insufficiency and skin afflictions. This recog-
nition is the reason why the main purpose of the Epi-
genetics Session on the occasion of the 10th International
Symposium on Sjögren’s Syndrome, in Brest, France,3
was to focus on academic works to allow a more com-
prehensive view of the current state of the related re-
search. Further insights into these mechanisms may lead
to the ability to restore epigenetic mechanisms, thus of-
fering an exciting way to control the inflammatory pro-
The Scope of Epigenetic Mechanisms
Three main epigenetic checkpoints exist in a normally
regulated genome, DNA methylation, histone adjust-
ments and micro-RNA. For transcription factors (TFs) to
promote gene expression, they need to attach to their
binding sites on DNA promoters, thereby activating
them, and their target DNA must be accessible. Post-
translational modifications of TFs contribute to nuclear
translocation, oligomerisation, and binding to their target
DNA. This bulk of reactions accounts for the earliest
epigenetics processes. The most efficient way to silence
gene transcription is to prevent the binding of TFs to
DNA. To achieve this, DNA methyl transferases (DN-
MTs) convey a methyl group to the 5’ carbon position of
cytosines of cytosine-P-guanosine (CpG) dinucleotides
Most CpG is gathered together within specific regions,
collectively designated CpG islands, that exist in regula-
tory areas of the gene. The concentration of CpG motifs
reveals the propensity of 5-methylcytosine to mutate to
thymidine when CpG motifs are present outside active
genomic areas. A number of distinct DNMTs can be mo-
bilized, viz. DNMT1, DNMT2, DNMT3a, DNMT3b,
and DNMT3L. Among them, DNMT3a and DNMT3b
induce new methylations, whereas DNMT1 requires a
methylated cytosine on either of the strands and contrib-
utes to the maintenance of the DNA methylation pattern.
DNA demethylation can be passive or active. Cellular
replication encourages passive DNA demethylation of
the newly synthesized strand, as confirmed by inhibition
of DNMTs at the G0/G1 interface of the cell cycle.4 In
addition, DNA can be actively demethylated by enzymes
independently from DNA replication.
The reverse phenomena may also occur, and, instead
of being methylated by DNMTs, DNA is demethylated
by methyl-CpG-binding domain (MBD) proteins. Meth-
yl-CpG-binding domain protein-4 (MBD4) is a DNA
glycosylase that acts preferentially on hemi-methylated
CpG, and thereby completes demethylation by replacing
5-methylcytosine with unmethylated cytosine. However,
some controversy exist over the efficacy of this process
in mammalian cells.5
The nucleosome is the basic subunit of chromatin. It
comprises 146 base pairs (bp) of DNA wrapped around
an octamer of two copies each of H2A, H2B, H3 and H4
classes of histones. Nucleosomes, present at an estimat-
ed 10 million per cell, are organized into regular arrays
(Fig. 2). These structures present as small glomerular
proteins with a flexible N-terminal tail protruding from
the nucleosome that is accessible to modifications that
Fig. 1 Structure of cytosine and 5-methylcytosine: DNA (cytosine-5) methyl transferases (DNMTs) are responsible for methylating
12 Renaudineau Y, et al: Epigenetics and Autoimmunity
impart functional capacities to the histones. The modifi-
cations include acetylation, methylation, ubiquitination,
phosphorylation, sumoylation, deimination/citrullination,
ADP-ribosylation and proline isomerization.6 Each mod-
ification serves a specific purpose. Good examples of
opposite effects are enhancement of transcription by his-
tone H3K9 acetylation and repression of transcription by
histone H3K9 methylation.
DNA methylation and histone adjustments are en-
twined by multiple mechanisms. For example, it has
been shown that the MBD proteins selectively bind
methylated CpG and recruit histone deacetylase or his-
tone methyltransferase.7 In contrast H3K4m3, a tran-
scriptionally active variant, blocks the binding of
DNMT3L to DNA, which is essential for the action of
DNMT3a, and abrogates DNA methylation within tran-
scriptionally active regions.8
Micro-RNAs (miRNAs) consist of 21-23 bps of RNA
and function as post-translational regulators of gene ex-
pression.9 One-third of the human transcriptome is regu-
lated by 1,000 miRNAs. Some of them interact with
transcripts of genes that modulate DNA and histone
methylation.10 Conversely, miRNA expression can be af-
fected by DNA methylation11 and histone accommoda-
Factors of epigenetics
Given the absence of genetic differences between
MTs, they are ideal to evaluate epigenetic modifications
that are caused by environmental factors. Using periph-
eral blood lymphocytes from elderly and young MTs,
Fraga et al. have established that the pattern of DNA
Fig. 2 Acetylation and deacetylation of histones participate in the control of transcription. Addition of an acetyl group (Ac) by histone
acetyl transferase to the N-terminal tail of histones (H) is sufficient to decondense the chromatin, permit transcription factor (TF)
binding, and enable transcription. In contrast, histone deacetylase mediates chromatin condensation and gene silencing by removing
acetyl groups from histones.
Keio J Med 2011; 60 (1): 10－16 13
methylation of the two members of a pair of MTs, as
well as their H3 and H4 acetylation profile, diversifies
increasingly as they age.13 One reason for this is that to-
tal genomic 5-methyl cytosine content decreases with
age, but at different rates in one twin than the other. Sim-
ilarly, in tissue culture, genomic DNA is demethylated in
the long term, particularly DNA of those genes involved
in cell differentiation.14 A supplementary reason for in-
creased diversity of acetylation with age is that environ-
mental exposure is cumulative, so that there is every
likelihood that small initial differences will become sub-
stantial with time. Interestingly, the environmental theo-
ry was further supported by the observation that MTs
with the greatest differences in epigenetic modifications
were in those who had spent less of their life together.
Females produce equivalent transcripts from their
X-linked genes, as compared with males, even though
they have two X chromosomes. Equivalency results
from the inactivation of one of the two X chromosome
in each cell by a process termed dosage compensation.15
The inactive X chromosome is referred to as Xi, and is
characterized by high levels of DNA methylation, his-
tone modifications, and recruitment of the silencing his-
tone variant macro H2A. Of note, 35% of Xi-p genes
and 5% of Xi-q genes are partially active. Whether the
maternally derived or paternally derived X chromosome
is inactivated is randomly determined at the embryonic
stage and is maintained throughout life.
A number of drugs have been suspected of causing
SLE, most notably, procainamide, hydralazine and
5-azacytidine. Evidence has been provided by Richard-
son’s group16,17 that these drugs inhibit DNA methyla-
tion. The same investigators have reported data support-
ing an increase in lymphocyte function-associated anti-
gen expression and the ensuing proliferation of autoreac-
tive T cells in SLE patients.18
Human endogenous retroviruses
Eight per cent of the human genome derives from the
integration of retroviral sequences, together with their
long terminal repeats, that were incorporated into our
DNA more than 25 millions years ago.19 These human
endoretroviruses (HERVs) generally lack an extracellu-
lar phase, and the genetic material is neutralized by
Hypomethylated T Lymphocytes in SLE
Accumulation of autoreactive lymphocytes and pro-
duction of antibodies (Abs) against a wide range of self
antigens (Ags) are the hallmarks of autoimmune diseas-
es20 that damage kidneys, skin, lung and other organs.
The role of genetics has been suggested by the observa-
tion that the incidence of SLE is 5-fold higher in MTs
than in dizygotic twins. However, the concordance rate
between MTs can range from 5% to 75%, and these vari-
ations suggest the involvement of additional triggers
from the environment.21
CD4+ T cells are hypomethylated in SLE
The CD4+ lymphocytes of SLE patients, but not their
CD8+ T lymphocytes, manifest a defective capacity to
methylate their DNA; the degree of this inhibition corre-
lates with disease activity.22 The consequence of this
fault is that several methylation-sensitive autoreactivity-
promoting genes are overexpressed in CD4+ T cells, in-
cluding23-28 those for perforin, immunoglobulin (Ig)-like
receptor, interleukin (IL)-4, IL-6, and the B cell co-stim-
ulatory molecules CD70, CD6 and CD154.
However, the results of studies of methylating and de-
methylating enzymes in SLE patients are conflicting.
For example, DNMT1 and DNMT3a are down-regulated
in CD4+ T cells from SLE patients with active disease in
some,29,30 but not in all studies.31,32 According to some
investigators, two DNMT1-targeting miRNAs are up-
regulated in a number of patients,23 whereas, according
to other investigators, the MBD4 protein is up-regulated
in CD4+ and CD8+ T cells, but not in B cells, from pa-
tients with SLE.31,34,35
Variations have also been described in histones of
CD4+ T cells from patients with SLE.36 In particular, H3
and H4 acetylation levels have been shown to correlate
negatively with disease activity. Nevertheless, the degree
of methylation of global histone H3K9, but not that of
methylation of H3K4, is reduced in CD4+ T cells from
SLE patients, irrespective of disease activity.
Regulatory T cells and hypomethylation
Regulatory T cells (Treg) are characterized phenotypi-
cally by the expression of CD25 on their surface and TF
Foxp3 in their cytoplasm. Functionally, they are defined
by their suppressive effects on effector T lymphocytes, B
lymphocytes, and Ag-presenting cells. Foxp3 is the mas-
ter TF of Treg cell development. Its expression is indis-
pensable for Treg cells to exert their function. However,
it is believed that not all Foxp3-positive T cells possess
suppressive function. Supporting this suspicion is the
fact that that some individuals develop SLE despite hav-
ing a normal number of Foxp3+ T cells.37 One possible
explanation is that such Foxp3+ T cells are not genuine
Treg cells, but result from hypomethylation-induced
overexpression of Foxp3 in T cells that are not likely to
serve as Treg cells.38
14 Renaudineau Y, et al: Epigenetics and Autoimmunity
X chromosome and CD40 ligand
The greater prevalence of SLE in men with Klinefel-
ter’s syndrome suggests that, despite the presence of one
Y chromosome, the coexistence of two X chromosomes
may lead to the development of SLE.39 Similarly, the re-
cent observation that demethylation of the inactivated X
chromosome in CD4+ T cells from female SLE patients
is associated with overexpression of the B cell-stimulat-
ing CD40 ligand points to a potential reason for the fe-
male sex predominance in SLE.28
B Cell Abnormalities in SLE
CD5+ B cells are hypomethylated
The co-receptor CD5 is expressed in all T lymphocytes
and in a minor subpopulation of B lymphocytes at vari-
ous developmental and activation stages. Thus, CD5-ex-
pressing B lymphocytes are referred to as B1 cells,
whereas conventional CD5-nonexpressing B lympho-
cytes are designated B2 cells. The finding that B1 cells
produce polyreactive Abs with low-affinity binding to
multiple Ags, including self Ags, suggests that they are
the main source of natural Abs, and leaves the possibility
that, subsequently, they can also secrete pathogenic au-
Several facts support the view that DNA in B1 cells is
hypomethylated, and thereby the gene for CD5 is likely
to be transcribed into messenger RNA (mRNA). First,
the activity of DNMT1 is reduced in CD5+ B cells.35
Second, CD5+ B cells express a fusion transcript be-
tween an HERV and the CD5 gene.41 This HERV was
integrated into the genome at a time between the diver-
gence of New World monkeys from Old World monkeys
and the divergence of humans from Old World mon-
keys.42 When we reported this phenomenon, the new
exon 1 was designated exon 1B, and the known exon 1
was renamed exon 1A. The transcription of exon 1B is
normally regulated by methylation, and, contrary to all
expectations, its expression is restricted to B cells, i.e., it
depends on the methylation status. The third supporting
fact is that incubation of B2 cells with DNA methylation
inhibitors induces the expression of CD5-E1B similar to
that of B1 cells.35
Interestingly, selection of HERV-exon 1B down-regu-
lates the membrane level of the protein product in B
lymphocytes of patients with SLE.43 Exon 1B-contain-
ing mRNA codes for a truncated variant of CD5. Owing
to the lack of leader peptide, the protein cannot be trans-
located to the membrane and be used to facilitate anergy
of autoreactive B cells. This raises the possibility that
HERV demethylation participates in the pathogenesis of
CD5-negative B cells are hypomethylated in SLE
Given that B cell receptor-stimulated B2 cells from
SLE patients, but not from controls, express high
amounts of CD5-E1B, we have explored the DNA meth-
ylation status of B2 cells from patients with SLE.35
Analysis of the CpG sites in the U3 promoter region
present in the 5’ long-terminal repeats of HERV-CD5 us-
ing methylation-sensitive endonuclease assays followed
by polymerase chain reaction and bisulfite sequencing
revealed that CpG motifs are hypomethylated in B2 cells
from patients with SLE, as compared with those from
healthy controls (Fig. 3).
In addition to these observations, our studies have in-
dicated that cytokines may be involved in influencing
epigenetics. For example, IL-6 enables B cell differenti-
ation, maturation and Ig secretion. This multifunctional
cytokine is synthesized predominantly by monocytes, fi-
broblasts and endothelial cells, but can also be produced
by T and B cells. In humans, IL-6 gene polymorphism is
associated with SLE, and elevated IL-6 levels parallel
high disease activity and raised titres of anti-double-
stranded DNA Abs. Further, it has been shown that auto-
reactive B cells from SLE patients release high amounts
of IL-6 and that IL-6 experimental antagonism abolishes
spontaneous Ig production by restoring DNA methyla-
tion in SLE B cells.
Effects on the genesis of SLE
The direct implication of hypomethylated DNA in B
cells at the outset of SLE has recently been confirmed.48
B cells were purified from mice, treated ex vivo with
DNMT inhibitors, and subsequently reintroduced in syn-
geneic mice by adoptive transfer. The treatment promot-
ed antinuclear autoAb production in the recipient mice.
One of the most intriguing characteristics of epi-
genetics is the reversibility of its modifications. Al-
though there remains a need for new animal models and
specific cell-lines to test for suitable agents, some drugs
have already been used to treat murine malignancies.
Because controlling DNA methylation remains a chal-
lenge, several approaches have been proposed. These in-
clude blocking the autocrine IL-6 loop in SLE B cells,35
preventing adenosylmethionine degradation by decar-
boxylase, or regulating miRNAs. While our knowledge
of epigenetics in SLE is limited, the epigenome revolu-
tion has started, and new tools for diagnosis, prognosis,
and therapy should emerge in the near future.49,50
Keio J Med 2011; 60 (1): 10－16 15
The authors are grateful to Professor Tsutomu Takeu-
chi who kindly gave them the unforgettable opportunity
to present their data at the Keio Medical School, in To-
kyo, Japan. The editorial assistance of Professor Rizgar
A Mageed, Barts and the London Queen Mary School of
Medicine, London, UK, is greatly appreciated. Thanks
are also due to Simone Forest and Geneviève Michel for
their secretarial help.
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