Journal of Autoimmunity 39 (2012) 451e465
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Epigenetics, autoimmunity and hematologic malignancies: A comprehensive review Owen Ngalamika a, c,1, Yiqun Zhang a,1, Heng Yin a,1, Ming Zhao a, M. Eric Gershwin b, Qianjin Lu a, * a
Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, #139 Renmin Middle Rd, Changsha, Hunan 410011, PR China b Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA c Department of Dermatovenereology, University Teaching Hospital, Lusaka, Zambia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 September 2012 Accepted 24 September 2012
The relationships between immunological dysfunction, loss of tolerance and hematologic malignancies have been a focus of attention in attempts to understand the appearance of a higher degree of autoimmune disease and lymphoma in children with congenital immunodeﬁciency. Although multiple hypotheses have been offered, it is clear that stochastic processes play an important role in the immunopathology of these issues. In particular, accumulating evidence is deﬁning a role of epigenetic mechanisms as being critical in this continuous spectrum between autoimmunity and lymphoma. In this review, we focus attention predominantly on the relationships between T helper 17 (Th17) and T regulatory populations that alter local microenvironments and ultimately the expression or transcription factors involved in cell activation and differentiation. Abnormal expression in any of the molecules involved in Th17 and/or Treg development alter immune homeostasis and in genetically susceptible hosts may lead to the appearance of autoimmunity and/or lymphoma. These observations have clinical signiﬁcance in explaining the discordance of autoimmunity in identical twins. They are also particularly important in the relationships between primary immune deﬁciency syndromes, immune dysregulation and an increased risk of lymphoma. Indeed, deﬁning the factors that determine epigenetic alterations and their relationships to immune homeostasis will be a challenge greater or even equal to the human genome project. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Autoimmune disease Hematological malignancy Treg cells Th17 cells Epigenetics
1. Introduction The mechanisms that lead to loss of tolerance include both genetic and environmental factors. Indeed, the understanding that environment plays a critical role in the development of autoimmunity was based in part on studies of concordance of speciﬁc autoimmune diseases in identical twins. Although identical twins share genetic elements, they differ in epigenetic alterations. Indeed, a recent symposium has highlighted the multiple environmental features that predispose to autoimmune disease. Interestingly, a number of these factors lead to changes at the epigenetic level which can result in immune dysregulation. It is such stochastic processes that lead to loss of tolerance in the genetically susceptible host. In contrast, hematologic malignancies are thought to arise from chromosomal translocations that are often associated with
* Corresponding author. Tel.: þ86 731 85295860; fax: þ86 731 85533525. E-mail address: [email protected]
(Q. Lu). 1 These authors contributed equally to this work. 0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2012.09.002
missing or extra copy of genes and thereby with altered expression of speciﬁc molecules. Patients with autoimmune disease often have a higher incidence of lymphoma and indeed children with immune deﬁciency syndromes may likewise have an increased incidence of autoimmunity and lymphoma. The mechanisms that lead to these associations are diverse but likely include the relationships between T regulatory (Tregs) and T helper 17 (Th17) cells. Regulatory T cells (Tregs) and T helper 17 (Th17) cells, two reciprocally related T cell subsets, are generally considered to play essential but opposing roles in modulating the immune response. Tregs, which express the transcription factor forkhead box P3 (Foxp3), are pivotal in the maintenance of self tolerance and immune homeostasis, while Th17 cells usually promote inﬂammatory conditions. In both autoimmune diseases and hematological malignancies, inherited or acquired changes at the genetic or epigenetic level can affect the expression of several cytokines and transcription factors, eventually leading to an imbalance in the ratio of Treg to Th17 cells that will in turn favor a particular disease condition. It has been observed that Treg number and function are both reduced in autoimmune diseases, whereas the opposite occurs
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in several hematological malignant conditions. On the other hand, Th17 cells are generally increased in number and function in most autoimmune diseases. In hematological malignancies, these cells may have a dual role where they either enhance anti-tumor immunity as expected or promote malignant disease by producing pro-oncogenic factors. In this review, we discuss the interplay between Tregs and Th17 cells in the development of autoimmune diseases and hematological malignancies, with a particular focus on the epigenetic mechanisms known to be involved. 2. Epigenetic mechanisms Epigenetics is the study of inherited changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. Such mechanisms include altering the levels of DNA and histone methylation and of histone acetylation, which leads to changes in the chromatin structure that can either activate or silence gene expression. Epigenetic modiﬁcations affect the degree of DNA compaction and the accessibility of the transcription machinery to the DNA strand, thus altering gene expression, phenotype and disease susceptibility . The study of epigenetic mechanisms has provided new insights into how environmental changes contribute to the pathogenesis of autoimmune diseases and hematological malignancy, and has helped justify the rising prevalence of these conditions. The major processes that establish the epigenetic memory through modulation of the chromatin architecture operate by recruiting various histone modiﬁer proteins as well as DNA methyltransferases. Histone deacetylases (HDAC) remove acetyl groups, which leads to gene silencing; whereas histone acetyl transferases (HAT) add acetyl groups, creating a more open chromatin structure for enhanced gene expression. Histone methylation by histone methyltransferases (HMT) affects the interaction of nucleosomes with other proteins and can lead to either activation or repression of transcription depending on the context. DNA methyltransferases (DNMT) add methyl groups to CpG islands in DNA promoter regions. High levels of DNA methylation silence transcription, while hypomethylation of gene promoter regions is associated with increased transcriptional activity [2,3]. 3. T helper 17 and regulatory T cells T helper 17 (Th17) cells are a proinﬂammatory subset of T helper cells that produce IL-17 cytokines (mainly IL-17A and IL-17F), as well as IL-21 and IL-22. They protect mucosal and epithelial surfaces against extracellular microbes by mediating the
recruitment of neutrophils and macrophages to infected tissues. They are developmentally distinct from Th1 and Th2 cells, and excessive amounts of Th17 cells have been linked to the development of various autoimmune diseases . The cytokines produced by Th17 cells stimulate the production of anti-microbial proteins by epithelial cells, which help combat certain types of microbes. They also express the transcription factor retinoic acid-related orphan receptor (ROR) gt, whose expression is required for the transcription of IL-17 and for regulating its production. The transcription factor nuclear factor of activated T cells (NFAT) is another important regulator of IL-17 production. Cytokines such as IL-6, IL-21 and IL23 activate the transcription factor STAT3, which has been shown to play an essential role in multiple aspects of Th17 cell biology [5,6]. Regulatory T cells (Tregs) are a subpopulation of T cells that suppress immune system activation and maintain self-antigen tolerance. They are involved in shutting down immune responses after the successful eradication of invading organisms, and also in regulating those immune responses that may potentially attack one’s own tissues. Evidence from experimental mouse models suggests that the immunosuppressive potential of Tregs can be used to treat autoimmune diseases  and manipulated to facilitate organ transplantation and cancer immunotherapy. Mature Tregs can arise naturally from the thymus (natural Tregs e nTregs), or from the differentiation of CD4þ T cells in the peripheral circulation (induced Tregs e iTregs). Upon cytokine stimulation, peripheral naïve CD4þ T cells can differentiate into either iTregs or Th17 cells (Fig. 1). The transcription factor Foxp3 (forkhead box p3) acts as a master switch governing the development of CD4þ regulatory T cells into iTregs, while RORgt is responsible for Th17 development. Recent studies have demonstrated that the speciﬁc induction of RORgt or Foxp3 is dependent on TGFb signaling and that the two transcription factors can directly interact, establishing a competitive antagonism that determines Th17 versus iTreg lineage speciﬁcation [8,9]. 4. Foxp3 epigenetics in Treg development Several cytokines are involved in the regulation of Foxp3. For example, IL-2 signaling activates STAT (signal transducer and activator of transcription) proteins, which bind to evolutionarily conserved regions in the Foxp3 locus and induce Foxp3 expression. TGFb plays a role in maintaining Foxp3 expression and levels in nTregs. It has also been shown that TGFb-inducible early gene 1 (TIEG1) can bind to the Foxp3 promoter and cooperate with itchy E3 ubiquitin protein ligase homolog (ITCH) to induce Foxp3 expression. In addition, retinoic acid has been found to indirectly enhance
Fig. 1. Schematic diagram showing the developmental relationship between iTreg and Th17 lineages, highlighting some of the main components and stages involved. Inhibition at any of the stages will lead to reduced or no production of that particular cell type and favor differentiation of the other.
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the induction of Foxp3 expression by inhibiting the production of counter-regulatory cytokines by CD44hi effector memory T cells. Several studies have clearly demonstrated the importance of epigenetic regulation in the control of Foxp3 expression. Epigenetic modiﬁcations affect gene transcription by altering the accessibility of distinct DNA regions to transcription factors and other DNAbinding molecules. These modiﬁcations include site-speciﬁc acetylation and/or methylation of histone proteins, which are essential for determining overall chromatin structure. Transcription can also be affected by either the methylation or demethylation of rare CpG motifs clustered within CpG-rich promoter regions. Methylated CpG motifs are often associated with chromatin remodeling factors, such as methyl-DNA binding proteins, which cause chromatin condensation. Demethylation of CpG motifs, on the other hand, results in chromatin loosening and increased target sequence accessibility, thereby allowing the binding of speciﬁc transcription factors. It is believed that epigenetic mechanisms of transcriptional control can imprint the activity state of speciﬁc gene loci, such that an environmentally induced phenotype might become heritable and maintained over numerous cell divisions . In mice and humans, speciﬁc DNA methylation patterns and histone modiﬁcations at distinct regions within the Foxp3 locus differ between Tregs and conventional T cells. Sequence analyses have revealed three highly conserved non-coding regions in the Foxp3 locus, all of which are subject to epigenetic modiﬁcations and involved in regulating Foxp3 transcription (Fig. 2). 4.1. Foxp3 promoter region The Foxp3 promoter is located 6.5 kb upstream of the ﬁrst coding exon of Foxp3. It is a TATA- and CAAT-box-containing promoter that is activated in response to T cell receptor (TCR) signaling, which induces the binding of NFAT and AP1 (activator protein 1) . Epigenetic modiﬁcation patterns at the Foxp3 promoter locus differ between conventional T cells and Tregs in both mice and humans, such that CpG motifs within the Foxp3 promoter are almost completely unmethylated in Tregs, but weakly methylated in resting conventional T cells . In addition, the Foxp3 promoter region is associated with hyperacetylated histones in Tregs, but not in conventional T cells . This hyperacetylation
is linked to increased Foxp3 promoter accessibility in Tregs, which leads to enhanced Foxp3 expression in Tregs compared to conventional T cells. Other important molecules that bind to the Foxp3 promoter in its accessible state include TGFb-inducible early gene 1 (TIEG1)  and STAT5 [15,16]. 4.2. TGFb-sensitive element This second highly conserved non-coding region in the Foxp3 locus contains binding sites for NFAT and SMAD3. The chromatin in this region is also in a more accessible state in Foxp3-expressing Tregs, as evidenced by increased levels of acetylated histone H4 in both natural and TGFb-induced Tregs . TGFb signaling likely induces chromatin remodeling in this region, which in turn affects the accessibility of the upstream Foxp3 promoter, as promoter demethylation levels have been found to be slightly increased in mouse T cells treated with TGFb . 4.3. TSDR (Treg cell-speciﬁc demethylated region) This highly conserved CpG-rich region exhibits the most striking differences in DNA methylation patterns between Tregs and conventional T cells within the Foxp3 locus. Studies have shown that the TSDR is fully unmethylated in Tregs and methylated in conventional T cells [19,20]. In Tregs, acetylated histones H3 and H4 and trimethylated lysine 4 in histone 3 have also been observed at the TSDR . Transcription factors like CREB (cyclic-AMPresponsive-element-binding protein) and ATF (activating transcription factor) can bind to the TSDR in its unmethylated state , while methylation of the TSDR reduces its enhancer activity . Recent evidence suggests that TSDR demethylation does not act as a simple on/off switch, but instead determines the stability of Foxp3 expression [20,21]. This idea is supported by the demonstration that TSDR methylation status is not directly indicative of Foxp3 expression levels; for example, TGFb-induced Tregs express Foxp3 levels comparable to those of nTregs despite their incomplete demethylation at the TSDR . Therefore, an unmethylated TSDR leads to stable Foxp3 expression in nTregs, whereas TSDR methylation is associated with transient Foxp3 expression in TGFbinduced Tregs [13,19].
Fig. 2. Epigenetic control in three conserved regulatory regions on the Foxp3 gene. The ﬁgure depicts differences in DNA methylation (represented by the blue circles labeled “CH3”) and histone acetylation (represented by the purple circles labeled “Ac”) between Foxp3þ nTregs and conventional T cells. The epigenetic modiﬁcations (DNA hypomethylation and histone acetylation) present in nTregs create a more open and exposed chromatin conﬁguration that is easily accessible to transcription factors and leads to stable expression of Foxp3 in these cells. In contrast, methylation and hypoacetylation in the three regions results in a more condensed chromatin inaccessible to transcription factors in conventional T cells. (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of this article.)
O. Ngalamika et al. / Journal of Autoimmunity 39 (2012) 451e465
In support of these ﬁndings, it was demonstrated that drugmediated DNA demethylation in conventional T cells induces stable Foxp3 expression and a Treg phenotype. Under these conditions, demethylation of the TSDR was only observed in the fraction of cells that expressed Foxp3 [13,21]. It is highly likely that the methylation statuses of the TSDR, the Foxp3 promoter and additional regulatory regions will be used as valuable biomarkers for the detection of stably suppressive Treg cells in the near future . In addition, as recent studies suggest that chromatinmodifying agents such as DNA methyltransferases and histone deacetylase inhibitors can be used to manipulate Treg cell biology [23,24], programming/reprogramming of Tregs at the epigenetic level may become an important approach for the development of drugs that target these cells. 5. Positive regulators of Th17 cell development Th17 cells are characterized by the production of IL-17A and IL-17F cytokines [25,26], and are an important component of the adaptive immune response to various microbes, particularly extracellular bacteria and fungi. Data from human autoimmunity studies as well as genome-wide association studies have revealed an association between Th17 cells and an increasing number of chronic autoinﬂammatory diseases. The discovery of this T cell subset has offered new insights into the complexity of selective cytokine gene expression regulation and how it might relate to lineage commitment, terminal differentiation and immunologic memory . Th17 cells express the transcription factor RORgt, whose expression is necessary for the production of IL-17. In addition, signals from the TCR and from the transcription factor NFAT are involved in regulating IL-17 production. The activation of the transcription factor STAT3 by other cytokines such as IL-6, IL-21 and IL-23 is also required for multiple aspects of Th17 biology. TCR signaling activates a number of pathways and transcription factors, and signals resulting from TCR occupancy are an integral aspect of Th17 differentiation and activation. In the case of memory T cells, for example, TCR occupancy alone is sufﬁcient to induce large amounts of IL-17 production . One of the major pathways activated by the TCR leads to the production of intracellular calcium, which in turn regulates the activation of NFAT. Studies have shown that the proximal promoter of the human IL-17A gene contains two NFAT binding sites, which play a key role in regulating its expression . Co-stimulatory signaling also contributes to this regulation, as anti-CD3-induced IL-17 production is enhanced by the addition of anti-CD28; however, the pathways responsible for these effects remain poorly understood . A number of other cytokines and transcription factors are involved in promoting the differentiation of naïve CD4 T cells into Th17 cells, including IL-6. Research has shown that IL-6/ mice have reduced but not absent numbers of Th17 cells . Furthermore, it was recently discovered that IL-21 is selectively produced by Th17 cells, in contrast with Th1 and Th2 cells, which only express very low levels. IL-21 promotes the production of IL-17 and inhibits IFNg production [31,32], whereas IL-23 is important for the survival and expansion of Th17 cells [33,34]. IL-23 also plays a signiﬁcant role in the initial differentiation of Th17 cells. IL-6, IL-21 and IL-23 can all activate Janus family kinases and preferentially activate STAT3, a crucial element of Th17 differentiation . STAT3 seems to directly regulate the production of IL-17, evidenced by the fact that RORgt expression is impaired in T cells lacking STAT3 and that retroviral overexpression of constitutively active STAT3 results in increased IL-17 production . STAT3 has also been shown to directly bind to the IL-17A/F promoter locus using chromatin immunoprecipitation assays . Moreover, STAT3 directly binds
and regulates the IL-21 locus, and also regulates the expression of RORgt and IL-23R . The lineage-speciﬁc transcription factor RORg belongs to the steroid nuclear receptor superfamily and is most closely related to the retinoic acid receptor (RAR) subfamily of transcription factors . The members of this subfamily bind retinoic acid (RA), the active metabolite of vitamin A. RORg has been found to be important in organogenesis and thymopoiesis [39e41]. RORgt is a thymus-speciﬁc splice variant of RORg that results from transcription initiation at a distinct promoter; as such, RORgt protein differs from RORg in its amino terminus. The mechanisms that regulate RORgt expression as well as its role in promoting IL-17 production are unclear, but we do know that STAT3 and RORgt act in parallel to induce the production of IL-17. A second member of the ROR family, RORa, is also associated with the Th17 development program, although it is not as critical as RORgt in promoting Th17 differentiation . The cytokine TGFb is important for Th17 cell differentiation and is also a critical regulator of Tregs . Stimulation of naïve T cells with TGFb and IL-6 induces RORgt expression, while combined stimulation with IL-2 and TGFb upregulates Foxp3 transcripts. TGFb suppresses Th1 and Th2 differentiation , thereby favoring the development of iTregs and Th17 cells. Furthermore, TGFb activates SMAD proteins like SMAD2, which positively regulates the generation of inﬂammatory Th17 cells . IL-1 is another inﬂammatory cytokine reported to positively regulate Th17 development. It synergizes with IL-6 and IL-23, leading to sustained RORgt induction [46e48]. Interferon regulatory factor (IRF) 4 has also been shown to play a role in Th17 development through its interaction with NFAT, which may contribute to the regulation of IL-17 production [48,49]. Results from various studies done on mice suggest that IRF 4 can cooperate with STAT3 as well, to induce RORgt expression. Moreover, Brüstle et al. found that IRF4-null mice exhibit impaired generation of Th17 cells in response to TGFb and IL-6 stimulation . 6. IL-17 cytokines and their epigenetic regulation 6.1. IL-17 cytokine family The Interleukin-17 family consists of six members; IL-17A, IL17B, IL-17C, IL-17D, IL-17E and IL-17F. All six share a similar protein structure, but differ in their tissue expression patterns. In mammals, the IL-17 receptor family is composed of ﬁve members: IL-RA, IL-RB, IL-RC, IL-RD and IL-RE, which are widely expressed in different body tissues . Binding of IL-17 family cytokines to speciﬁc IL-17 receptors is required to elicit biological activity . There is signiﬁcant overlap in receptor binding patterns between IL-17 family members, but binding afﬁnities differ between the various combinations . IL-17 cytokines function in immune responses either as homodimers or as heterodimers with other family members in humans and mice [54,55]. IL-17A and IL-17F share the highest degree of homology, with approximately 50% conserved amino acid sequence identity. They also map to the same chromosomal location, 6p12. Interleukins 17B through E are less identical (about 16e30% amino acid sequence similarity) and map to different chromosomal locations . IL-17 cytokines are important in host defense against extracellular bacterial and fungal infections. They also contribute to the pathogenesis of various autoimmune processes and play a key role in antitumor immunity [56,57]. The IL-17A homodimer, together with its receptor IL-17RA, has been the most widely studied and is known to be implicated in the generation of autoimmunity. IL-17A is primarily expressed by activated T cells and upregulated in inﬂammatory conditions such as asthma, rheumatoid arthritis,
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multiple sclerosis, psoriasis and inﬂammatory bowel disease. Its main function is to promote the expression of proinﬂammatory cytokines and chemokines, thus participating in host defense and inﬂammation. It also enhances the surface expression of ICAM1 (intercellular adhesion molecule 1) in ﬁbroblasts. The IL-17F homodimer is the second most studied member of the IL-17 family. It is expressed in activated monocytes and activated CD4þ T cells , where it is involved in neutrophil recruitment and immunity to extracellular pathogens. IL-17A and IL-17F can also combine to form the heterodimer IL-17AF, whose functions are similar to both IL-17A and IL-17F. All three of these dimers can mediate immune responses at mucosal surfaces and have been found at lesion sites in inﬂammatory bowel disease, asthma, rheumatoid arthritis, atopic dermatitis and other inﬂammatory conditions. 6.2. IL-17A and IL-17F epigenetic regulation The Il17a and Il17f genes are linked in a tail to tail conﬁguration on chromosome 6, and their expression appears to be linked. The promoter regions of these two genes are known to undergo histone H3 acetylation and K4 (Lysine 4) trimethylation in response to TGFb-1 and IL-6 signaling. This leads to increased DNA accessibility at the Il17a/f locus, which in turn promotes IL-17A/F production and a Th17 phenotype . IL-17A and IL-17F promoter regions have been found to be hypoacetylated at histone H3 in Th1 and Th2 cells, consistent with their lack of expression in these cells, thus indicating that epigenetic mechanisms are involved in silencing IL-17A/F expression in cell types other than the Th17 subset. There are eight conserved non-coding sequences in the combined Il17a/f locus, four of which are located within the intergenic region and most of which (7 of 8) have been demonstrated to undergo lineage-speciﬁc hyperacetylation of histone H3 during Th17 development. The above ﬁndings suggest that Th17 differentiation is associated with epigenetic changes at the Il17a/f locus that promote a chromatin structure that is associated with gene activation and is required for T cell development and function . Some studies have reported that IL-12 signaling leads to silencing of the Il17a/f gene locus in a STAT4-dependent process . STAT4 binds to the same intergenic conserved non-coding sequences as STAT3 and could therefore initiate epigenetic remodeling, either through direct antagonistic competition with STAT3  or indirectly by recruiting other factors that silence the Il17a/f locus. A number of other studies have explored the role of IL-2-STAT5 signaling in the epigenetic regulation of the Il17a/f locus . IL-2 stimulation leads to a speciﬁc decrease in the levels of histone H3 acetylation at the IL-17a promoter, with little effect on the IL-17f promoter. IL-2 stimulation has also been associated with decreased levels of trimethylated histone H3 K4 throughout the Il17a/f locus. While trimethylated histone H3 K4 promotes gene transcription, trimethylated histone H3K27 is associated with inhibition of gene transcription, and binding of STAT5 to the Il17a/f locus has been associated with an increase in trimethylated histone H3 K2 . It has been demonstrated that STAT5 is able to recruit and interact with the histone deacetylator adaptor protein NCoR2 (Nuclear receptor co-repressor 2) . NCoR2 facilitates the recruitment of histone deacetylase 3 (HDAC3) to DNA promoter regions, thereby assisting in the downregulation of target gene expression [63,64]. In response to IL-2 signaling, STAT5 displaces STAT3 from the STAT binding sites within the Il17a/f locus, resulting in a loss of permissive histone modiﬁcations and promoting the recruitment of the NCoR2 repressor. These ﬁndings demonstrate that the IL-2-STAT5 pathway leads to epigenetic changes that
silence the Il17a/f gene locus, while STAT3 binding promotes a transcriptionally permissive chromatin structure. In a study by Thomas Rauen et al., cAMP responsive element modulator (CREM)a was found to induce IL-17A expression and mediate epigenetic alterations at the IL-17A locus in T cells of SLE patients . CREMa is a transcription factor that binds to the cAMP responsive element (CRE) within the proximal human IL-17A promoter and increases its activity. CREMa binding is associated with signiﬁcant CpG-DNA hypomethylation of the IL-17A gene in SLE T cells. Its recruitment to the IL-17A promoter also promotes histone modiﬁcations such as increased acetylation of histone H3K18 and reduced H3K27 trimethylation . The result is an IL17A gene locus that is accessible to transcription enhancers such as IRF-4, STAT3 and RORgt. Studies have shown that the elevated levels of CREMa seen in T cells of SLE patients are due to increased CREM promoter activity and are correlated with SLE disease activity [66,67]. It is also worth noting that while CREMa binding promotes epigenetic changes that lead to the upregulation of IL-17A expression, it has the opposite effect at the IL-2 promoter where it recruits DNMT3a and HDAC1, thereby silencing the gene . 7. Childhood immune deﬁciency syndromes, autoimmunity and lymphoma Childhood immune deﬁciency syndromes, or more precisely primary immunodeﬁciency diseases (PIDs), are a group of diseases characterized by a congenital immune defect with an increased susceptibility to infections. PIDs result from an impaired function or absence of lymphocytes, phagocytes or a constituent of the complement system, leading to various symptoms depending on the affected component of the immune system. Recurrent infections are the most signiﬁcant clinical feature of PIDs . With the majority being monogenic disorders diagnosed in infancy, primary immunodeﬁciency diseases provide us a unique opportunity to understand the function and regulation of the immune system. The fact that a substantial proportion of patients with PIDs are predisposed to autoimmune diseases and/or lymphoma (Table 1) emphasizes the role of immune dysregulation in the pathogenesis of lymphoma in this population. Indeed, the suggestion has already been offered in understanding the alterations in both organ and organ non-speciﬁc autoimmune diseases [3,70e80]. 7.1. Autoimmunity and PIDs Even though primary immunodeﬁciency disorders are characterized by an under-responsive immune system, most of them have been found to be concurrent with autoimmune diseases which are a result of an over-responsive immune system. In fact, some PIDs are such as Autoimmune Polyendocrinopathy-CandidiasisEctodermal Dystrophy syndrome (APECED), Autoimmune lymphoproliferative syndrome (ALPS) and Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) are deﬁned by the occurrence of autoimmune manifestations . Although the underlying mechanisms by which PIDs are closely associated with autoimmunity are not clear, it is generally thought that a loss in tolerance and defects in suppressing autoreactive B and T cells due to deﬁciencies in Treg cells may contribute to this phenomenon. 7.2. Lymphoma and PIDs Despite improved treatment and survival, malignancy has become the second leading cause of death in PID patients . According to the Immunodeﬁciency Cancer Registry (ICR), almost 60% of malignancies seen in PID patients are lymphomas. They are
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Table 1 Incidence of autoimmunity and lymphoma in selected primary immunodeﬁciency diseases. PIDs
B cell (antibody) deﬁciencies XLA None HIGM Sclerosing cholangitis Autoimmune cytopenias Inﬂammatory bowel diseases Arthritis SIgAD Total Juvenile SLE Rheumatoid arthritis CVID Total Inﬂammatory bowel disease Autoimmune cytopenias Rheumatoid arthritis T cell deﬁciencies APECED Hypoparathyroidism Adrenocortical insufﬁciency Gonadal failure Type 1 diabetes mellitus Pernicious anemia ALPS Total AIHA ITP Autoimmune neutropenia IPEX Autoimmune enteropathy Type 1 diabetes mellitus Hypothyroidism AIHA Combined T and B cell deﬁciencies SCID Alopecia Autoimmune thrombocytopenia WAS
Defective phagocytes CGD
11.5%e20.6% 1%e5% 2%e4% 22%e50% 30% 11%e17%
NHL MALT lymphoma
4%e6.5% 3.5% 3%
   [89,90] 
85% 72% 60% 18% 13% 50%e70% 29e38% 23e34% 19e27% 100% 87% 70% 90%
Total AIHA Vasculitis
on occasion [96,97] [98,99]
Lupus (for X-linked recessive kindreds)
Lupus (for autosomal recessive kindreds)
 Lymphoma HL NHL
 Complement deﬁciencies C1q deﬁciency SLE C1r/s deﬁciency SLE C4 deﬁciency SLE C2 deﬁciency SLE or SLE-like disease
92% 60%e75% 60%e75% 50%
   
Rare Rare Rare Rare
PIDs: Primary Immunodeﬁciency Diseases, XLA: X-linked Agammaglobulinemia, SIgAD: Selective IgA Deﬁciency, HIGM: Hyper IgM syndrome, APECED: Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy syndrome, ALPS: Autoimmune lymphoproliferative syndrome, IPEX: immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, SCID: Severe Combined Immunodeﬁciency, WAS: Wiskott-Aldrich Syndrome, CVID: Common variable immunodeﬁciency, CGD: Chronic Granulomatous Disease, AIHA: autoimmune hemolytic anemia, ITP: idiopathic thrombocytopenic purpura, NHL: Non-Hodgkin’s lymphoma, HL: Hodgkin’s lymphoma, DLBL: Diffuse large B-cell lymphoma.
the most common type of PID-associated cancer and comprise of Non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma which account for 48.6% and 10% of all malignancies respectively . Furthermore, a recent study by the Australasian Society of Clinical Immunology and Allergy (ASCIA) PID Registry (1990e2008) reports that NHL represents 27.6% of all malignant neoplasms associated with PID. PID-related lymphoma tends to be more commonly observed in patients with ataxia-telangiectasia (AT), common variable immunodeﬁciency (CVID), Wiskott-Aldrich syndrome (WAS) and severe combined immunodeﬁciency (SCID) . The lymphomas commonly seen in PID patients are of B-cell origin, having a diffuse large cell histology and present in extranodal sites . Host defects in immune regulation, chronic oncogenic viral infections and genetic factors are believed to promote lymphoma development in PID patients [81,104,105]. Although viral infections such as EBV in WAS , human herpes virus type 8 in CVID  are responsible for lymphoma development in PIDs through
chronic antigen stimulation, there is a high number of PID patients who develop lymphoma with no obvious oncogenic viral infections but have autoimmune manifestations This partially explains the role of immune regulation in protection against lymphoma and autoimmune diseases in individuals with congenital immunodeﬁciency disorders. In the following section, we will describe several wellcharacterized PIDs which are linked with autoimmunity and lymphoma. We will also provide deeper insights into the nature of the underlying immunological dysregulation. 7.3. Some speciﬁc PIDs 7.3.1. Primarily T cell and combined T & B cell deﬁciencies 220.127.116.11. IPEX. IPEX is a rare but fatal monogenic primary immunodeﬁciency caused by mutations of Foxp3  which controls the development and function of Tregs [109e111]. Without normal Tregs, T cells are overactivated and patients with IPEX soon present
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with aggressive systemic autoimmune manifestations including severe neonatal enteropathy, eczematous dermatitis, endocrinopathy (type 1 diabetes mellitus or thyroid disease) and elevated IgE serum levels [95,112,113]. IPEX, usually resulting in death before the age of two , serves as a strong demonstration of the important role of Tregs in preventing autoimmunity. Furthermore, a recent study in IPEX-like syndrome  using TSDR methylation analysis showed a reduced amount of peripheral Tregs in IPEX-like patients. 18.104.22.168. ALPS. ALPS is caused by mutation of genes involved in cell apoptosis, including Fas, FasL, caspase 8 and caspase 10 . It is characterized by autoimmune diseases and lymphoproliferation, including lymphadenopathy as well as splenomegaly of childhood onset. Due to a defect in apoptosis pathways, patients with ALPS fail to induce programmed death of activated lymphocytes and thus result in a loss of peripheral tolerance [117,118]. Approximately 50%e70% of ALPS cases have autoimmune manifestations, with autoimmune cytopenias being the most common . Other autoimmune manifestations in ALPS include glomerulonephritis, optic neuritis, GuillainBarré syndrome, arthritis, cutaneous vasculitis , primary biliary cirrhosis, autoimmune hepatitis , blistering dermatosis  or acquired factor VIII deﬁciency . With germline mutations of Fas, both ALPS patients and their families have a remarkably increased risk of developing Hodgkin’s (51-fold increase) and non-Hodgkin’s (14-fold increase) lymphoma (NHL) [93,123]. On the contrary, somatic Fas mutations were identiﬁed in 11% of non-Hodgkin’s lymphoma cases . All these data suggest that Fas-mediated apoptosis play a crucial role in getting rid of excess proliferating lymphocytes which may promote autoimmunity and cancer. 22.214.171.124. APECED. APECED is an autosomal recessive syndrome with defects in the gene AIRE, which encodes a transcription regulator required to establish thymic self-tolerance [125,126]. The typical clinical manifestations of APECED consist of chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufﬁciency . AIRE controls the expression of a wide array of peripheral tissue antigens in thymus . It also promotes the negative selection of self-reactive T cells. Other organ-speciﬁc autoimmune manifestations include hypoadrenalism, ovarian or testicular failure, hypothyroidism, insulin-dependent diabetes mellitus, chronic hepatitis, alopecia, and vitiligo [129,130]. Mice deﬁcient in AIRE also show evidence of spontaneous organ-speciﬁc autoimmunity . 126.96.36.199. WAS. WAS is a rare X-linked recessive PID with dysfunction of WAS protein (WASP), which is found in all hematopoietic stem cell-derived lineages. WASP plays a role in transmitting cell surface signals to the actin cytoskeleton. Its deﬁciency may lead to reduced cell proliferation, motility, and adhesion . Classic clinical presentations of WAS include a bleeding tendency due to low platelets, eczema and recurrent infections. Approximately 70% of WAS patients have at least 1 autoimmune or inﬂammatory complication, with autoimmune hemolytic anemia being the most common. Other autoimmune conditions such as neutropenia (25%), arthritis (29%), skin vasculitis (22%), cerebral vasculitis (7%), inﬂammatory bowel disease (9%), and renal disease (3%) are also observed . Malignant lymphoma (mainly diffuse large B cell lymphomas presenting in extranodal sites or brain) was observed in 18% of WAS patients. There is a distinct predominance of NHL over Hodgkin’s disease with a ratio of 8:1 . Sullivan et al reported that WAS patients with autoimmune disorders were at an increased risk (75%) of developing malignancy . 7.3.2. Primary B cell deﬁciencies 188.8.131.52. CVID. CVID is a heterogeneous group of disorders characterized by hypogammaglobulinemia. Despite being the most
common type of PID, CVID is not well-deﬁned at the molecular level. Clinical manifestations of CVID are diverse. Apart from recurrent bacterial infections, there is a high occurrence of autoimmune diseases and lymphoma in CVID patients. About 20% of patients with CVID develop an autoimmune complication, most often autoimmune cytopenia . It has been reported that compared with normal individuals, patients suffering from CVID have on average a 10-fold risk of developing lymphoma . NonHodgkin’s lymphomas (mostly the B cell type) are found in 50% of CVID patients . In more recent studies, mucosa-associated lymphoid tissue (MALT) lymphomas, which are low-grade B cell lymphomas and newly assigned as a separate entity in lymphoid malignancies, have been found to occur with high a frequency in CVID patients . 7.4. Tregs in PID-associated autoimmunity and lymphoma Since its discovery, the Treg cell has attracted considerable interest from immunologists owing to its pivotal role in maintaining immune tolerance and suppressing overreactivity . A qualitative or quantitative defect in the Treg population contributes to a loss of peripheral tolerance and notably is the main cause of some PIDs including IPEX, APECED, and WAS. As stated above, Foxp3 mutations in IPEX directly lead to signiﬁcantly reduced or even absent numbers of Tregs and consequently development of multi-organ autoimmunity with abnormal autoreactive T cell populations [111,137e139]. In APECED, decreased expression and function of Tregs and alterations in the TCR repertoire have been reported . Studies in WAS patients show that there are no associated signiﬁcantly reduced levels of peripheral Tregs with WASP deﬁciency. However, the ability of those Tregs to suppress proliferation of autologous and allogeneic CD4þ effector T cells is clearly impaired [141e144]. In particular, an observation in a WAS patient with a reversed WASP mutation generated WASPþ Tregs that correlated with decreased autoimmune disease activity and an improved clinical condition , which provides another strong support for the causative role of defective Tregs in autoimmune features in WAS. Tregs also seem to contribute play a big role in some other PIDs such as Omenn syndrome, CD25 deﬁciency, and STAT5b deﬁciency [145,146]. These monogenic disorders have expanded our understanding of how the breakdown in tolerance can lead to autoimmunity [147,148]. Tregs in PID-associated lymphoma are not as thoroughly investigated as those in PID-associated autoimmune conditions, perhaps due in part to the scarcity of cases in the former. However, there are some associations between Tregs and lymphoma which turn out to be very complex. Four types of Tregs e suppressor Tregs, malignant Tregs, direct tumor-killing Tregs and incompetent Tregs e are categorized in terms of their various roles in lymphoma . Suppressor Tregs or malignant Tregs seem to suppress anti-tumor cytotoxicity and their increase in number indicates a poor prognosis. On the contrary, tumor-killing Tregs and incompetent Tregs enhance anti-tumor cytotoxicity or anti-autoimmune activities, thereby their presence in large numbers is related with a good prognosis . However, peripheral blood Tregs levels are have no effect on the status of NHL, which is the predominant type of PIDrelated lymphoma . In a B cell lymphoma model, Elpek et al. demonstrated that Tregs dominate multiple immune evasion mechanisms in early but not late phases of lymphoma development . Actually, lymphoma cells themselves can function as Tregs, downregulate host immunity and promote tumor survival . In addition, Tregs attenuate the anti-tumor immunity in EBVassociated malignancies . In general, Tregs serve as important modulators for the interaction between lymphomas and the host microenvironment. But given the variable role of Tregs in
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lymphoma, further research is needed in this aspect, and perhaps PID-related lymphoma is a good model to begin with. 7.5. Th17 in PID-associated autoimmunity and lymphoma Although there isn’t much data with regard to Th17 in PIDs, some informative ﬁndings have been presented by some recent studies. Mutation of STAT3, a key transcription factor which mediates Th17 differentiation, was identiﬁed recently as the molecular cause of autosomal dominant Hyper-IgE Syndrome (HIES) [154,155], which is one PID characterized by recurrent pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue . Patients suffering from HIES lack Th17 cells in their peripheral blood and have an impaired Th17 differentiation, which makes them uniquely susceptible to Candida infections . In accordance with this, patients with chronic mucocutaneous candidiasis (CMC) disease, characterized by recurrent or persistent infection with Candida albicans and Staphylococcus aureus, were reported to have an autosomal recessive deﬁciency in IL-17RA or an autosomal dominant deﬁciency of IL17F . All these data demonstrate a protective role of Th17 against certain fungal infections. Importantly, both lymphoma (especially NHL in about 6%)  and to a lesser extent autoimmunity are observed in HIES patients [160,161]. A possible etiologic relationship of STAT3 mutations with diffuse large B cell lymphoma in HIES was proposed , though more intensive studies are still needed. 8. Tregs and Th17 cells in the pathogenesis of autoimmune diseases and hematological malignancies Molecules such as IL-10, cytotoxic T-Lymphocyte antigen 4 (CTLA-4), indoleamine 2,3-dioxygenase (IDO) and granzyme/perforin are known to contribute to the suppressive activities of Tregs. Although Tregs are likely to use multiple mechanisms to suppress immune responses, CTLA-4 is believed to play a dominant role in this process. In vivo studies have shown that CTLA-4 is essential for the inhibitory action of Tregs on antigen presenting cells (APCs) . CTLA-4, a member of the immunoglobulin superfamily, is expressed on the surface of helper T cells and transmits an inhibitory signal to activated proinﬂammatory T cells. Intracellular CTLA4 is also found in Tregs and may be important for their function. Two major mechanisms by which CTLA-4 inhibits T cell responses have been proposed . The ﬁrst is by directly delivering an inhibitory signal through its cytoplasmic tail to inhibit downstream signaling from TCR and CD28 . The second is by indirectly competing with CD28 for binding to CD80/86 ligands on APCs . Mutations in the CTLA4 gene leading to reduced expression and abnormal function of the CTLA-4 protein have been found to contribute to the development of various autoimmune diseases, such as type 1 diabetes , multiple sclerosis , systemic lupus erythematosus , rheumatoid arthritis , and autoimmune thyroiditis . Tregs are downregulated while Th17 cells are upregulated in systemic lupus erythematosus (SLE) , in part through the actions of IL-6 and TNF-alpha. IL-6 increases the resistance of effector T cells to Treg-mediated suppression . It has also been found to interfere with Treg function and can convert Tregs into IL17 producing Th17 cells . These ﬁndings explain at least some of the increase in IL-17 levels observed in autoimmune diseases like SLE. TNFa can downregulate Foxp3 expression through TNF receptor 2 signaling, thereby diminishing the suppressive capacity of Tregs . These results are consistent with studies showing that TNFa inhibition can improve or cure certain autoimmune
diseases such as uveoretinitis  and inﬂammatory bowel disease . Th17 cells also play a big role in the pathogenesis of rheumatoid arthritis , where IL-17 directly promotes stromal cell inﬂammation by inducing the production of IL-6, IL-8 and TNF from synovial cells . Treg prevalence is increased in the peripheral blood and tumor microenvironment of patients with various hematological malignancies. Tumor inﬁltrating lymphocytes (TILs) are white blood cells that leave the bloodstream and migrate into a tumor. They may either protect or attack the tumor, depending on the predominant cell type . TILs have recently been found to consist largely of Tregs. Tregs are known to accumulate in tumors and in the peripheral blood of patients with Hodgkin’s lymphoma  and Non-Hodgkin’s lymphoma . Increased Treg frequency has generally been considered as a marker of poor prognosis in hematological malignancies, presumably due to Treg-mediated suppression of anti-tumor immunity, which has been shown to beneﬁt tumor development in B-cell non-Hodgkin’s lymphoma , Adult T-cell leukemia/lymphoma (ATLL) , Cutaneous T cell lymphoma  and multiple myeloma . The discovery of Th17 cells has complicated our understanding of the role played by Foxp3þ Tregs in cancer. Th17 cells accumulate in certain human tumors, much like Foxp3þ Tregs do; however, the relationship between the two cell types is not clear. Tumor inﬁltrating Th17 cells secrete IL-17, which may act with interferongamma to stimulate the production of chemokines that recruit effector T cells to the tumor microenvironment and hence promote anti-tumor immunity . Under normal circumstances, Th17 cells protect against extracellular pathogens, but in certain conditions they may enhance carcinogenesis by promoting oncogenic factors . For example, in a study by Prabhala et al, it was observed that IL-17 producing Th17 cells release cytokines that promote myeloma cell growth and suppress immune responses in patients with multiple myeloma . On the other hand, in primary intraocular B-cell lymphoma (PIOL) which is a subtype of non-Hodgkin’s lymphoma, Th17 cells have been found to inﬁltrate the tumor and release cytokines that counteract tumor progression. In PIOL, IL-17A production by Th17 cells was negatively correlated with tumor burden . Current data therefore suggests that Treg and Th17 cell counts can have variable prognostic values depending on the tumor type. The dual role of these two cell types in the pathogenesis of autoimmune diseases and cancer requires further in-depth investigation. Several lines of evidence clearly demonstrate that dysregulation of the Treg/Th17 balance is vital in the development of autoimmune diseases and hematological malignancies. A mutation or epigenetic change causing an increase in the expression of any of the main molecules involved in Th17 development will lead to an abnormal rise in the production and activity of these cells, which will favor an autoimmune state . If a similar process occurs in a molecule that regulates Treg development, it will likewise cause an abnormal rise in Treg production and activity, but lead instead to an increased state of immune suppression. Correlations between Treg number and/or activity and disease status have been observed in studies involving patients with autoimmune disorders as well as hematoproliferative disorders. Speciﬁcally, decreased Treg numbers and activity have been linked to many autoimmune diseases [190e192] whereas increased levels of Tregs have been observed in a variety of hematological malignancies [193e195]. For example, mutations or deletions in the Foxp3 gene locus have been shown to cause a severe autoimmune disease in mice and humans, due to failure to generate nTregs (CD25highCD4þFoxp3þ T cells) in the thymus . The presence of Tregs within tumor masses confers protection to tumors from proinﬂammatory cell attacks (Fig. 3),
O. Ngalamika et al. / Journal of Autoimmunity 39 (2012) 451e465
Fig. 3. Schematic representation of two possible scenarios of tumor growth based on Treg frequency. The high proportion of Tregs in growth A protects it from recognition and attack by the immune system, resulting in its persistence and possible malignant transformation. Growth B, having few or no Tregs, is recognized and contained by the immune system.
which likely plays a crucial role in tumor progression and poor prognosis. The opposite would be expected with Th17 cells, where genetic or epigenetic changes causing their upregulation leads to the development of autoimmune diseases, and changes causing
their downregulation are very likely to be associated with malignant neoplasms. The table below highlights some of the autoimmune and hematological conditions in which Tregs and Th17 cells affect disease pathogenesis (Table 2).
Table 2 Genes/epigenetic mechanisms associated with autoimmune diseases and hematological malignancies in Tregs, Th17 cells. Disease
Autoimmune diseases Type 1 diabetes Multiple sclerosis Systemic lupus erythematosus Rheumatoid arthritis Sjögren’s syndrome Behçet’s disease Inﬂammatory bowel disease Primary biliary cirrhosis Psoriasis Pemphigus vulgaris Bullous pemphigoid Vitiligo Alopecia areata Autoimmune hemolytic anemia Autoimmune hepatitis Autoimmune uveoretinitis Myasthenia gravis Guillain-Barré syndrome Grave’s disease Hashimoto’s thyroiditis Goodpasture’s syndrome Hematological malignancies Acute myelogenous leukemia Chronic myeloid leukemia Chronic lymphocytic leukemia Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Multiple myeloma
Y Y Y Y Y ND Y Y [/Y Y Y [/Y Y Y Y Y Y Y N/Y Y Y
CTLA-4, Foxp3 CD25 CTLA-4, CD25 Foxp3 hypermethylation, CTLA-4, TGFb CTLA-4, CD25 ND ND CTLA-4 Foxp3 CTLA-4, Foxp3, CD25 Foxp3 Foxp3 CTLA-4, CD25 Foxp3 Foxp3, CTLA-4, CD25 Foxp3, CD25 Foxp3, CTLA-4 ND Foxp3 ND CTLA-4, Foxp3 CTLA-4 Foxp3, CD25 Foxp3, CD25
[ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [
IL-23, IL-17 ND IL-17A histone acetylation IL-23 IL-17A IL-17 IL-17, RORC IL-17A/F, IL-23R IL-17, IL-23 IL-23, IL-23R, IL-17, IL-21, IL-2 IL-17, IL-23 IL-17 IL-17 IL-17RA ND IL-17 ND ND IL-17 IL-23, IL-23R IL-23R, IL-17 IL-17
[166,196e198] [167,199,200] [65,168,201e203] [169,177]  [205e209] [210e212] [4,213,214] [215e218]  [220,221] [222,223] [224,225]  [227e229]  [231,232] [233,234] [235e237] [238,239] [240,241]
[ [ [ [ [ [
Foxp3 Foxp3 Foxp3 Foxp3 Foxp3 Foxp3, CTLA-4
Y [ [ ND Y [
IL-17 IL-17 IL-17 ND IL-17A IL-17
  [244,245]   [184,247,248]
Y, down-regulated; [, up-regulated; N, normal; ND, not determined.
O. Ngalamika et al. / Journal of Autoimmunity 39 (2012) 451e465
9. Conclusion Proinﬂammatory Th17 cells and immunosuppressive Treg cells should be maintained at an equilibrium to prevent the development of autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis and ulcerative colitis; and of hematological conditions related to immunosuppression like lymphoma, leukemia and multiple myeloma. Th17 cells and the proinﬂammatory cytokines they produce are signiﬁcantly increased in autoimmune diseases [201,249,250], while Treg numbers and activity are reduced . The opposite occurs in conditions of immune tolerance and relative immunodeﬁciency such as hematological malignancies . Establishing and maintaining a balance between these two cell types is therefore essential for the successful management of autoimmune diseases and cancers, and for achieving successful organ transplantations. Ongoing studies are showing promise in the use of IL-17A inhibitors for the management of autoimmune diseases like rheumatoid arthritis and inﬂammatory bowel disease. The expression levels of cytokines required for Th17 or Treg differentiation are an important factor to consider when assessing the prevalence and activity of these cells in the body. Increased or decreased expression of these cytokines may result from genetic mutations, epigenetic activation or silencing of genes, or posttranslation factors. In several autoimmune diseases, genetic mutations are undetected , which has led to increased exploration into the role of epigenetics in autoimmune disease development. Though substantial research has conclusively demonstrated the importance of Foxp3 epigenetics in Treg development, very little is known concerning the epigenetic factors and processes that regulate Th17 plasticity. Epigenetic studies targeting essential cytokines and transcription factors involved in Th17 development might give us the answers we need to understand the cause of increased Th17 cell production in various autoimmune diseases. To obtain these answers, genes encoding transcription factors such as RORgt, STAT3 and NFAT, and cytokines such as IL-17a, IL-17f and IL-6 should undergo extensive epigenetic research. Results from these studies will potentially uncover novel strategies that target genes at the epigenetic level in the screening, diagnosis, prevention and treatment of various autoimmune diseases and hematological malignancies. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 30730083, No. 81101194 and No. 30901300) and the National Basic Research Program of China (973 Plan) (2009CB825605). References  Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009;462:315e22.  Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. Journal of Autoimmunity 2009;33:3e11.  Zhao M, Sun Y, Gao F, Wu X, Tang J, Yin H, et al. Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modiﬁcations in lupus CD4þ T cells. Journal of Autoimmunity 2010;35: 58e69.  Rong G, Zhou Y, Xiong Y, Zhou L, Geng H, Jiang T, et al. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine proﬁle and peripheral cell population. Clinical and Experimental Immunology 2009;156:217e25.  Fischer A. Human immunodeﬁciency: connecting STAT3, Th17 and human mucosal immunity. Immunology and Cell Biology 2008;86:549e51.  Stepkowski SM, Chen W, Ross JA, Nagy ZS, Kirken RA. STAT3: an important regulator of multiple cytokine functions. Transplantation 2008;85:1372e7.
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