review article epigenetic modulation as a...

Review ArticleEpigenetic Modulation as a Therapeutic Prospectfor Treatment of Autoimmune Rheumatic Diseases

Marzena Ciechomska1 and Steven OrsquoReilly2

1National Institute of Geriatrics Rheumatology and Rehabilitation Department of Pathophysiology and ImmunologyWarsaw Poland2Faculty of Health and Life Sciences Northumbria University Newcastle upon Tyne UK

Correspondence should be addressed to Marzena Ciechomska mmciechomskagmailcom

Received 20 May 2016 Accepted 12 July 2016

Academic Editor Nona Janikashvili

Copyright copy 2016 M Ciechomska and S OrsquoReilly This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Systemic inflammatory rheumatic diseases are considered as autoimmune diseases meaning that the balance between recognitionof pathogens and avoidance of self-attack is impaired and the immune system attacks and destroys its own healthy tissue Treatmentwith conventional DiseaseModifying Antirheumatic Drugs (DMARDs) andor Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)is often associated with various adverse reactions due to unspecific and toxic properties of those drugs Although biologic drugshave largely improved the outcome in many patients such drugs still pose significant problems and fail to provide a solution to allpatientsTherefore development of more effective treatments and improvements in early diagnosis of rheumatic diseases are badlyneeded in order to increase patientrsquos functioning and quality of life The reversible nature of epigenetic mechanisms offers a newclass of drugs that modulate the immune system and inflammation In fact epigenetic drugs are already in use in some types ofcancer or cardiovascular diseases Therefore epigenetic-based therapeutics that control autoimmunity and chronic inflammatoryprocess have broad implications for the pathogenesis diagnosis and management of rheumatic diseases This review summarisesthe latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities andinflammation of rheumatic diseases

1 Autoimmune Rheumatic Diseases

Systemic autoimmune rheumatic diseases are characterisedby pain and chronic joint inflammation There are morethan 200 different conditions that are labelled as rheumaticdiseases including rheumatic arthritis systemic sclerosissystemic lupus erythematosus psoriatic arthritis ankylosingspondylitis and Sjogren syndrome Moreover autoimmunerheumatic diseases share many common features whichmakes themdifficult to differentiate within the group Indeedup to 50 percent of patients with autoimmune rheumatic dis-eases cannot be easily categorised with a specific disorder inthe first 12 months of follow-up [1]

One of the major characteristics of rheumatic diseasesis chronic inflammation and autoimmunity which conse-quently leads to tissue destruction and reduces patientsrsquo

mobility Immune cells play a key role in inflammation dueto involvement in initiation and maintenance of the chronicinflammatory stages In particular circulating monocytesthat may differentiate towards macrophages or dendritic cellsare able to produce proinflammatory cytokines includinginterleukin-1 (IL-1) IL-6 IL-8 and tumour necrosis factor-120572 (TNF-120572) [2] Monocytes are also responsible for the pro-duction of inflammatorymediators including reactive oxygenspecies (ROS) and cyclooxygenase-2 (COX-2) [3] COX-2is a key enzyme in prostaglandins biosynthesis driving theinflammatory response Monocytes can produce chemokineswhich attract T and B cells for the secretion of proin-flammatory cytokines Activated B cells are able to presentautoantigens and produce autoantibodies maintaining theinflammatory process leading to tissue destruction Thepresence of autoantibodies is a hallmark of autoimmune

Hindawi Publishing CorporationMediators of InflammationVolume 2016 Article ID 9607946 11 pageshttpdxdoiorg10115520169607946

2 Mediators of Inflammation

rheumatic diseases [4] Also a subset of helper CD4+ T cellsTh17 is reported to be involved in rheumatic pathogenesis[5] Th17 cells are characterised by production of IL-17This interleukin is a potent proinflammatory cytokine thatamplifies ongoing inflammation by induction of TNF-120572 IL-1120573 and IL-6 inmacrophages as well as of other cell types suchas keratinocytes fibroblasts and synoviocytes Fibroblast-like synoviocytes (FLS) located inside joints in the synoviumalso play a key role in pathogenesis of rheumatic diseases dueto their production of proinflammatory cytokines adhesionmolecules and matrix proteases contributing to cartilagedestruction Rheumatoid FLS develop a unique autoaggres-sive phenotype that increases invasiveness into the extracel-lular matrix promotes inflammatory cell recruitment andelevates production of COX-2 NSAIDs are widely used anti-inflammatory agents that act through the inhibition of theCOX enzymes Although COX-inhibitors lead to reducedsynthesis of prostaglandins at the site of inflammation sup-pression of gastrointestinal or renal prostaglandins synthesisis associated with mechanism-based toxicities This limitsthe usefulness of these otherwise potent drugs In additionCOX-2 inhibitors have been found to increase the riskof myocardial infarction Thus finding new agents whichwill specifically block inflammation may provide therapeuticopportunities in immune-mediated rheumatic diseases

2 Overview on Epigenome-Influencing Drugs

Epigenetics is defined as reversible and heritable changesin gene function without alteration of the underlying DNAsequence itself [6] Epigenetic mechanisms are sensitive toexternal stimuli bridging the gap between environmentaland genetic factors In particularmonozygotic (MZ) twins donot show complete concordance for many complex diseasesMZ discordance rates for autoimmune diseases are 20ndash80percent indicating a substantial role of epigenetic factors inthe development of these disorders [7 8] Indeed it has beenreported that epigenetic mechanisms mediate developmentof chronic inflammation by modulating the expression ofproinflammatory cytokines including TNF-120572 IL-6 and IL-1 and induction of COX-2 and transcription factor NF-120581BThese molecules are constitutively produced by a variety ofimmune cells under chronic inflammatory conditions whichconsequently leads to the development of many diseasesincluding cancer cardiovascular diseases or autoimmunerheumatic disorders

3 Noncoding RNA

Three main epigenetic mechanisms have been describedincluding noncoding RNA species DNA methylation andhistone modification The first group of noncoding RNAsincludes microRNA (miRNA) and long noncoding RNA(lncRNA) MicroRNAs (miRNAs) are endogenous single-stranded RNAs of 19ndash25 nucleotides in length which cannegatively regulate gene expression on posttranscriptionallevel In particular miRNA can hybridise to 3ndash8 nucleotideswithin 31015840-untranslated region (31015840UTR) of target messengerRNA (mRNA) referred to as ldquoseed sequencerdquo [9] The

Table 1 FDA-approved epigenetic drugs

Drug Epigenetic effect Clinical trialMiravirsen Neutralisation of miRNA-122 Phase II [13]MRX34 Ectopic expression of miRNA-34 Phase I [9]Azacitidine(Vidaza) DNA methyltransferase inhibitor Phase III [15]

Decitabine(Dacogen) DNA methyltransferase inhibitor Phase III [17]

Vorinostat(Zolinza) Pan-HDAC inhibitor Phase II [24]

formation of such miRNA-mRNA duplexes leads to mRNAdegradation or translational repression miRNAs have beenstudied extensively due to their role in regulation of almostevery cellular process It is known that miRNAs can act asa fine-tuner of gene expression and can negatively regulateapproximately 30 percent of human protein-coding genes[10] In additionmiRNAs are attractive as potential biomark-ers Some of miRNAs have been already tested in preclinicalstudies that aimed to treat cancer including lung prostateor leukemia [11] Interestingly randomised phase IIa doubleblind clinical trial (test numberNCT01200420) has been con-ducted to treat hepatitis C virus (HCV) using locked nucleicacid inhibitor of miRNA-122 (Table 1) miRNA-122 is crucialfor viral replication in hepatocytes thus the reintroduction ofmiRNA-122 inhibitor significantly reduced virus replication[12 13] Recent phase I clinical trial has also tested thedrug called MRX34 MRX34 is a double-stranded miRNA-34 encapsulated in liposomal nanoparticles miRNA-34arepresses the expression of more than 20 oncogenes whichresults in inhibition cancer cell viability stemness metastasisor chemoresistance Thus MRX34 is widely tested in solidtumours and hematological malignancies [9] Many studieshave also shown the role of lncRNA in diverse cellular pro-cesses lncRNAs are non-protein-coding transcripts longerthan 200 nucleotides regulating gene expression Howeverthe exact functional roles and mechanisms of lncRNAs arestill unclear

4 DNA Methylation

Another mechanism of epigenetic changes is DNA methyla-tion induced by a highly conserved family of DNA methyl-transferases (DNMTs) DNMT1 is the most abundant DNAmethyltransferase in mammalian cells [14] The insertion ofmethyl group to cytosine at the carbon 5 position leads tostructural changes in chromatin and ismostly associatedwithgene silencing In humans methylation mainly occurs whencytosine is followed by guanine and is linked with phosphatecalled CpG islands Approximately 1 percent of the genomeconsists of CpG islands [11] Also it is reported that roughly60ndash70 percent of human genes are linked to promoter CpGislands which suggests that methylation of CpG island isan important regulatory mechanism of gene expression [12]It has been shown that vitamin B12 rich diet (B vitaminsacted as methyl donors) in agouti mouse model preventedfrom development of inflammation mediated diabetes and

Mediators of Inflammation 3

cancer In contrastmicewhich did not receive vitaminBwerepredisposed for these diseases [14] Therefore methylationplays a key role in physiological conditions and the alterationin DNA methylation signature can have impact on diseasedevelopment One of the Food and Drug Administration-(FDA-) approved drugs inhibiting DNA methylation is 51015840-azacytidine (commercial name Vidaza) This drug has beenalready used in phase III randomised controlled trial totreat myelodysplastic syndrome and leukemia [15] Similarinhibitory effect on DNA methyltransferases has the 5-aza-21015840-deoxycytidine or 51015840-AZA (knownunder commercial nameDecitabine) which is used to treat many types of cancer andthe myelodysplastic syndrome [16 17] DNA hydroxymethy-lation is also epigeneticmodificationmediated by Ten-ElevenTranslocation (TET) family proteins which were discoveredrelatively recently [18] TET enzymes are dioxygenases capa-ble of oxidizing the methyl group of 5-methylcytosine (5mC)and converting 5mC into 5-hydroxymethylcytosine (5hmC)which results in DNA demethylation It has been shownthat the increased expression of TET1ndashTET3 enzymes inmonocytes and TET2 in T cells leads to aberrant global DNAhydroxymethylation of early RA patients [19] Interestinglytreatment with methotrexate partially reduces the DNAhydroxymethylation level Indirect TET inhibition inducedby AGI-5198 compound leads to growth suppression andpromotes differentiation of glioma cells [20] Similarly HMS-101 inhibitor limits the growth of acute myeloid leukemiacells suggesting potential therapeutic application of TETinhibitors in cancer and also in rheumatic diseases [21]

5 Histone Modification

Another epigenetic phenomenon is histone modificationThis modification alters the electrostatic charge of thehistones resulting in conformational changes in proteinbinding sites and facilitating or blocking DNA accessibil-ity Histone modifications can be mostly represented byacetylation methylation phosphorylation ubiquitinationribosylation citrullination biotinylation and sumoylationof histone N-terminal tail domains and also core domains[22] It is believed that the histone acetylation is usuallyassociated with increased binding of transcription factorsto nucleosomal DNA and facilitates transcription initiationwhereas histone methylation can either activate or repressgene expression Acetylation removes the positive charge onthe histones and reduces the interaction between histonesand negatively charged phosphate groups on DNA [23]Therefore the condensed heterochromatin is transformedinto a more relaxed euchromatin that is associated withgreater levels of gene transcription Vorinostat (also known assuberanilohydroxamic acid SAHA) has been shown to bindto the active site of histone deacetylases (HDACs) HDACscatalyse the removal of acetyl group from lysine residueInhibition of HDACs by Vorinostat leads to accumulationof hyperacetylated histones This drug was the first histonedeacetylase inhibitor to be approved by FDA (2006) to treatcutaneous T cell lymphoma with substantial response ratesover 30 percent in patients [24] Unlike in the cancer fieldthere is still no epigenetics-based drug on the market to

treat rheumatic disorders Finding new agents is greatlyneeded because the economic burden of rheumatic diseasesis substantialTheir cost is estimated at more than 200 billionEuros per year in Europe and they are the most expensive ofall diseases for the European health care systems [25] Thisreview highlights the impact of chronic inflammation andimmune disability on globally disturbed DNA methylationpattern aberrant histone modificationrsquo profile and divergentmiRNA signature that is observed in autoimmune rheumaticdiseases However it is a chicken or egg dilemma and it needsto be further investigated to find out whether inflammationtriggers epigenetic changes or epigenetic alteration drivesinflammation Epigenome-influencing drugsmay have futureimpact on diagnosis andor therapeutics of rheumatic dis-eases Epigenetic mechanisms which modify immune cellsand fibroblasts in rheumatic diseases are depicted in Figure 1

6 Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common inflamma-tory joint disease which affects approximately 1 of the pop-ulation worldwide with unknown etiology RA is a chronicautoimmune inflammatory condition which is characterisedby an influx of inflammatory cells from the blood streaminto the synovial membrane or synovial fluid Such influxof immune cells producing inflammatory cytokines resultsin progressive erosion of articular cartilage PhagocytesB cells and T cells are the most prominent cells in therheumatoid synovium Macrophages along with granulo-cytes are an important source of proinflammatory cytokineschemokines and reactive oxygen species (ROS) that accom-pany inflammatory processes [4]On the other hand antigen-specific B cells are involved in autoantigens presentation toT cells and in production of autoantibodies which mediatesin joint destruction In addition the presence of ectopicfollicular structures in chronically inflamed tissues resem-bling germinal centres provides strong evidence of ongoingimmune reactions [26] Recent studies have indicated thatmiRNA plays a critical role in pathogenesis of RA Raj andMufti showed that miRNA-346 regulates TNF-120572 synthesis(one of the major proinflammatory cytokines involved in thepathogenesis of RA) in LPS stimulated synovial fibroblasts[15] The level of miRNA-146a is significantly upregulatedin CD4+ T cell subset and positively correlates with TNF-120572 concentration in RA patients [16 17] Also the level ofmiRNA-150 is elevated in IL-17 producing T cells [27] Incontrast Zhang et al reported that miRNA-23b inhibits IL-17-associated autoimmune inflammation by targeting TGF-120573 binding protein 2 (TAB2) and TAB3 [18] Emergingevidence revealed that lncRNAs have various expression inautoimmune diseases It has been shown that adalimumab(anti-TNF-120572 antibody) and tocilizumab (anti-IL-6R anti-body) treated RA patients have differential expression of 85lncRNAs inCD14+monocytes [28] Similarly Song et al haveshown elevated expression level of lncRNAs called Hotair inPBMC and serum exosome suggesting that lncRNAs couldbe used as potential biomarkers for diagnosing RA [29]while overexpression of Hotair by introduction of lentiviralconstruct results in decreased expression of MMP-2 and


DNA methylation

T cell

Fibroblast

B cell

Histone modification

Apicidin(SSc)AcetMeth

Phosph

DZNep

(SSc)

Ubi

Hyper

Hypo

miRNA-23b

miRNA-29

miRNA-30a

miRNA-346

miRNA-135b

miRNA-146a

miRNA-203

miRNA-21

miRNA-155

miRNA-124

miRNA inhibition

mRNA

miRNA

Curcumin

(RA)

TSA(SSc)

uarr IL-10 (RA)

darr Ras (SLE)

uarr COL1A2 (SSc)

uarr IgG (SSc)darr COL1A1 (SSc)

uarr CD11a (SSc)

darr ANTRX2 (AS)

darr AID (SLE)

darr DNMT1 (SLE)

darr STAT6 (SSc)

IRAK4 (RA PsA SLE) darr

darr BAFF (SSc)

TAB2 and TAB3 (RA)darr

darr COL1A1 and TAB1 (SSc)

M120601

darrTNF-120572 (RA)

3998400UTRdarr SOD3 TNF-120572 IL-24 (PsA)

5998400-AZA

Figure 1 Epigenetic agents modulating immune response in rheumatic diseases including RA SSc SLE AS and PsA Schematic of theepigenetic modulations represented by DNA methylation histone modification and RNA interference influencing immune cells (B cells Tcells and monocytes) and fibroblasts DNA methylation refers to covalent addition of a methyl group to the 5-position of the cytosine ringwhich can be inhibited by 51015840-AZA 51015840-AZA induces DNA hypomethylation and drives differential gene expressionHistone modifications arereversible and site-specific histone alterations including acetylation (Acet) methylation (Meth) phosphorylation (Phosph) or ubiquitination(Ubi) Histonemethylation or acetylation can be either activated by apicidin andTSAor inhibited byDZNep and curcuminmiRNA inhibitionis a formation of miRNA-mRNA duplexes in the position of 31015840UTRThis leads gene silencing (genes in black) by specific miRNAs (in red)

MMP-13 in FLS from RA patients DNA methylation patternis also impaired in RA affecting immune-related genes andconsequently influencing immune responses In particularglobal DNAhypomethylation is observed in peripheral bloodmononuclear cells (PBMCs) derived from RA patients [30]It has been shown that hypomethylated promoter region ofchemokine CXCL12 leads to increasedMMPs expression andjoint destruction in RA patients [31] Similarly the methy-lation levels of IL-6 promoter in PBMCs was significantlylower in RA patients than those in controls [32] In contrastgene coding for dual specific phosphate 22 (DUSP22) ishypermethylated in T cells of RA and in Sjogrenrsquos syndromepatients [33 34] DUSP22 is a tyrosine phosphatase whichnegatively regulates the IL-6 transcription factor STAT3 It isknown that IL-6 plays a pivotal role in chronic inflammationin autoimmune diseases [35] Another group has identifiedthat the promoter of anti-inflammatory cytokine IL-10 ishypermethylated in four different regions of CpG site [36]The level of IL-10 which is mainly produced by monocytesand T reg cells is reduced in RA It has been shown thatPBMCs treated with 51015840-AZA have increased production ofIL-10 This suggests that specific demethylation of IL-10promoter induced by 51015840-AZA can prevent development ofRA by induction of anti-inflammatory IL-10 and suppressionof immune responses It has been also found that alterationin histone modification can contribute to RA developmentThe balance of histone acetylase (HAT) versus HDAC isstrongly shifted towards chronic histone hyperacetylation in

RApatients [37]This consequently leads to proinflammatorygenes expression including IL-6 and IL-8 Indeed the level ofhistone H3 acetylation in the IL-6 promoter is significantlyelevated in RA synoviocytes resulting in enhanced IL-6secretion and joint destruction [38] Surprisingly treatmentwith curcumin abrogated H3 acetylation and reduced IL-6 secretion which suggests that epigenetic mechanisms areimplicated in targeting RA pathogenesis

7 Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissuedisease characterised by autoimmunity vascular abnormal-ities and fibrosis via accumulation of extracellular matrix(ECM) proteins Uncontrolled fibrosis progression oftenresults in dysfunction of the affected organs and consequentlyleads to premature death in SSc patients [39] The role ofmiRNA has also been demonstrated in SSc pathogenesis Ithas been shown that the family of miRNA-29 plays a pivotalrole in SSc skin fibrosis by targeting collagen expression [1920] In addition we have shown that SSc fibroblasts are able toreverse fibrotic phenotype following miRNA-29 transfectionWe found that miRNA-29 can modulate its novel targetgene TAB1 and that it downregulates tissue inhibitor ofmetalloproteinases-1 (TIMP-1) expression as a result of TAB1degradation [21] Similarly transfection of miRNA-30a-3pin IFN-120574-activated SSc fibroblasts decreases synthesis of Bcell-activating factor (BAFF) [40] BAFF plays a central


role in the survival and homeostasis of B cells and plasmacells Autoreactive B cells are strongly dependent on BAFFpresence and the increased level of BAFF correlates with highautoantibody titers andwith disease activity in SScThereforemiRNA-30 targeting BAFF expression could be used in SSctherapy In addition 51015840-AZA-treated SSc T cell has shownincreased CD11a expression whereas 51015840-AZA-treated SSc Tcells cocultured with either B cells or fibroblasts resulted inincreased production of IgG or COL1A2 respectively [41]These data suggest that demethylation of CD11a regulatoryelements and subsequentCD11a overexpression inT cellsmaymediate immunological abnormalities and fibrotic processesin SSc Therapies which reduce CD11a due to specific DNAmethylation are needed in SSc On the contrary our latestresults have shown that 51015840-AZA-treated fibroblasts decreasedexpression of collagen and upregulated the miRNA-135bexpression level miRNA-135b targets STAT6 and attenuatesthe IL-13-induced collagen expression This indicates thatspecific targeting DNA methylation may represent a noveltherapeutic approach for the treatment of SSc

Another hallmark of SSc is perivascular infiltration ofimmune cells mainly monocytes which are the first immunecells to infiltrate the SSc skin The results from our groupdemonstrated that circulating monocytes from SSc patientscontribute to the imbalance between TIMP-1 and MMPsand to increased profibrotic IL-6 production upon TLR8agonist stimulation (ssRNA) [42ndash44] Interestingly we havealso shown that epigenetic modification induced by DZNep(histone methyltransferases) or apicidin (inhibitor of his-tone acetylases) in SSc monocytes can modulate TIMP-1expression and subsequently fibroblasts transdifferentiation[44] Another study has shown that global H4 but not H3acetylation of SSc B cells was positively correlated withdisease activity and that the expression of HDAC2 proteinwas negatively correlatedwith skin thickness [45]This clearlyindicates that epigenetic alteration plays an important role inthe pathogenesis of SSc

8 Psoriatic Arthritis

Psoriatic Arthritis (PsA) is a chronic inflammatory skindisease with unknown etiology The interactions betweengenetics and the environmental factors in PsA are stillnot well defined The disease is characterised by abnor-mal proliferation and differentiation of keratinocytes Inaddition infiltration of immune cells which secrete highlevel of various immune-regulated inflammatory cytokinesand chemokines is observed in PsA Recently imbalance inepigenetic networks has been indicated to be an importantelement in psoriasis development Several studies have shownthat differentially expressed miRNAs levels play a role inpsoriasis pathogenesis In particular it has been reportedthat miRNA-203 expression is downregulated in psoriaticlesion Based on bioinformatic analysis miRNA-203 targetsgene suppressors of cytokine signalling 3 (SOC3) SOC3is involved in negative regulation of the IL-6 transcriptionfactor STAT3 Furthermore miRNA-203 directly targetsTNF-120572 and proinflammatory IL-24 in primary keratinocytes[46] Another group identified that miRNA-146a is also

dysregulated in psoriatic lesions miRNA-146a targets theTNF receptor-associated factor 6 (TRAF6) and the IL-1receptor-associated kinase 1 (IRAK1) Activation of IRAK1triggers the production of TNF-120572 IL-6 IL-8 and IL-1120573 Xia etal also found that the increased level of miRNA-146a is posi-tively correlated with the Psoriasis Symptom Inventory (PSI)score [47] In contrast the addition of anti-TNF-120572 blockingantibody reduced the level ofmiRNA-146a in patientsrsquo serumThese data suggest that overexpression of miRNA-203 andmiRNA-146a may be useful in repression of the immune-mediated inflammation process and may provide potentialtherapeutic strategy in psoriasis pathogenesis Another studyreported that the DNA methylation pattern is changed inpsoriatic skin in comparison to normal tissue They showedstrong correlation between S100 Calcium Binding Protein A9(S100A9) andDNAmethylation signature of psoriasis patientsamples fallowing phototherapy [48] S100A9 is a calciumbinding protein which plays a prominent role in regulation ofinflammatory processes and immune response Also Gervinet al have demonstrated that monozygotic twins (MT) have adifferentmethylation pattern between an unaffected twin anda twin suffering for PsA [8] They showed the differences inDNAmethylation pattern of proinflammatory TNF-120572 ligand11 also known as the receptor activator of nuclear factorkappa-B ligand (RANKL) in MZ twins Moreover DNAmethylation signature of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene is altered in psoriaticMZ twin ALOX5AP is involved in catalysis of arachidonicacid regulating inflammation via leukotrienes productionAnother study has shown that 50 of CpG islands in thepromoter region of p16 gene are hypermethylated in psoriaticepidermis and correlated with diseases activity [49] p16 isan antiapoptotic protein that supports the concept of anabnormal mechanism of hyperproliferative skin diseasesAbnormal expression of HATs and HDACs regulating geneexpression has been also observed in PsA Indeed Ham et alhave shown that the promoter region of HDAC-6 is hyper-methylated in naive CD4+ T cells in patients Furthermorethe level of HDAC-1 in skin samples and PBMCs from PsApatients is increased compared to healthy subjects [50 51]These findings implicate that novel therapy for PsA should bealso supplemented with agents altering the abnormal histonemodification pattern

9 Systemic Lupus Erythematosus

Theetiology of Systemic Lupus Erythematosus (SLE) remainsto be elucidated however it is an autoimmune disorderwith clear links to the innate and adaptive immune systemsEnvironmental triggers may initiate the disease on a geneticsusceptibility background SLE is a multiorgan disorder inwhich there are autoantibodies toDNA that are not only diag-nostic of the disease but also pivotal in disease pathogenesis

It was as early as 1990 that methylation abnormalitieswere first described in SLE T cells The most convincingevidence comes from the fact that procainamide and 51015840-AZA(both hypomethylating drugs) treated CD4+ T cells cause alupus-like disease in mice [52] This suggests a critical roleof hypomethylation in T cells in mediating SLE [52] It was


suggested that decreased Ras signalling is involved also inDNA hypomethylation in T cells [53] Other studies havesuggested that growth arrest and DNA damage-induced gene45120572 (GADD45120572) are associated with DNA hypomethylationin SLE [54] In further support of this it was demonstratedthat increased oxidative stress in T cell in SLE may alter theexpression of various proteins but also force downregula-tion of DNMT1 expression and thus hypomethylation [55]Indeed adoptive transfer of T cells modified by oxidativestress into syngeneic mice resulted in lupus-like disease withreduced methylation [56] A study found that isolated T cellsfrom SLE patients were globally hypomethylated The genesmethylated include CD11a and CD70 [57] CD11a of courseforms lymphocyte function-associated antigen 1 and wouldbe important in immune responses The X chromosome inwomen with lupus is hypomethylated suggesting a reason forthe preponderance in females [58] A large scale genomewideDNA methylation study in isolated CD4+ T cells from lupuspatients found 236 hypomethylated CG sites Enrichmentof genes associated with apoptosis was found A furtherstudy of DNA methylation in isolated T cells found thata large amount of interferon regulated genes is methylateddifferently The authors suggest that there is an epigeneticalteration of interferon genes which explains the interferonresponse in SLE [59] Similarly it has been found that inter-feron regulated genes in CD4+ T cells of SLE patients thathad quiescent disease are hypomethylated which suggeststhat they are poised ldquoto triggerrdquo [60] Recently a study ofSLE patients has demonstrated that altered DNAmethylationpattern of interferon genes is associated with production ofautoantibodies characterising SLE [61] As well as T cellsplaying a critical role B cells have also been described tobe involved in SLE pathogenesis Indeed hypomethylationof SLE B cells has been described and blocking IL-6 witha monoclonal antibody restores B cell methylation levelsThese data suggest that IL-6 is driving B cell alterations [62]Interestingly miRNA-155 targets Activation Induced Cyti-dine Deaminase (AICDA) which is critical in B cell develop-ment It has been demonstrated that AICDA is dysregulatedin SLE miRNA-29b appears to be overexpressed in SLECD4+ T cells and indirectly regulates hypomethylation bytargeting DNMT1 DMNT1 is an enzyme which is importantin DNA methylation [63] The important negative regulatorsof TLR signalling are miRNA-146a and miRNA-29 which aredysregulated in SLE [64 65] It was also further shown thatmiRNA-21 additionally targets DNMT1 in SLE CD4+ T cells[66] Interestingly the authors demonstrated that targets ofmiRNA-146 included the interferon regulatory factor 5 andSTAT1 a downstream target of IFN activation and theseare indeed dysregulated in SLE A great study demonstratedthat miRNA-3148 affects the stability and regulation of TLR7[67] TLR7 is the receptor for RNA and this is clearlyimportant in SLE and is highly expressed on dendritic cellsand may link RNA TLR and miRNAs together In T cellsmiRNA-31 has also been found to be dysregulated in Tcells and this dysregulation is associated with the impairedproduction of IL-2 a critical T cell growth factor [68] Itis clear that a multitude of miRNAs are dysregulated inSLE therefore cell-free miRNAs have recently emerged as

noninvasive biomarkers [69] miRNA-146 and miRNA-155have been found to be a possible biomarker in SLE derivedfromurinary sediment [69] Abnormal histonemodificationshave also been described in SLE It has been reported thatin SLE patients there is a global histone hypoacetylationdue to downregulation of Ezh2 enzyme Ezh2 is involved inhistone methylation [70] The epigenetic modifying enzymeEzh2 has been also found to be downregulated in the SLET cells and this is one of the enzymes that methylate thehistones [70] Ezh2 has been also shown to be regulating theexpression of the transcription factor STAT5 to epigeneticallyrepress the immunoglobulin K chain complex critical in Bcell lineages [71] Using the lupus-prone mouse model itwas found in the isolated T cells from this model that theHDACs were dysregulated suggestive of the mechanism ofaltered histone methylation [72] Histone H3 trimethylationhas also been described to be altered in SLE [73] The majorhistone modifications which are implicated in SLE includemethylation and acetylation and both are reversible It hasbeen shown in the lupus mouse model that introduction ofTSA (a broad spectrum HDAC inhibitor) reduced IL-6 leveland proteinuria [74] CD70 is also elevated on CD4+ T cellsfrom SLE patients and associated with higher dimethylatedH3 lysine 4 in these patients [75]

10 Sjogrenrsquos Syndrome

Sjogrenrsquos syndrome (SS) is an autoimmune disorder thataffects the lacrimal and salivary glands causing hypofunctionwhich leads to dry eyes and dry mouth (xerostomia) Thereare a large prominent lymphocytic infiltrate in the salivaryglands and also specific autoantibodies in the disease tooPatients with SS have a 20ndash40-fold increased risk of devel-oping lymphomaThere are both associations with the innateand adaptive immune systems Because the innate immunesystem has been heavily implicated in disease pathogenesismany studies have focussed on this system One of the firstmiRNAs that has been shown to be dysregulated is miRNA-146a [76] miRNA-146a has been found to be elevated inPBMCs of SS patients however the precise cell type of thePBMCs has not been confirmed [76 77] More importantlyPauley et al have shown that enhanced miRNA-16a levelsin monocytes lead to increased phagocytosis in functionalassays This could represent a mechanism to help restorethe altered phagocytosis seen in the disease A follow-upstudy confirmed the increased miRNA-146a levels and thedecreased target gene IRAK1 levels in PBMCs [78] Using theminor salivary gland and whole miRNA arrays a number ofdifferentially regulated miRNAs in salivary glands from SSpatients was found however their targets and the functionalconsequences of the differentially expressed miRNAs are stillunknown [79] A very interesting recent study showed thatthe SS related antigen B promotes global miRNA processing[80]

It has been recently shown that salivary gland epithelialcells are globally hypomethylated compared to controls [81]A very interesting observation was that the global glandepithelial cells hypomethylation may be attributed to B cellsas treatment with the B cell depleting antibody rituximab


had more methylation In isolated T cells from SS patients ithas been found that they have lower FoxP3 expression levelsboth mRNA and protein levels and that this is associatedwith hypermethylation of the promoter region [82] Thisobservation could explain the reduced number of T reg cellsin SS A recent genomewide methylation study in isolatedCD4+ T helper cells identified a multitude of genes that aredifferentially regulated in SS The interferon pathways genesSTAT1 IFI44L and USP18 are all hypomethylated [83]

11 Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic and commoninflammatory rheumatic disease characterised by new boneformation ankyloses and inflammation of the hips and spinemiRNA-16 andmiRNA-221 are aberrantly expressed in T cells[84] A functional SNP variant in miRNA-196a was foundto be associated with Behcetrsquos disease but not AS [85] Arecent study in AS demonstrated that miRNA-124 is elevatedin peripheral blood cell of AS patients miRNA-124 targetsAnthrax Toxin Receptor 2 (ANTXR2) which is associatedwith risk of AS development [86] Interestingly inhibitionof ANTXR2 by miR-mimics in vitro caused autophagy andsubsequently protects T cells from apoptosis conferringadvantage Niu et al have looked at common polymorphismin miRNA-146a associated with AS However no polymor-phism was associated [87] In AS T cells are proposed to playa role however their precise role is unclear It was shown thatFoxP3 positive T cells are elevated in the inflamed joint inAS and that the FoxP3 locus is demethylated This suggeststhat epigenetic mechanisms control FoxP3 expression [88]Recently in serum it was found that there were higher levelsof SOCS1 methylation as compared to healthy controls andhigher levels of SOCS methylation associated with higherIL-6 levels [89] SOCS1 is the negative regulator of STAT1signalling which is initiated after IL-6 stimulation thus areduction in the negative regulator of STAT1 would lead tounperturbed STAT1 signalling

Reduced HDAC and HAT activities have been describedin AS in PBMCs compared to controls [90] The functionalrelevance of this is unknown because the balance betweenthese two enzymes was not different Furthermore after anti-TNF-120572 therapy HAT activity increased in AS patients witha clear increase in the HATHDAC balance [91] Only onemanuscript has demonstrated the altered histonemethylationin CD4+ T cells in AS In particular it has been shown thatspecific AS SNP genotype has an altered histonemodificationprofile and possibly alters binding to important transcriptionfactors critical in the disease [92]

12 Giant Cell Arteritis

Giant Cell Arteritis (GCA) is a systemic autoimmune dis-ease primarily affecting the elderly It is characterised byinflammation of the large- and medium-sized arteries GCAtypically affects the temporal arteries One of the mostdevastating features of the disease can be acute visual lossand patients can be present with ischaemic complications ofthe disease One study found 853 hypomethylated genes in

temporal arteries from GCA patients compared to controlsMany of these hypomethylated genes were associated withboth Th1 and Th17 cells [93] DNA methylation was alsofound to be altered in nuclear factor of activated T cells(NFAT) which was confirmed to be altered by immuno-histochemistry [93] NFAT is a critical factor mediatingproduction of proinflammatory cytokines including IL-23Thus methylation regulation of NFAT may be crucial indriving the activation of Th17 cells in GCA Only one reportof dysregulated miRNA has been published in GCA andthis study found that miRNA-21 was dysregulated in GCAtemporal biopsies [94] miRNA-21 was overexpressed in thebiopsies and this appears to be tissue specific as the use ofPBMCs derived from the same donorswhen compared acrossgroups demonstrated no difference These data suggest thatthe increase of miRNA-21 level is tissue specific [94] To thisday only a handful of studies have looked at the epigenomein GCA and this is a rich area for research Epigenetics couldunderpin the variable clinical course of the disease

13 Conclusions

It is now clear that in all the autoimmune rheumatic diseasesthere are various epigenetic aberrations (Figure 1) Eachspecific disease is likely to have its own epigenetic signaturefor example RA appears to be hypomethylated whereas inSSc the fibroblasts at least appear hypermethylated Thusdifferent approaches to treatmentwill bewarranted It is likelythat in the hypermethylated state in SSc the use of decitabinemay be useful but in RA where the fibroblasts are alreadyhypermethylated this would exacerbate the situationHistonemodifications are also likely to differ in different diseases andany drugs that target specific histone modifications must beused with knowledge of the precise histone modificationsoccurring in that particular setting This will be critical inthe treatment regime Noncoding RNAs like miRNAs arenow emerging as excellent druggable targets however issuesregarding their stability and targeting in vivo still remainunclear How do we get the right miR-mimic or antagomiRto the precise tissue This is an active area of research and itis already bearing fruit with the use of aptamers Epigenetictherapies are now coming to the fore and the use of the firstmiRNA therapy in HCV appears to be a success

Competing Interests

There are no competing interests

Authorsrsquo Contributions

Marzena Ciechomska and Steven OrsquoReilly wrote the paperMarzenaCiechomska takes the responsibility for the integrityof the paper

Acknowledgments

Thisworkwas supported by 201516SNZ600041 grant fromthe National Science Centre (Poland) (Marzena Ciechom-ska)


References

[1] G S Alarcon G V Williams J Z Singer et al ldquoEarly undiffer-entiated connective tissue disease I Early clinicalmanifestationin a large cohort of patients with undifferentiated connectivetissue diseases compared with cohorts of well establishedconnective tissue diseaserdquoThe Journal of Rheumatology vol 18no 9 pp 1332ndash1339 1991

[2] G Arango Duque and A Descoteaux ldquoMacrophage cytokinesinvolvement in immunity and infectious diseasesrdquo Frontiers inImmunology vol 5 article 491 2014

[3] Y Lu and L M Wahl ldquoOxidative stress augments the pro-duction of matrix metalloproteinase-1 cyclooxygenase-2 andprostaglandin E2 through enhancement of NF-120581B activityin lipopolysaccharide-activated human primary monocytesrdquoJournal of Immunology vol 175 no 8 pp 5423ndash5429 2005

[4] A Aggarwal ldquoRole of autoantibody testingrdquo Best Practice ampResearch Clinical Rheumatology vol 28 no 6 pp 907ndash9202014

[5] N Qu M Xu I Mizoguchi et al ldquoPivotal roles of T-helper17-related cytokines IL-17 IL-22 and IL-23 in inflammatorydiseasesrdquo Clinical and Developmental Immunology vol 2013Article ID 968549 13 pages 2013

[6] A P Feinberg ldquoPhenotypic plasticity and the epigenetics ofhuman diseaserdquo Nature vol 447 no 7143 pp 433ndash440 2007

[7] M Wahren-Herlenius and T Dorner ldquoImmunopathogenicmechanisms of systemic autoimmune diseaserdquoThe Lancet vol382 no 9894 pp 819ndash831 2013

[8] K Gervin M D Vigeland M Mattingsdal et al ldquoDNAmethylation and gene expression changes in monozygotictwins discordant for psoriasis identification of epigeneticallydysregulated genesrdquo PLoS Genetics vol 8 no 1 Article IDe1002454 2012

[9] B D Adams C Parsons and F J Slack ldquoThe tumor-suppressiveand potential therapeutic functions of miR-34a in epithelialcarcinomasrdquo Expert Opinion onTherapeutic Targets 2015

[10] J Lu and A G Clark ldquoImpact of microRNA regulation onvariation in human gene expressionrdquo Genome Research vol 22no 7 pp 1243ndash1254 2012

[11] X-M Hua J Wang D-M Qian et al ldquoDNA methylationlevel of promoter region of activating transcription factor 5 ingliomardquo Journal of Zhejiang University Science B vol 16 no 9pp 757ndash762 2015

[12] M Weber I Hellmann M B Stadler et al ldquoDistributionsilencing potential and evolutionary impact of promoter DNAmethylation in the human genomerdquoNature Genetics vol 39 no4 pp 457ndash466 2007

[13] H L A Janssen H W Reesink E J Lawitz et al ldquoTreatmentof HCV infection by targeting microRNArdquo The New EnglandJournal of Medicine vol 368 no 18 pp 1685ndash1694 2013

[14] D C Dolinoy ldquoThe agouti mouse model an epigenetic biosen-sor for nutritional and environmental alterations on the fetalepigenomerdquo Nutrition Reviews vol 66 supplement 1 pp S7ndashS11 2008

[15] K Raj and G J Mufti ldquoAzacytidine (Vidaza5) in the treatmentof myelodysplastic syndromesrdquo Therapeutics and Clinical RiskManagement vol 2 no 4 pp 377ndash388 2006

[16] D Wu X Du J Jin et al ldquoDecitabine for treatment ofmyelodysplastic syndromes in Chinese patients an open-labelphase-3b studyrdquo Advances in Therapy vol 32 no 11 pp 1140ndash1159 2015

[17] M Lubbert S Suciu A Hagemeijer et al ldquoDecitabine improvesprogression-free survival in older high-risk MDS patientswith multiple autosomal monosomies results of a subgroupanalysis of the randomized phase III study 06011 of the EORTCLeukemia Cooperative Group and GermanMDS Study GrouprdquoAnnals of Hematology vol 95 no 2 pp 191ndash199 2016

[18] H Zhang X Zhang E Clark M Mulcahey S Huang andY G Shi ldquoTET1 is a DNA-binding protein that modulatesDNA methylation and gene transcription via hydroxylation of5-methylcytosinerdquo Cell Research vol 20 no 12 pp 1390ndash13932010

[19] M C de Andres E Perez-PampinM Calaza et al ldquoAssessmentof global DNAmethylation in peripheral blood cell subpopula-tions of early rheumatoid arthritis before and after methotrex-aterdquo Arthritis Research and Therapy vol 17 no 1 article 2332015

[20] D Rohle J Popovici-Muller N Palaskas et al ldquoAn inhibitor ofmutant IDH1 delays growth and promotes differentiation ofglioma cellsrdquo Science vol 340 no 6132 pp 626ndash630 2013

[21] A Chaturvedi M M Araujo Cruz N Jyotsana et al ldquoMutantIDH1 promotes leukemogenesis in vivo and can be specificallytargeted in human AMLrdquo Blood vol 122 no 16 pp 2877ndash28872013

[22] E L Mersfelder and M R Parthun ldquoThe tale beyond the tailhistone core domain modifications and the regulation of chro-matin structurerdquoNucleic Acids Research vol 34 no 9 pp 2653ndash2662 2006

[23] A J Bannister and T Kouzarides ldquoRegulation of chromatin byhistone modificationsrdquo Cell Research vol 21 no 3 pp 381ndash3952011

[24] M B Wozniak R Villuendas J R Bischoff et al ldquoVorinostatinterferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinaseinhibitors in cutaneous T-cell lymphomardquo Haematologica vol95 no 4 pp 613ndash621 2010

[25] ldquoHorizon 2020 Framework Programme EULARrsquos position andrecommendationsrdquo httpwwweularorgmyUploadDatafilesEU Horizon 2020 EULAR position paperpdf

[26] F Humby M Bombardieri A Manzo et al ldquoEctopic lym-phoid structures support ongoing production of class-switchedautoantibodies in rheumatoid synoviumrdquo PLoSMedicine vol 6article e1 2009

[27] T Niimoto T Nakasa M Ishikawa et al ldquoMicroRNA-146aexpresses in interleukin-17 producing T cells in rheumatoidarthritis patientsrdquoBMCMusculoskeletalDisorders vol 11 article209 2010

[28] N Muller F Doring M Klapper et al ldquoInterleukin-6 andTumourNecrosis Factor-120572 differentially regulate lincRNA tran-scripts in cells of the innate immune system in vivo in humansubjects with rheumatoid arthritisrdquo Cytokine vol 68 no 1 pp65ndash68 2014

[29] J Song D Kim J Han Y Kim M Lee and E-J Jin ldquoPBMCand exosome-derived Hotair is a critical regulator and potentmarker for rheumatoid arthritisrdquo Clinical and ExperimentalMedicine vol 15 no 1 pp 121ndash126 2014

[30] C-C Liu T-J Fang T-T Ou et al ldquoGlobal DNA methylationDNMT1 and MBD2 in patients with rheumatoid arthritisrdquoImmunology Letters vol 135 no 1-2 pp 96ndash99 2011

[31] E Karouzakis Y Rengel A Jungel et al ldquoDNA methylationregulates the expression of CXCL12 in rheumatoid arthritissynovial fibroblastsrdquo Genes and Immunity vol 12 no 8 pp643ndash652 2011


[32] K Ishida T Kobayashi S Ito et al ldquoInterleukin-6 gene pro-moter methylation in rheumatoid arthritis and chronic peri-odontitisrdquo Journal of Periodontology vol 83 no 7 pp 917ndash9252012

[33] J R Glossop R D Emes N B Nixon et al ldquoGenome-wideDNA methylation profiling in rheumatoid arthritis identifiesdisease-associated methylation changes that are distinct toindividual T- and B-lymphocyte populationsrdquo Epigenetics vol9 no 9 pp 1228ndash1237 2014

[34] N Altorok P Coit T Hughes et al ldquoGenome-wide DNAmeth-ylation patterns in naive CD4+ t cells from patients withprimary Sjogrenrsquos syndromerdquo Arthritis and Rheumatology vol66 no 3 pp 731ndash739 2014

[35] S OrsquoReilly R Cant M Ciechomska and J M van LaarldquoInterleukin-6 a new therapeutic target in systemic sclerosisrdquoClinical amp Translational Immunology vol 2 no 4 p e4 2013

[36] L-H Fu C-L Ma B Cong S-J Li H-Y Chen andJ-G Zhang ldquoHypomethylation of proximal CpG motif ofinterleukin-10 promoter regulates its expression in humanrheumatoid arthritisrdquo Acta Pharmacologica Sinica vol 32 no11 pp 1373ndash1380 2011

[37] L C Huber M Brock H Hemmatazad et al ldquoHistonedeacetylaseacetylase activity in total synovial tissue derivedfrom rheumatoid arthritis and osteoarthritis patientsrdquo Arthritisand Rheumatism vol 56 no 4 pp 1087ndash1093 2007

[38] T TWada Y Araki K Sato et al ldquoAberrant histone acetylationcontributes to elevated interleukin-6 production in rheuma-toid arthritis synovial fibroblastsrdquo Biochemical and BiophysicalResearch Communications vol 444 no 4 pp 682ndash686 2014

[39] M R York T Nagai A J Mangini R Lemaire J M VanSeventer and R Lafyatis ldquoA macrophage marker siglec-1 isincreased on circulating monocytes in patients with systemicsclerosis and induced by type I interferons and toll-like receptoragonistsrdquo Arthritis and Rheumatism vol 56 no 3 pp 1010ndash1020 2007

[40] G Alsaleh A Francois L Philippe et al ldquoMiR-30a-3p neg-atively regulates BAFF synthesis in systemic sclerosis andrheumatoid arthritis fibroblastsrdquo PLoS ONE vol 9 no 10Article ID e111266 2014

[41] Y Wang Y Shu Y Xiao et al ldquoHypomethylation and over-expression of ITGAL (CD11a) in CD4+ T cells in systemicsclerosisrdquo Clinical Epigenetics vol 6 no 1 article 25 2014

[42] M Ciechomska C A Huigens T Hugle et al ldquoToll-likereceptor-mediated enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis role ofserum factorsrdquo Annals of the Rheumatic Diseases vol 72 no 8pp 1382ndash1389 2013

[43] S OrsquoReilly R Cant M Ciechomska et al ldquoSerum amyloid Ainduces interleukin-6 in dermal fibroblasts via Toll-like receptor2 interleukin-1 receptor-associated kinase 4 and nuclear factor-120581Brdquo Immunology vol 143 no 3 pp 331ndash340 2014

[44] M Ciechomska S OrsquoReilly S Przyborski F Oakley KBogunia-Kubik and J M van Laar ldquoHistone demethylationand toll-like receptor 8-dependent cross-talk in monocytespromotes transdifferentiation of fibroblasts in systemic sclerosisvia fra-2rdquo Arthritis amp Rheumatology vol 68 no 6 pp 1493ndash1504 2016

[45] YWang Y Yang Y Luo et al ldquoAberrant histonemodification inperipheral blood B cells from patients with systemic sclerosisrdquoClinical Immunology vol 149 no 1 pp 46ndash54 2013

[46] M N Primo R O Bak B Schibler and J G MikkelsenldquoRegulation of pro-inflammatory cytokines TNF120572 and IL24 by

microRNA-203 in primary keratinocytesrdquo Cytokine vol 60 no3 pp 741ndash748 2012

[47] P Xia X Fang Z-H Zhang et al ldquoDysregulation ofmiRNA146a versus IRAK1 induces IL-17 persistence in thepsoriatic skin lesionsrdquo Immunology Letters vol 148 no 2 pp151ndash162 2012

[48] X Gu E Nylander P J Coates R Fahraeus and K NylanderldquoCorrelation between reversal of DNAmethylation and clinicalsymptoms in psoriatic epidermis following narrow-band UVBphototherapyrdquo Journal of Investigative Dermatology vol 135 no8 pp 2077ndash2083 2015

[49] M Chen Z-Q Chen P-G Cui et al ldquoThemethylation patternof p16INK4a gene promoter in psoriatic epidermis and itsclinical significancerdquo British Journal of Dermatology vol 158no 5 pp 987ndash993 2008

[50] L E Tovar-Castillo J C Cancino-Dıaz F Garcıa-Vazquez et alldquoUnder-expression of VHL and over-expression of HDAC-1HIF-1120572 LL-37 and IAP-2 in affected skin biopsies of patientswith psoriasisrdquo International Journal ofDermatology vol 46 no3 pp 239ndash246 2007

[51] P Zhang Y Su M Zhao W Huang and Q Lu ldquoAbnormalhistone modifications in PBMCs from patients with psoriasisvulgarisrdquo European Journal of Dermatology vol 21 no 4 pp552ndash557 2011

[52] J Quddus K J Johnson J Gavalchin et al ldquoTreating activatedCD4+T cells with either of two distinct DNAmethyltransferaseinhibitors 5-azacytidine or procainamide is sufficient to causea lupus-like disease in syngeneic micerdquo Journal of ClinicalInvestigation vol 92 no 1 pp 38ndash53 1993

[53] C Deng M J Kaplan J Yang et al ldquoDecreased ras-mitogen-activated protein kinase signaling may cause DNA hypomethy-lation in T lymphocytes from lupus patientsrdquo Arthritis andRheumatism vol 44 no 2 pp 397ndash407 2001

[54] Y Li M Zhao H Yin et al ldquoOverexpression of the growtharrest and DNA damage-induced 45120572 gene contributes toautoimmunity by promoting DNA demethylation in lupus Tcellsrdquo Arthritis and Rheumatism vol 62 no 5 pp 1438ndash14472010

[55] Y Li G Gorelik F M Strickland and B C RichardsonldquoOxidative stress T cell dna methylation and lupusrdquo Arthritisand Rheumatology vol 66 no 6 pp 1574ndash1582 2014

[56] FM Strickland Y Li K Johnson Z Sun and B C RichardsonldquoCD4+ T cells epigenetically modified by oxidative stress causelupus-like autoimmunity in micerdquo Journal of Autoimmunityvol 62 pp 75ndash80 2015

[57] Q Lu M Kaplan D Ray et al ldquoDemethylation of ITGAL(CD11a) regulatory sequences in systemic lupus erythemato-susrdquo Arthritis and Rheumatism vol 46 no 5 pp 1282ndash12912002

[58] Q Lu A Wu L Tesmer D Ray N Yousif and B RichardsonldquoDemethylation of CD40LG on the inactive X in T cells fromwomen with lupusrdquo The Journal of Immunology vol 179 no 9pp 6352ndash6358 2007

[59] P Coit M Jeffries N Altorok et al ldquoGenome-wide DNAmethylation study suggests epigenetic accessibility andtran-scriptional poising of interferon-regulated genes in naıve CD4+T cellsfrom lupus patientsrdquo Journal of Autoimmunity vol 43 pp78ndash84 2013

[60] D M Absher X Li L L Waite et al ldquoGenome-wide DNAmethylation analysis of systemic lupus erythematosus reveals


persistent hypomethylation of interferon genes and composi-tional changes to CD4+ T-cell populationsrdquo PLoS Genetics vol9 no 8 article e1003678 2013

[61] S A Chung J Nititham E Elboudwarej et al ldquoGenome-wideassessment of differential DNA methylation associated withautoantibody production in systemic lupus erythematosusrdquoPLoS ONE vol 10 no 7 Article ID e0129813 2015

[62] T Fali C Le Dantec Y Thabet et al ldquoDNA methylationmodulates HRES1p28 expression in B cells from patients withlupusrdquo Autoimmunity vol 47 no 4 pp 265ndash271 2014

[63] H Qin X Zhu J Liang et al ldquoMicroRNA-29b contributesto DNA hypomethylation of CD4+ T cells in systemic lupuserythematosus by indirectly targeting DNA methyltransferase1rdquo Journal of Dermatological Science vol 69 no 1 pp 61ndash672013

[64] Y Tang X Luo H Cui et al ldquoMicroRNA-146a contributes toabnormal activation of the type I interferon pathway in humanlupus by targeting the key signaling proteinsrdquo Arthritis andRheumatism vol 60 no 4 pp 1065ndash1075 2009

[65] Y Hong J Wu J Zhao et al ldquomiR-29b and miR-29c areinvolved in toll-like receptor control of glucocorticoid-inducedapoptosis in human plasmacytoid dendritic cellsrdquo PLoS ONEvol 8 no 7 article e69926 2013

[66] W Pan S Zhu M Yuan et al ldquoMicroRNA-21 and microRNA-148a contribute toDNAhypomethylation in lupus CD4+T cellsby directly and indirectly targeting DNA methyltransferase 1rdquoThe Journal of Immunology vol 184 no 12 pp 6773ndash6781 2010

[67] Y Deng J Zhao D Sakurai et al ldquoMicroRNA-3148 modulatesallelic expression of toll-like receptor 7 variant associated withsystemic lupus erythematosusrdquo PLoS Genetics vol 9 no 2Article ID e1003336 2013

[68] W Fan D Liang Y Tang et al ldquoIdentification of microRNA-31 as a novel regulator contributing to impaired interleukin-2 production in T cells from patients with systemic lupuserythematosusrdquo Arthritis amp Rheumatism vol 64 no 11 pp3715ndash3725 2012

[69] G Wang L-S Tam B C-H Kwan et al ldquoExpression of miR-146a and miR-155 in the urinary sediment of systemic lupuserythematosusrdquo Clinical Rheumatology vol 31 no 3 pp 435ndash440 2012

[70] N Hu X Qiu Y Luo et al ldquoAbnormal histone modificationpatterns in lupus CD4+ T cellsrdquo The Journal of Rheumatologyvol 35 no 5 pp 804ndash810 2008

[71] M Mandal S E Powers M Maienschein-Cline et al ldquoEpige-netic repression of the Igk locus by STAT5-mediated recruit-ment of the histone methyltransferase Ezh2rdquo Nature Immunol-ogy vol 12 no 12 pp 1212ndash1220 2011

[72] H Long W Huang H Yin S Zhao M Zhao and Q LuldquoAbnormal expression pattern of histone demethylases in CD4+ T cells of MRLlpr lupus-like micerdquo Lupus vol 18 no 14 pp1327ndash1328 2009

[73] Q Zhang H long J Liao et al ldquoInhibited expression ofhematopoietic progenitor kinase 1 associated with loss ofjumonji domain containing 3 promoter binding contributesto autoimmunity in systemic lupus erythematosusrdquo Journal ofAutoimmunity vol 37 no 3 pp 180ndash189 2011

[74] NMishra CM Reilly D R Brown P Ruiz andG S GilkesonldquoHistone deacetylase inhibitors modulate renal disease in theMRL-lprlpr mouserdquo Journal of Clinical Investigation vol 111no 4 pp 539ndash552 2003

[75] Y Zhou X Qiu Y Luo et al ldquoHistone modifications andmethyl-CpG-binding domain protein levels at the TNFSF7

(CD70) promoter in SLE CD4+ T cellsrdquo Lupus vol 20 no 13pp 1365ndash1371 2011

[76] K M Pauley C M Stewart A E Gauna et al ldquoAltered miR-146a expression in Sjogrenrsquos syndrome and its functional role ininnate immunityrdquo European Journal of Immunology vol 41 no7 pp 2029ndash2039 2011

[77] H Shi L-Y Zheng P Zhang and C-Q Yu ldquomiR-146a andmiR-155 expression in PBMCs from patients with Sjogrenrsquossyndromerdquo Journal of Oral Pathology and Medicine vol 43 no10 pp 792ndash797 2014

[78] E Zilahi T Tarr G Papp Z Griger S Sipka and M ZeherldquoIncreased microRNA-146ab TRAF6 gene and decreasedIRAK1 gene expressions in the peripheral mononuclear cells ofpatients with Sjogrenrsquos syndromerdquo Immunology Letters vol 141no 2 pp 165ndash168 2012

[79] M Tandon A Gallo S-I Jang G G Illei and I AlevizosldquoDeep sequencing of short RNAs reveals novel microRNAs inminor salivary glands of patients with Sjogrenrsquos syndromerdquoOralDiseases vol 18 no 2 pp 127ndash131 2012

[80] C Liang K Xiong K E Szulwach et al ldquoSjogren syndromeantigen B (SSB)La promotes global microRNA expression bybindingmicroRNAprecursors through stem-loop recognitionrdquoJournal of Biological Chemistry vol 288 no 1 pp 723ndash736 2013

[81] Y Thabet C Le Dantec I Ghedira et al ldquoEpigenetic dysregu-lation in salivary glands from patients with primary Sjogrenrsquossyndrome may be ascribed to infiltrating B cellsrdquo Journal ofAutoimmunity vol 41 pp 175ndash181 2013

[82] X Yu G Liang H Yin et al ldquoDNA hypermethylation leadsto lower FOXP3 expression in CD4+ T cells of patients withprimary Sjogrenrsquos syndromerdquo Clinical Immunology vol 148 no2 pp 254ndash257 2013

[83] N Altorok P Coit T Hughes et al ldquoGenome-wide DNAmethylation patterns in naive cd4+ t cells from patients withprimary sjogrenrsquos syndromerdquo Arthritis and Rheumatology vol66 no 3 pp 731ndash739 2014

[84] N-S Lai H-C Yu H-C Chen C-L Yu H-B Huangand M-C Lu ldquoAberrant expression of microRNAs in T cellsfrom patients with ankylosing spondylitis contributes to theimmunopathogenesisrdquo Clinical amp Experimental Immunologyvol 173 no 1 pp 47ndash57 2013

[85] J Qi S Hou Q Zhang et al ldquoA functional variant of pre-miRNA-196a2 confers risk for Behcetrsquos disease but not for Vogt-Koyanagi-Harada syndrome orAAU in ankylosing spondylitisrdquoHuman Genetics vol 132 no 12 pp 1395ndash1404 2013

[86] Y Xia K Chen M-H Zhang et al ldquoMicroRNA-124 involvesin ankylosing spondylitis by targeting ANTXR2rdquo ModernRheumatology vol 25 no 5 pp 784ndash789 2015

[87] Z Niu J Wang H Zou C Yang W Huang and L JinldquoCommon MIR146A polymorphisms in Chinese ankylosingspondylitis subjects and controlsrdquo PLoS ONE vol 10 no 9Article ID e0137770 2015

[88] H Appel P Wu R Scheer et al ldquoSynovial and peripheralblood CD4+FoxP3+ T cells in spondyloarthritisrdquo The Journalof Rheumatology vol 38 no 11 pp 2445ndash2451 2011

[89] N-S Lai J-L Chou G C W Chen S-Q Liu M-C Lu andMWY Chan ldquoAssociation between cytokines andmethylationof SOCS-1 in serum of patients with ankylosing spondylitisrdquoMolecular Biology Reports vol 41 no 6 pp 3773ndash3780 2014

[90] E Toussirot W Abbas K A Khan et al ldquoImbalance betweenHAT and HDAC activities in the PBMCs of patients withankylosing spondylitis or rheumatoid arthritis and influence of


HDAC inhibitors on TNF alpha productionrdquo PLoS ONE vol 8no 8 Article ID e70939 2013

[91] E Toussirot D Wendling and G Herbein ldquoBiological treat-ments given in patients with rheumatoid arthritis or anky-losing spondylitis modify HATHDAC (histone acetyltrans-ferasehistone deacetylase) balancerdquo Joint Bone Spine vol 81no 6 pp 544ndash545 2014

[92] A R Roberts M Vecellio L Chen et al ldquoAn ankylosingspondylitis-associated genetic variant in the IL23R-IL12RB2intergenic region modulates enhancer activity and is associatedwith increasedTh1-cell differentiationrdquoAnnals of the RheumaticDiseases 2016

[93] P Coit L B De Lott B Nan V M Elner and A H SawalhaldquoDNA methylation analysis of the temporal artery microen-vironment in giant cell arteritisrdquo Annals of the RheumaticDiseases vol 75 no 6 pp 1196ndash1202 2016

[94] S Croci A Zerbini L Boiardi et al ldquoMicroRNA markers ofinflammation and remodelling in temporal arteries frompatients with giant cell arteritisrdquo Annals of the RheumaticDiseases vol 75 no 8 pp 1527ndash1533 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


rheumatic diseases [4] Also a subset of helper CD4+ T cellsTh17 is reported to be involved in rheumatic pathogenesis[5] Th17 cells are characterised by production of IL-17This interleukin is a potent proinflammatory cytokine thatamplifies ongoing inflammation by induction of TNF-120572 IL-1120573 and IL-6 inmacrophages as well as of other cell types suchas keratinocytes fibroblasts and synoviocytes Fibroblast-like synoviocytes (FLS) located inside joints in the synoviumalso play a key role in pathogenesis of rheumatic diseases dueto their production of proinflammatory cytokines adhesionmolecules and matrix proteases contributing to cartilagedestruction Rheumatoid FLS develop a unique autoaggres-sive phenotype that increases invasiveness into the extracel-lular matrix promotes inflammatory cell recruitment andelevates production of COX-2 NSAIDs are widely used anti-inflammatory agents that act through the inhibition of theCOX enzymes Although COX-inhibitors lead to reducedsynthesis of prostaglandins at the site of inflammation sup-pression of gastrointestinal or renal prostaglandins synthesisis associated with mechanism-based toxicities This limitsthe usefulness of these otherwise potent drugs In additionCOX-2 inhibitors have been found to increase the riskof myocardial infarction Thus finding new agents whichwill specifically block inflammation may provide therapeuticopportunities in immune-mediated rheumatic diseases

2 Overview on Epigenome-Influencing Drugs

Epigenetics is defined as reversible and heritable changesin gene function without alteration of the underlying DNAsequence itself [6] Epigenetic mechanisms are sensitive toexternal stimuli bridging the gap between environmentaland genetic factors In particularmonozygotic (MZ) twins donot show complete concordance for many complex diseasesMZ discordance rates for autoimmune diseases are 20ndash80percent indicating a substantial role of epigenetic factors inthe development of these disorders [7 8] Indeed it has beenreported that epigenetic mechanisms mediate developmentof chronic inflammation by modulating the expression ofproinflammatory cytokines including TNF-120572 IL-6 and IL-1 and induction of COX-2 and transcription factor NF-120581BThese molecules are constitutively produced by a variety ofimmune cells under chronic inflammatory conditions whichconsequently leads to the development of many diseasesincluding cancer cardiovascular diseases or autoimmunerheumatic disorders

3 Noncoding RNA

Three main epigenetic mechanisms have been describedincluding noncoding RNA species DNA methylation andhistone modification The first group of noncoding RNAsincludes microRNA (miRNA) and long noncoding RNA(lncRNA) MicroRNAs (miRNAs) are endogenous single-stranded RNAs of 19ndash25 nucleotides in length which cannegatively regulate gene expression on posttranscriptionallevel In particular miRNA can hybridise to 3ndash8 nucleotideswithin 31015840-untranslated region (31015840UTR) of target messengerRNA (mRNA) referred to as ldquoseed sequencerdquo [9] The

Table 1 FDA-approved epigenetic drugs

Drug Epigenetic effect Clinical trialMiravirsen Neutralisation of miRNA-122 Phase II [13]MRX34 Ectopic expression of miRNA-34 Phase I [9]Azacitidine(Vidaza) DNA methyltransferase inhibitor Phase III [15]

Decitabine(Dacogen) DNA methyltransferase inhibitor Phase III [17]

Vorinostat(Zolinza) Pan-HDAC inhibitor Phase II [24]

formation of such miRNA-mRNA duplexes leads to mRNAdegradation or translational repression miRNAs have beenstudied extensively due to their role in regulation of almostevery cellular process It is known that miRNAs can act asa fine-tuner of gene expression and can negatively regulateapproximately 30 percent of human protein-coding genes[10] In additionmiRNAs are attractive as potential biomark-ers Some of miRNAs have been already tested in preclinicalstudies that aimed to treat cancer including lung prostateor leukemia [11] Interestingly randomised phase IIa doubleblind clinical trial (test numberNCT01200420) has been con-ducted to treat hepatitis C virus (HCV) using locked nucleicacid inhibitor of miRNA-122 (Table 1) miRNA-122 is crucialfor viral replication in hepatocytes thus the reintroduction ofmiRNA-122 inhibitor significantly reduced virus replication[12 13] Recent phase I clinical trial has also tested thedrug called MRX34 MRX34 is a double-stranded miRNA-34 encapsulated in liposomal nanoparticles miRNA-34arepresses the expression of more than 20 oncogenes whichresults in inhibition cancer cell viability stemness metastasisor chemoresistance Thus MRX34 is widely tested in solidtumours and hematological malignancies [9] Many studieshave also shown the role of lncRNA in diverse cellular pro-cesses lncRNAs are non-protein-coding transcripts longerthan 200 nucleotides regulating gene expression Howeverthe exact functional roles and mechanisms of lncRNAs arestill unclear

4 DNA Methylation

Another mechanism of epigenetic changes is DNA methyla-tion induced by a highly conserved family of DNA methyl-transferases (DNMTs) DNMT1 is the most abundant DNAmethyltransferase in mammalian cells [14] The insertion ofmethyl group to cytosine at the carbon 5 position leads tostructural changes in chromatin and ismostly associatedwithgene silencing In humans methylation mainly occurs whencytosine is followed by guanine and is linked with phosphatecalled CpG islands Approximately 1 percent of the genomeconsists of CpG islands [11] Also it is reported that roughly60ndash70 percent of human genes are linked to promoter CpGislands which suggests that methylation of CpG island isan important regulatory mechanism of gene expression [12]It has been shown that vitamin B12 rich diet (B vitaminsacted as methyl donors) in agouti mouse model preventedfrom development of inflammation mediated diabetes and









DNA methylation

T cell

Fibroblast

B cell



Phosph

DZNep

(SSc)

Ubi

Hyper

Hypo

miRNA-23b

miRNA-29

miRNA-30a

miRNA-346

miRNA-135b

miRNA-146a

miRNA-203

miRNA-21

miRNA-155

miRNA-124

miRNA inhibition

mRNA

miRNA

Curcumin

(RA)

TSA(SSc)

uarr IL-10 (RA)

darr Ras (SLE)

uarr COL1A2 (SSc)


uarr CD11a (SSc)

darr ANTRX2 (AS)

darr AID (SLE)

darr DNMT1 (SLE)

darr STAT6 (SSc)


darr BAFF (SSc)



M120601

darrTNF-120572 (RA)


5998400-AZA





























13 Conclusions


Competing Interests




Acknowledgments



References











































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























DNA methylation

T cell

Fibroblast

B cell



Phosph

DZNep

(SSc)

Ubi

Hyper

Hypo

miRNA-23b

miRNA-29

miRNA-30a

miRNA-346

miRNA-135b

miRNA-146a

miRNA-203

miRNA-21

miRNA-155

miRNA-124

miRNA inhibition

mRNA

miRNA

Curcumin

(RA)

TSA(SSc)

uarr IL-10 (RA)

darr Ras (SLE)

uarr COL1A2 (SSc)


uarr CD11a (SSc)

darr ANTRX2 (AS)

darr AID (SLE)

darr DNMT1 (SLE)

darr STAT6 (SSc)


darr BAFF (SSc)



M120601

darrTNF-120572 (RA)


5998400-AZA





























13 Conclusions


Competing Interests




Acknowledgments



References











































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































13 Conclusions


Competing Interests




Acknowledgments



References











































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References











































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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