REVIEW

Epigenetics and Autoimmunity,with Special Emphasis on Methylation
Yves Renaudineau and Pierre Youinou

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)

Epigenetics signifies stable and heritable changes in gene expression without changes in thegenetic code. There is a wealth of emerging evidence for such processes in promoting autoimmunity. The first clue is that inhibition of DNA methyl transferases (DNMTs) induces systemic
lupus erythematosus (SLE) in animals. Similar immune-mediated disorders have been generated 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 fromrheumatoid arthritis, and neural cells from multiple sclerosis patients. It has also been shownthat DNA hypomethylation of T and B cells correlates with reduced DNMT efficacy and histone 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 endogenous 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 thesechanges 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
Introduction

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 andtranslation machineries between the genotype upstream
and the phenotype downstream. The discordance results,
at least in part, from epigenetics, which has been cited asa mechanism by which cells with as few as 30,000 genes
differentiate into so many different cell types and varyso extensively at different developmental and functional
stages.
In essence, gene mutations are permanent and affectall cells when passed through the germline. In contrast,
epigenetics consists of stable (but reversible), and cell
type-specific (but heritable) changes in gene expression

The sequence of events that leads to autoimmunity remains unknown. Although variations in a number ofgenes have been claimed to be associated with susceptibility 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 involvement of such factors is reflected by the facts that the frequency of the consequential abnormalities differs fromcountry to country and that geographic segregation ofpatients suffering from a given autoimmune disease has
been identified. The perplexing observation that concor-

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:youinou@univ-brest.fr
Copyright © 2011 by The Keio Journal of Medicine
10Keio J Med 2011; 60 (1): 10－16

11Fig. 1 Structure of cytosine and 5-methylcytosine: DNA (cytosine-5) methyl transferases (DNMTs) are responsible for methylatingDNA.

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 immune system is tightly regulated at the epigenetic level.
Furthermore, ensuing alterations antedate the emergenceof autoimmune traits and render genetically predisposed
individuals at risk of developing overt autoimmune disease.2 Of critical importance, these disturbances are not
restricted to idiopathic disorders, but have been implicated in the pathogenesis of autoimmune diseases inducedby chemicals or drugs.
Epigenetic modifications of the kind described above
are associated not only with autoimmune disorders but
also with various pathological conditions, including cancer, heart insufficiency and skin afflictions. This recognition is the reason why the main purpose of the Epigenetics 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 comprehensive view of the current state of the related research. Further insights into these mechanisms may leadto the ability to restore epigenetic mechanisms, thus offering an exciting way to control the inflammatory process.
The Scope of Epigenetic Mechanisms
Main processes
DNA methylation
Three main epigenetic checkpoints exist in a normallyregulated genome, DNA methylation, histone adjustments and micro-RNA. For transcription factors (TFs) topromote gene expression, they need to attach to theirbinding sites on DNA promoters, thereby activating
them, and their target DNA must be accessible. Posttranslational 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 silencegene transcription is to prevent the binding of TFs toDNA. To achieve this, DNA methyl transferases (DNMTs) convey a methyl group to the 5’ carbon position ofcytosines of cytosine-P-guanosine (CpG) dinucleotides(Fig. 1).
Most CpG is gathered together within specific regions,collectively designated CpG islands, that exist in regulatory areas of the gene. The concentration of CpG motifs
reveals the propensity of 5-methylcytosine to mutate tothymidine when CpG motifs are present outside active
genomic areas. A number of distinct DNMTs can be mobilized, viz. DNMT1, DNMT2, DNMT3a, DNMT3b,and DNMT3L. Among them, DNMT3a and DNMT3b
induce new methylations, whereas DNMT1 requires amethylated cytosine on either of the strands and contributes 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, insteadof being methylated by DNMTs, DNA is demethylated
by methyl-CpG-binding domain (MBD) proteins. Methyl-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
Histone adjustments
The nucleosome is the basic subunit of chromatin. It
comprises 146 base pairs (bp) of DNA wrapped aroundan octamer of two copies each of H2A, H2B, H3 and H4classes of histones. Nucleosomes, present at an estimated 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 fromthe nucleosome that is accessible to modifications that

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Renaudineau Y, et al: Epigenetics and Autoimmunity

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.

impart functional capacities to the histones. The modifications include acetylation, methylation, ubiquitination,
phosphorylation, sumoylation, deimination/citrullination,
ADP-ribosylation and proline isomerization.6 Each modification serves a specific purpose. Good examples of
opposite effects are enhancement of transcription by histone H3K9 acetylation and repression of transcription byhistone H3K9 methylation.
DNA methylation and histone adjustments are entwined by multiple mechanisms. For example, it has
been shown that the MBD proteins selectively bind
methylated CpG and recruit histone deacetylase or histone methyltransferase. 7 In contrast H3K4m3, a transcriptionally active variant, blocks the binding of
DNMT3L to DNA, which is essential for the action of
DNMT3a, and abrogates DNA methylation within transcriptionally active regions.8

Micro-RNA
Micro-RNAs (miRNAs) consist of 21-23 bps of RNA
and function as post-translational regulators of gene expression.9 One-third of the human transcriptome is regulated by 1,000 miRNAs. Some of them interact withtranscripts of genes that modulate DNA and histone
methylation.1 0 Conversely, miRNA expression can be affected by DNA methylation11 and histone accommodation.12
Factors of epigenetics
Age
Given the absence of genetic differences between
MTs, they are ideal to evaluate epigenetic modifications
that are caused by environmental factors. Using peripheral blood lymphocytes from elderly and young MTs,
Fraga et al. have established that the pattern of DNA

Keio J Med 2011; 60 (1): 10－16

methylation of the two members of a pair of MTs, aswell as their H3 and H4 acetylation profile, diversifies
increasingly as they age.1 3 One reason for this is that total genomic 5-methyl cytosine content decreases withage, but at different rates in one twin than the other. Similarly, in tissue culture, genomic DNA is demethylated in
the long term, particularly DNA of those genes involvedin cell differentiation.1 4 A supplementary reason for increased diversity of acetylation with age is that environmental exposure is cumulative, so that there is every
likelihood that small initial differences will become substantial with time. Interestingly, the environmental theory 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.
GenderFemales produce equivalent transcripts from their
X-linked genes, as compared with males, even though
they have two X chromosomes. Equivalency resultsfrom the inactivation of one of the two X chromosome
in each cell by a process termed dosage compensation.1 5
The inactive X chromosome is referred to as Xi, and ischaracterized by high levels of DNA methylation, histone modifications, and recruitment of the silencing histone variant macro H2A. Of note, 35% of Xi-p genes
and 5% of Xi-q genes are partially active. Whether thematernally derived or paternally derived X chromosome
is inactivated is randomly determined at the embryonicstage and is maintained throughout life.
Drugs
A number of drugs have been suspected of causing
SLE, most notably, procainamide, hydralazine and5-azacytidine. Evidence has been provided by Richardson’s group1 6, 1 7 that these drugs inhibit DNA methylation. The same investigators have reported data supporting an increase in lymphocyte function-associated antigen expression and the ensuing proliferation of autoreactive T cells in SLE patients.18
Human endogenous retroviruses
Eight per cent of the human genome derives from theintegration of retroviral sequences, together with theirlong terminal repeats, that were incorporated into our
DNA more than 25 millions years ago.1 9 These humanendoretroviruses (HERVs) generally lack an extracellular phase, and the genetic material is neutralized bymethylation.
Hypomethylated T Lymphocytes in SLE
Accumulation of autoreactive lymphocytes and production of antibodies (Abs) against a wide range of self
antigens (Ags) are the hallmarks of autoimmune diseases2 0 that damage kidneys, skin, lung and other organs.

13

The role of genetics has been suggested by the observation 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 variations 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 theirCD8+ T lymphocytes, manifest a defective capacity tomethylate their DNA; the degree of this inhibition correlates with disease activity. 2 2 The consequence of thisfault is that several methylation-sensitive autoreactivitypromoting genes are overexpressed in CD4+ T cells, including23-28 those for perforin, immunoglobulin (Ig)-likereceptor, interleukin (IL)-4, IL-6, and the B cell co-stimulatory molecules CD70, CD6 and CD154.
However, the results of studies of methylating and demethylating enzymes in SLE patients are conflicting.
For example, DNMT1 and DNMT3a are down-regulated
in CD4+ T cells from SLE patients with active disease insome,2 9, 3 0 but not in all studies.3 1, 3 2 According to someinvestigators, two DNMT1-targeting miRNAs are upregulated in a number of patients,2 3 whereas, according
to other investigators, the MBD4 protein is up-regulated
in CD4+ and CD8+ T cells, but not in B cells, from patients with SLE.31, 34, 35
Variations have also been described in histones of
CD4+ T cells from patients with SLE.3 6 In particular, H3
and H4 acetylation levels have been shown to correlate
negatively with disease activity. Nevertheless, the degreeof methylation of global histone H3K9, but not that ofmethylation 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 phenotypically by the expression of CD25 on their surface and TF
Foxp3 in their cytoplasm. Functionally, they are definedby their suppressive effects on effector T lymphocytes, B
lymphocytes, and Ag-presenting cells. Foxp3 is the master TF of Treg cell development. Its expression is indispensable 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 thefact that that some individuals develop SLE despite having a normal number of Foxp3+ T cells.3 7 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 toserve as Treg cells.38

Renaudineau Y, et al: Epigenetics and Autoimmunity

14

X chromosome and CD40 ligand

CD5-negative B cells are hypomethylated in SLE

The greater prevalence of SLE in men with Klinefelter’s syndrome suggests that, despite the presence of one
Y chromosome, the coexistence of two X chromosomes
may lead to the development of SLE.3 9 Similarly, the recent observation that demethylation of the inactivated X
chromosome in CD4+ T cells from female SLE patientsis associated with overexpression of the B cell-stimulating CD40 ligand points to a potential reason for the female sex predominance in SLE.28

Given that B cell receptor-stimulated B2 cells from
SLE patients, but not from controls, express highamounts of CD5-E1B, we have explored the DNA methylation status of B2 cells from patients with SLE. 3 5
Analysis of the CpG sites in the U3 promoter region
present in the 5’ long-terminal repeats of HERV-CD5 using methylation-sensitive endonuclease assays followedby polymerase chain reaction and bisulfite sequencing
revealed that CpG motifs are hypomethylated in B2 cells
from patients with SLE, as compared with those fromhealthy controls (Fig. 3).
In addition to these observations, our studies have indicated that cytokines may be involved in influencing
epigenetics. For example, IL-6 enables B cell differentiation, maturation and Ig secretion. This multifunctional
cytokine is synthesized predominantly by monocytes, fibroblasts 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-doublestranded DNA Abs. Further, it has been shown that autoreactive B cells from SLE patients release high amountsof IL-6 and that IL-6 experimental antagonism abolishes
spontaneous Ig production by restoring DNA methylation in SLE B cells.

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 various developmental and activation stages. Thus, CD5-expressing B lymphocytes are referred to as B1 cells,
whereas conventional CD5-nonexpressing B lymphocytes are designated B2 cells. The finding that B1 cells
produce polyreactive Abs with low-affinity binding tomultiple 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 autoAbs.40
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. 3 5
Second, CD5 + B cells express a fusion transcript between an HERV and the CD5 gene.4 1 This HERV wasintegrated into the genome at a time between the divergence of New World monkeys from Old World monkeys
and the divergence of humans from Old World monkeys. 4 2 When we reported this phenomenon, the newexon 1 was designated exon 1B, and the known exon 1
was renamed exon 1A. The transcription of exon 1B isnormally 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 tothat of B1 cells.35
Interestingly, selection of HERV-exon 1B down-regulates the membrane level of the protein product in B
lymphocytes of patients with SLE.4 3 Exon 1B-containing mRNA codes for a truncated variant of CD5. Owing
to the lack of leader peptide, the protein cannot be translocated to the membrane and be used to facilitate anergyof autoreactive B cells. This raises the possibility that
HERV demethylation participates in the pathogenesis of
SLE.44, 45

Effects on the genesis of SLE
The direct implication of hypomethylated DNA in B
cells at the outset of SLE has recently been confirmed.4 8
B cells were purified from mice, treated ex vivo with
DNMT inhibitors, and subsequently reintroduced in syngeneic mice by adoptive transfer. The treatment promoted antinuclear autoAb production in the recipient mice.
Conclusions
One of the most intriguing characteristics of epigenetics is the reversibility of its modifications. Although there remains a need for new animal models andspecific cell-lines to test for suitable agents, some drugs
have already been used to treat murine malignancies.
Because controlling DNA methylation remains a challenge, several approaches have been proposed. These include blocking the autocrine IL-6 loop in SLE B cells,3 5preventing adenosylmethionine degradation by decarboxylase, or regulating miRNAs. While our knowledgeof epigenetics in SLE is limited, the epigenome revolution 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

Fig. 3 B cells from patients with systemic lupus erythematosus (SLE) are characterized by a reduced capacity to methylate their DNA.
Demethylation is more pronounced following anti-IgM stimulation. Bisulfite sequencing (left), and comparison of polymerase chain
reaction products of methylation-sensitive endonuclease HaeII and methylation-insensitive MspI restriction enzymes (right), indicatethat cytosine-P-guanosine (CpG) islands are demethylated in the CD5-E1B promoter from SLE B cells as compared to normal B cells.

Acknowledgments
The authors are grateful to Professor Tsutomu Takeuchi who kindly gave them the unforgettable opportunity
to present their data at the Keio Medical School, in Tokyo, 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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