TY - JOUR
AU - Jamshidi, Ahmad Reza
AB - Abstract Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease, characterized by typically an axial arthritis. AS is the prototype of a group of disorders called spondyloarthropathies, which is believed to have common clinical manifestations and genetic predisposition. To date, the exact etiology of AS remains unclear. Over the past few years, however, the role of genetic susceptibility and epigenetic modifications caused through environmental factors have been extensively surveyed with respect to the pathogenesis of AS, resulted in important advances. This review article focuses on the recent advances in the field of AS research, including HLA and non-HLA susceptibility genes identified in genome-wide association studies (GWAS), and aberrant epigenetic modifications of gene loci associated with AS. HLA genes most significantly linked with AS susceptibility include HLA-B27 and its subtypes. Numerous non-HLA genes such as those in ubiquitination, aminopeptidases and MHC class I presentation molecules like ERAP-1 were also reported. Moreover, epigenetic modifications occurred in AS has been summarized. Taken together, the findings presented in this review attempt to explain the circumstance by which both genetic variations and epigenetic modifications are involved in triggering and development of AS. Nonetheless, several unanswered dark sides continue to clog our exhaustive understanding of AS. Future researches in the field of epigenetics should be carried out to extend our vision of AS etiopathogenesis. Ankylosing spondylitis, Gene variation, Epigenetic modifications, Genetic predisposition Introduction Ankylosing spondylitis (AS) is an autoimmune spondyloarthropathy with a chronic disabling course, characterized by inflammatory circumstances that follows with bone resorption and bone formation [1]. Despite an unknown etiopathology, susceptibility to disease and severity of manifestations are remarkably believed to be heritable. It is nowadays a matter of consensus that the major gene association with AS is Human Leukocyte Antigen (HLA)-B27 with approximately 95% of patients positive for the gene [2–5]. However, only about 5% of individuals harboring the HLA-B27 suffer from AS. This implies that genes other than HLA-B27 play role in disease susceptibility. According to studies around twin and familial form of AS, it has been suggested that HLA- B27 accounts for only less than 50% of the total risk for AS [2,4]. Nowadays, genetic-association studies have discovered new genes, however specific or non-specific, associated with AS [6,7]. Not to mention, the precise mechanism by which genetic factors are involved in AS susceptibility remains unclear. Epigenetics studies mechanisms that determine and perpetuate heritable genomic functions without alteration in DNA sequence. Accordingly, epigenome and/or epigenotype is regarded as a cell-specific and stable pattern of gene expression induced by such epigenetic mechanisms. In the functional viewpoint, epigenetic mechanisms are vital for cell-type development and differentiation through expression or repression of specific genes. However, environmental factors play a paramount role in triggering of disease conditions by impressing the epigenetic modifications [8]. Furthermore, numerous recent studies clearly show that there is epigenetic control of major immune cell functions, including antigen–receptor rearrangement and allelic exclusion, hematopoietic lineage diverge, and immune responses to pathogens [9,10]. To our best knowledge, this review for the first time tends to go through the recent studies regarding to genetic and epigenetic mechanisms involved in the triggering, initiation, development, and pathogenesis of AS. Genetics of ankylosing spondylitis AS and major histocompatibility complex genes AS has long been observed to be occurred prevalently in families. The risk of AS in the first-degree relatives of AS patients is almost more than 52 times compared to that of unrelated individuals [11]. Not until after a study in 1970 reported an association of the HLA-B27 allele with AS, could we relate the disease to shared genetic or environmental factors [12,13]. Nowadays HLA-B27 association with AS is regarded as a strongest genetic association with human disease; nonetheless the precise molecular mechanism by which this association contributes to AS development remains obscure. It has been almost documented that HLA-B27 is strongly associated with AS in approximately all the populations investigated worldwide. AS has been shown to be associated with the following subtypes: B*2702 [5,14,15], *2703 [16], *2704 [5,17], *2705 [5,14,15], *2706 [18], *2707 [5,19], *2708 [19], *2710 [20], *2714 [21], *2715 [21], *2719 [22]. The association of non-HLA-B27 MHC alleles has been believed to be involved in AS [23]. HLA-B60 has been reported to increase the risk of AS for the first time by Robinson et al. [24] and further studied confirmed the association in European [25] and east Asian [26] populations. The International Genetics of Ankylosing Spondylitis Consortium has attempted to provide new insights towards MHC gene association with AS, surveying 10,619 AS patients and 15,145 healthy controls. A remarkable observation reported from this study was the identification of rs116488202 SNP, which was significantly specific for HLA-B27 (>98.5%) [12,13,27]. It seems that this result can be contributing for genetic screening of AS in previously explained cases which is at high risk or in the general population either. Also these studies have revealed significant association of HLA-A*0201 with AS with odds ratios of 1.21 and 1.36 in HLA-B27 positive and negative subjects, respectively [28]. Of other SNPs within MHC region, rs13202464 represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese population [29]. Moreover, an association of HLA-B39 with HLA-B27-negative AS patients has been observed [30]. Adrian Cortes et al., in a marked study, genotyped 7264 MHC SNPs in 22,647 AS patients and controls of European descent to provide better comprehension of the genetic basis of the MHC susceptibility loci. They observed that in addition to the effects due to HLA-B*27 alleles, several other HLA-B alleles also affect proneness to AS. After controlling for the associated haplotypes in HLA-B, independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci were observed [31] (Table 1). Table 1. Loci significantly associated with AS. Gene rs number Locus Sequence change Presumptive Function Ref HLA Genes HLA-A*0201 rs2975033 6p21.3 Upstream gene variant Peptide presentation to T cells [23] HLA-B rs116488202 6p21.3 Downstream gene variant Peptide presentation to T cells; misfolding of peptide results in endoplasmic reticulum stress; homodimer formation cause NK cell activation [12,13,27] HLADRB1*0103 rs17885388 6p21.3 Glu98Glu/synonymous Peptide presentation to T cells [23] HLA-DPB1 rs1126513 6p21.3 Gly40Val/missense Peptide presentation to T cells [23] Non-HLA Genes MHC class I Presentation Pathway UBE2E3 rs12615545 2q31 Intron Variant Ubiquination [23] ERAP1 rs10050860 5q15 p.Asp575Asn/missense Peptide trimming in endoplasmic reticulum [50] rs1065407 3′ UTR variant [6] rs30187 p.Lys528Arg/missense rs17482078 p.Arg725Gln/missense [50] ERAP2 rs2910686 5q15 Intron Variant Peptide trimming in endoplasmic reticulum [23] rs2248374 Intron Variant [64] rs2549782 p.Lys392Asp/missense [28,65] NPEPPS rs9901869 17q21 Intron Variant Peptide trimming in endoplasmic reticulum [23] UBE2L3 rs2283790 22q11 Intron Variant Ubiquination [23] IL-23 pathway IL-23R rs11209026 1p31 p.Arg381Gln/missense Cell activation an differentiation [6] rs12141575 Downstream gene variant IL12B rs6871626 5q33 Intron Variant Activation and differentiation of IL-23R expressing cells [70] rs6556416 Intron Variant TYK2 rs35164067 19p13 Intron Variant Involved in signalling through cytokine receptors, like IL-23R [23] rs6511701 p.Ala207Ala/synonymous IL-1 cluster genes IL6R rs4129267 1q21 Intron Variant TH17 differentiation [92] IL1R2-R1 rs4851529 2q11 Downstream gene variant IL-1 response [23] rs2192752 Intron Variant Lymphocyte development and activation RUNX3 rs6600247 1p36 Regulatory region variant Reduction of CD8 T-cell counts [50] EOMES rs13093489 3p24 Regulatory region variant Lymphocyte differentiation [23] IL7R rs11742270 5p13 Downstream gene variant Lymphocyte differentiation [23] BACH2 rs17765610 6q15 Intron Variant B cell differentiation [23] CARD9 rs1128905 9q34 Downstream gene variant Activation of TH17 following β-glucan exposure [50] ZMIZ1 rs1250550 10q22 Intron Variant T cell differentiation [23] IL27 rs75301646 16p11 Intron Variant Maintaining a differentiation balance of TH17/TH1 ratio [23] rs35448675 p.Arg46His/missense TBX21 rs11657479 17q21 3′ UTR variant Differentiation of innate lymphoid cells (ILCs) [50] ICOSLG rs7282490 21q22 Regulatory region variant T cell differentiation [23] G-protein coupled receptors GPR25-KIF21B rs41299637 1q32 Intron Variant Not identified [70] GPR35 rs4676410 2q37 Intron Variant Receptor for 2-Acyl-1 lysophosphatidic acid (2-acyl-LPA) [23] GPR37 rs2402752 7q31 Intron Variant Not idetified [23] GPR65 rs11624293 14q31 Intron Variant Receptor for glycosphingolipids [23] Intergenic regions – rs2836883 21q22 – – [92] – rs6759298 2p15 – – Gene rs number Locus Sequence change Presumptive Function Ref HLA Genes HLA-A*0201 rs2975033 6p21.3 Upstream gene variant Peptide presentation to T cells [23] HLA-B rs116488202 6p21.3 Downstream gene variant Peptide presentation to T cells; misfolding of peptide results in endoplasmic reticulum stress; homodimer formation cause NK cell activation [12,13,27] HLADRB1*0103 rs17885388 6p21.3 Glu98Glu/synonymous Peptide presentation to T cells [23] HLA-DPB1 rs1126513 6p21.3 Gly40Val/missense Peptide presentation to T cells [23] Non-HLA Genes MHC class I Presentation Pathway UBE2E3 rs12615545 2q31 Intron Variant Ubiquination [23] ERAP1 rs10050860 5q15 p.Asp575Asn/missense Peptide trimming in endoplasmic reticulum [50] rs1065407 3′ UTR variant [6] rs30187 p.Lys528Arg/missense rs17482078 p.Arg725Gln/missense [50] ERAP2 rs2910686 5q15 Intron Variant Peptide trimming in endoplasmic reticulum [23] rs2248374 Intron Variant [64] rs2549782 p.Lys392Asp/missense [28,65] NPEPPS rs9901869 17q21 Intron Variant Peptide trimming in endoplasmic reticulum [23] UBE2L3 rs2283790 22q11 Intron Variant Ubiquination [23] IL-23 pathway IL-23R rs11209026 1p31 p.Arg381Gln/missense Cell activation an differentiation [6] rs12141575 Downstream gene variant IL12B rs6871626 5q33 Intron Variant Activation and differentiation of IL-23R expressing cells [70] rs6556416 Intron Variant TYK2 rs35164067 19p13 Intron Variant Involved in signalling through cytokine receptors, like IL-23R [23] rs6511701 p.Ala207Ala/synonymous IL-1 cluster genes IL6R rs4129267 1q21 Intron Variant TH17 differentiation [92] IL1R2-R1 rs4851529 2q11 Downstream gene variant IL-1 response [23] rs2192752 Intron Variant Lymphocyte development and activation RUNX3 rs6600247 1p36 Regulatory region variant Reduction of CD8 T-cell counts [50] EOMES rs13093489 3p24 Regulatory region variant Lymphocyte differentiation [23] IL7R rs11742270 5p13 Downstream gene variant Lymphocyte differentiation [23] BACH2 rs17765610 6q15 Intron Variant B cell differentiation [23] CARD9 rs1128905 9q34 Downstream gene variant Activation of TH17 following β-glucan exposure [50] ZMIZ1 rs1250550 10q22 Intron Variant T cell differentiation [23] IL27 rs75301646 16p11 Intron Variant Maintaining a differentiation balance of TH17/TH1 ratio [23] rs35448675 p.Arg46His/missense TBX21 rs11657479 17q21 3′ UTR variant Differentiation of innate lymphoid cells (ILCs) [50] ICOSLG rs7282490 21q22 Regulatory region variant T cell differentiation [23] G-protein coupled receptors GPR25-KIF21B rs41299637 1q32 Intron Variant Not identified [70] GPR35 rs4676410 2q37 Intron Variant Receptor for 2-Acyl-1 lysophosphatidic acid (2-acyl-LPA) [23] GPR37 rs2402752 7q31 Intron Variant Not idetified [23] GPR65 rs11624293 14q31 Intron Variant Receptor for glycosphingolipids [23] Intergenic regions – rs2836883 21q22 – – [92] – rs6759298 2p15 – – Open in new tab Table 1. Loci significantly associated with AS. Gene rs number Locus Sequence change Presumptive Function Ref HLA Genes HLA-A*0201 rs2975033 6p21.3 Upstream gene variant Peptide presentation to T cells [23] HLA-B rs116488202 6p21.3 Downstream gene variant Peptide presentation to T cells; misfolding of peptide results in endoplasmic reticulum stress; homodimer formation cause NK cell activation [12,13,27] HLADRB1*0103 rs17885388 6p21.3 Glu98Glu/synonymous Peptide presentation to T cells [23] HLA-DPB1 rs1126513 6p21.3 Gly40Val/missense Peptide presentation to T cells [23] Non-HLA Genes MHC class I Presentation Pathway UBE2E3 rs12615545 2q31 Intron Variant Ubiquination [23] ERAP1 rs10050860 5q15 p.Asp575Asn/missense Peptide trimming in endoplasmic reticulum [50] rs1065407 3′ UTR variant [6] rs30187 p.Lys528Arg/missense rs17482078 p.Arg725Gln/missense [50] ERAP2 rs2910686 5q15 Intron Variant Peptide trimming in endoplasmic reticulum [23] rs2248374 Intron Variant [64] rs2549782 p.Lys392Asp/missense [28,65] NPEPPS rs9901869 17q21 Intron Variant Peptide trimming in endoplasmic reticulum [23] UBE2L3 rs2283790 22q11 Intron Variant Ubiquination [23] IL-23 pathway IL-23R rs11209026 1p31 p.Arg381Gln/missense Cell activation an differentiation [6] rs12141575 Downstream gene variant IL12B rs6871626 5q33 Intron Variant Activation and differentiation of IL-23R expressing cells [70] rs6556416 Intron Variant TYK2 rs35164067 19p13 Intron Variant Involved in signalling through cytokine receptors, like IL-23R [23] rs6511701 p.Ala207Ala/synonymous IL-1 cluster genes IL6R rs4129267 1q21 Intron Variant TH17 differentiation [92] IL1R2-R1 rs4851529 2q11 Downstream gene variant IL-1 response [23] rs2192752 Intron Variant Lymphocyte development and activation RUNX3 rs6600247 1p36 Regulatory region variant Reduction of CD8 T-cell counts [50] EOMES rs13093489 3p24 Regulatory region variant Lymphocyte differentiation [23] IL7R rs11742270 5p13 Downstream gene variant Lymphocyte differentiation [23] BACH2 rs17765610 6q15 Intron Variant B cell differentiation [23] CARD9 rs1128905 9q34 Downstream gene variant Activation of TH17 following β-glucan exposure [50] ZMIZ1 rs1250550 10q22 Intron Variant T cell differentiation [23] IL27 rs75301646 16p11 Intron Variant Maintaining a differentiation balance of TH17/TH1 ratio [23] rs35448675 p.Arg46His/missense TBX21 rs11657479 17q21 3′ UTR variant Differentiation of innate lymphoid cells (ILCs) [50] ICOSLG rs7282490 21q22 Regulatory region variant T cell differentiation [23] G-protein coupled receptors GPR25-KIF21B rs41299637 1q32 Intron Variant Not identified [70] GPR35 rs4676410 2q37 Intron Variant Receptor for 2-Acyl-1 lysophosphatidic acid (2-acyl-LPA) [23] GPR37 rs2402752 7q31 Intron Variant Not idetified [23] GPR65 rs11624293 14q31 Intron Variant Receptor for glycosphingolipids [23] Intergenic regions – rs2836883 21q22 – – [92] – rs6759298 2p15 – – Gene rs number Locus Sequence change Presumptive Function Ref HLA Genes HLA-A*0201 rs2975033 6p21.3 Upstream gene variant Peptide presentation to T cells [23] HLA-B rs116488202 6p21.3 Downstream gene variant Peptide presentation to T cells; misfolding of peptide results in endoplasmic reticulum stress; homodimer formation cause NK cell activation [12,13,27] HLADRB1*0103 rs17885388 6p21.3 Glu98Glu/synonymous Peptide presentation to T cells [23] HLA-DPB1 rs1126513 6p21.3 Gly40Val/missense Peptide presentation to T cells [23] Non-HLA Genes MHC class I Presentation Pathway UBE2E3 rs12615545 2q31 Intron Variant Ubiquination [23] ERAP1 rs10050860 5q15 p.Asp575Asn/missense Peptide trimming in endoplasmic reticulum [50] rs1065407 3′ UTR variant [6] rs30187 p.Lys528Arg/missense rs17482078 p.Arg725Gln/missense [50] ERAP2 rs2910686 5q15 Intron Variant Peptide trimming in endoplasmic reticulum [23] rs2248374 Intron Variant [64] rs2549782 p.Lys392Asp/missense [28,65] NPEPPS rs9901869 17q21 Intron Variant Peptide trimming in endoplasmic reticulum [23] UBE2L3 rs2283790 22q11 Intron Variant Ubiquination [23] IL-23 pathway IL-23R rs11209026 1p31 p.Arg381Gln/missense Cell activation an differentiation [6] rs12141575 Downstream gene variant IL12B rs6871626 5q33 Intron Variant Activation and differentiation of IL-23R expressing cells [70] rs6556416 Intron Variant TYK2 rs35164067 19p13 Intron Variant Involved in signalling through cytokine receptors, like IL-23R [23] rs6511701 p.Ala207Ala/synonymous IL-1 cluster genes IL6R rs4129267 1q21 Intron Variant TH17 differentiation [92] IL1R2-R1 rs4851529 2q11 Downstream gene variant IL-1 response [23] rs2192752 Intron Variant Lymphocyte development and activation RUNX3 rs6600247 1p36 Regulatory region variant Reduction of CD8 T-cell counts [50] EOMES rs13093489 3p24 Regulatory region variant Lymphocyte differentiation [23] IL7R rs11742270 5p13 Downstream gene variant Lymphocyte differentiation [23] BACH2 rs17765610 6q15 Intron Variant B cell differentiation [23] CARD9 rs1128905 9q34 Downstream gene variant Activation of TH17 following β-glucan exposure [50] ZMIZ1 rs1250550 10q22 Intron Variant T cell differentiation [23] IL27 rs75301646 16p11 Intron Variant Maintaining a differentiation balance of TH17/TH1 ratio [23] rs35448675 p.Arg46His/missense TBX21 rs11657479 17q21 3′ UTR variant Differentiation of innate lymphoid cells (ILCs) [50] ICOSLG rs7282490 21q22 Regulatory region variant T cell differentiation [23] G-protein coupled receptors GPR25-KIF21B rs41299637 1q32 Intron Variant Not identified [70] GPR35 rs4676410 2q37 Intron Variant Receptor for 2-Acyl-1 lysophosphatidic acid (2-acyl-LPA) [23] GPR37 rs2402752 7q31 Intron Variant Not idetified [23] GPR65 rs11624293 14q31 Intron Variant Receptor for glycosphingolipids [23] Intergenic regions – rs2836883 21q22 – – [92] – rs6759298 2p15 – – Open in new tab AS and non-major histocompatibility complex genes Even though the association of HLA-B27 was almost accepted with AS, epidemiological studies had evidenced of plausible non-MHC genes association (Table 1). First degree relatives of AS subjects with HLA-B27 positive status are approximately 5.6–16 times more likely to develop disease in comparison to HLA-B27 positive individuals in the general population [32,33]. Furthermore, identical twins have been observed to be more likely concordant for AS (60–75%) than HLA-B27-positive dizygotic twins (24%) [2,34]. The genome-wide association studies have discovered non-MHC genes associated with AS, including genes involved in pathways in AS pathogenesis like the IL-23 pathway, aminopeptidases and peptide presentation (such as endoplasmic reticulum aminopeptidases 1 and 2), innate immune stimulation molecules. MHC class I presentation pathway Ubiquitination is a cytoplasmic process, in which ubiquitin groups are added onto proteins. Ubiquitination directs the proteins to a sub-cellular compartment, called proteasome, for degradation [35]. Afterwards, the produced peptides can be presented on MHC class I molecules on the cell surface to T cells. Accordingly, ubiquitination determines what antigens are loaded on MHC class I molecules to be presented to the immune system. UBE2E3 and UBE2L3 genes which encode UbcH9 and UbcH7, respectively, have been associated with AS [28]. Furthermore, gene variations in UBE2L3 have been shown to be associated with a number of other inflammatory diseases, suggesting this signaling pathway is a potential shared pathogenic pathway in various inflammatory disorders [36]. Four aminopeptidases which are encoded by genes in the two loci on the chromosomes 5p15 and 17q21 has been associated with AS [28]. The chromosome 5p15 locus consists of genes encoding the endoplasmic reticulum aminopeptidase (ERAP)-1 and ERAP2, and the chromosome 17q21 locus contains the aminopeptidase puromycin sensitive (NPEPPS) gene that encodes puromycin-sensitive aminopeptidases. A same haplotype of ERAP1 has been associated with the etiopathology of both AS and psoriasis [23,37]. Moreover, an ERAP2 haplotype associated with AS is also linked with both inflammatory bowel disease and psoriasis [38].On the other side, ERAP1 variants have been suggested that may be associated with type 1 diabetes and cervical cancer, despite definite associations have not been reported [39,40]. ERAP1 and 2 are found in the endoplasmic reticulum (ER) and play roles in the MHC class I peptide presentation pathway. Processed peptides by the proteasome are transported into the ER through a homodimer located on the ER membrane called Transporter associated with Antigen Processing (TAP). Afterwards, ERAP1 and ERAP2 trim peptides longer than 9 aminoacids to the length appropriate for loading onto MHC class I molecules like HLA-B27 [41,42]. The first aminopeptidase reported to be associated with AS was ERAP1 [6]. After that, the association has been widely investigated in numerous replicated studies with a result of similar allelic and haplotypic associations in both white European and east Asian populations, suggesting common variants involvement [29,43–48]. Furthermore, a study performed by our team had shown the relation of ERAP-1 single nucleotide polymorphisms with Iranian populations of AS [49]. According to the fine-mapping studies, the SNP rs30187 is directly associated with AS, and the SNP rs10050860 marks an AS-associated haplotype that also harbor rs17482078 [50]. The linkage disequilibrium between rs10050860 and rs17482078 is very strong, and it is not been clearwhether these two polymorphisms are the key AS-associated variants individually or both of them at the same time [50]. In vitro studies of ERAP1 peptidase activity and variants indicate that the two protective variants of rs30187 and rs17482078 are associated with a 40% reduction in peptidase activity, while the rs10050860 has no effect on enzyme activity [50]. This observation implies that the rs10050860 is not the real disease-associated variant, whereas the rs17482078 is. Using recombinant ERAP1 and comparing wild type protein with rs30187 and rs27044 variants, demonstrates that the functional properties of these variants are under impression of the substrate sequence and concentration [51]. On the other side, the ERAP1 rs30187 SNP association with AS is not restricted only to those harboring HLA-B27, but also found in HLA-B*4001 carriers independently of HLA-B27 genotype [31]. Through ERAP1 enzyme structure studies, it has been shown that AS related variants are commonly located in the C-terminal cavity, transition zone, and in the active site of enzyme [52,53]. ERAP1 usually prefers peptides charged positively in side chains and with a large hydrophobic C terminal residue as well efficiently processes peptides with a 9–16 residues long [41,51]. Nonetheless, studies attest that variants with functionally negative effect on trimming activity (rs30187 and rs17482078) influence the transition of the enzyme structure from the open status to the closed state [50,52]. It can be implied, therefore, that the other mapped variants are not the functionally important, however are in Linkage Disequilibrium with the other transition status variants. ERAP1 knockout mice have been observed to have about 20–80% reduced amount of cell surface class I MHC molecules as well a diminished stability of MHC-peptide complexes [54]. However, siRNA-treated HeLa cells present significantly increased MHC class I [42]. This may show that ERAP1 degrades some antigenic peptides, but prevents their presentation with MHC class I molecules. Accordingly, it can be implied that AS-associated variants in ERAP1 influence disease risk by modifying the amount and length of presented peptides as well the stability of the MHC-peptide complexes [55]. Genetic haplotypes of ERAP1 are also associated with AS, as well other rheumatic diseases. Disease-associated variants of ERAP1 in AS have been demonstrated to have interactions with disease-associated HLA class I alleles, influencing the disease risk. While disease-associated missense variants in ERAP1 can change ERAP1 enzymatic function, other disease-associated variants might influence expression of ERAP1. As a result, ERAP1 haplotypes (or allotypes) are of remarkable importance in evaluation of the gene regulation and function of the protein encoded by each allotype [56]. Six ERAP1 variants were evaluated in three case–control sets, including 992 AS patients collectively in Canada. In this investigation, three ERAP1 variants of rs26653 C/G, rs30187 A/G, and rs10050860 G/A, were observed to impress significantly AS risk. Moreover, several specific haplotypes affecting the AS risk were recognized through evaluating the contiguous 3-marker haplotypes of the six ERAP1 variants. Among the most strongly associated haplotypes with AS, was the susceptibility haplotype of rs30187-rs10050860-rs27044 (AGG), whereas the haplotype of rs26653-rs26618-rs30187 (CAG) protected against AS [47]. Examination of AS-associated loci to identify gene-gene interactions revealed an epistasis between HLA-B27 and ERAP1. Furthermore, AS patients homozygous for rs30187-rs10050860 (GA) showed 3–4 times decreased AS risk [50]. A study in case-control cohorts from France and Belgium found out rs30187-rs10050860-rs17482078 (GAA) as an AS-protective haplotype and rs30187-rs10050860-rs17482078 (AGG) as an AS-risk haplotype [57]. Bettencourt et al. investigated those variants, which have been identified through the Wellcome Trust Case Control Consortium (WTCCC) study, in two categories of 200 HLA-B27-positive AS patients and 200 HLA-B27-positive healthy subjects. Although the study re-demonstrated the associations of each of these five SNPs with AS, rs30187 showed the strongest association with AS susceptibility. Haplotype analysis of the surveyed SNPs eventuated in two haplotypes of rs2287987-rs30187-rs10050860-rs17482078 (GGAA) as an AS-protective haplotype and rs2287987-rs30187-rs10050860-rs17482078 (AAGG) as an AS-risk haplotype [58]. ERAP1 locus confers two independent effects of either protection or susceptibility towards AS risk. Allotypic investigations provide the understanding that the ultimate consequence of protection or susceptibility may be underpinned through the operation of allotypes instead of single genetic variants. ERAP2 association with AS was indicated once the association of ERAP1 with the disease was explained [6]. Harvey et al. observed an association of ERAP1 haplotype without association of all individual SNPs of this locus [45], and a haplotype comprised of both ERAP1 and ERAP2 SNPs to be associated with AS was demonstrated [59]. ERAP2 is also located in ER and an aminopeptidase that usually trims peptides before loading onto MHC class I molecules [60]. ERAP1 and ERAP2 form a heterodimer and cleave peptides collaboratively [61]. The crystal structure study of ERAP2 shows that the internal cavity of the enzyme has higher positively charged side chains compared with ERAP1, suggesting a different preferences of peptides for trimming [60]. Moreover, given the absence of additional pocket for C-terminal peptide recognition in ERAP2, the enzyme cannot trim peptides in a length dependent way as ERAP1 does [60]. ERAP2 has also been linked with inflammatory bowel disease, juvenile idiopathic arthritis, and psoriasis [38,62,63]. Two functionally important variants in ERAP2 have been reported to have association with AS [28]. The most important is the rs2248374 which modifies the strength of the exon 10 splice site, leading to a prolonged exon 10 transcript with two stop codons [64]. Once the short mRNA transcribed is degraded by nonsense-mediated decay and therefor is never translated to protein. This variant results in no ERAP2 protein and is associated with decreased surface expression of MHC class I molecules in cell lines [64]. This loss-of-enzyme causing variant has been observed to be protective SNP of AS [28]. Another variant (rs2549782) which is also associated with AS and is in strong LD with rs2248374 (D′ = 1.00, r2 = 0.90) has been observed to impress both the velocity of action and specificity of ERAP2 activity of trimming [28,65]. The aminopeptidase IRAP which is encoded by the leucyl/cystinyl aminopeptidases (LNPEP), which is located in the same locus encoding ERAP2, is involved in trimming of peptides during the process of cross-presentation. The identified functional variants in LNPEP gene associated with AS and the cross-presentation process relevant to AS is still unknown [28,66]. Puromycin-sensitive aminopeptidases (NPEPPS) is an enzyme, encoded by NPEPPS gene at the chromosome 17, functions in the cytoplasm and is the only cytosolic aminopeptidase known to cleave polyQ sequences [67]. Study in murine models of neurodegenerative diseases demonstrated that the overexpression of NPEPPS reduces protein accumulation and enhances macro-autophagy [68]. Evidence of autophagy has been observed in ileal biopsies from AS patients, and has been shown to be a stimulator of IL-23 expression in the gut [69]. However it is obscure whether NPEPPS play a role in AS through effects on autophagy or by alternate impression on intracellular peptide processing. IL-23 pathway Two subunits of the IL-23 cytokine are IL23p19 and IL-12p40, which the latter is encoded by the IL12B gene. It has been observed that the variants in the vicinity of IL12B have association with AS [50,70], in addition to two variants of rs6871626 and rs12141575 in IL12B itself [70] (Table 1). Moreover, protective variants has been found that reduce sensitivity to IL-23 stimulation, are associated with AS [6,71,72]. The association of IL23R variants was first explained in white Europeans [6], but the corresponding alleles were not polymorphic in Han Chinese population [44]. However, different IL23R variants through a sequencing study of Han Chinese were found to be associated with AS [73]. On the other hand, of several previously associated SNPs with AS in other populations, a discrepancy was seen in Iranian AS patients, and only rs1004819 was significantly frequent in patients [74]. The genes encoding the molecules in IL-23R signaling such as TYK2, JAK2, and STAT3 were reported to be associated with AS susceptibility [28,70]. With an odds ratio of 7.7 for the disease, a variant of TYK2 by affecting the TYK2 splicing is the strongest non-MHC gene associated with AS regarding odds ratio measurement [28]. These observations were the first evidence demonstrating the IL-23 pathway involved in AS and opened novel horizons towards trials of this pathway in treatment of AS. It has been demonstrated that the IL-23 pathway is a prominent pathway in the etiopathology of AS, and in mouse models overexpression of IL-23 alone is sufficient to elicit spondyloarthritis [75]. IL-23 has shown to be overexpressed in the bowel of AS patients [76] and upregulation of IL-23 with a mini-circle vector has been demonstrated to cause arthritis [75]. By endogenously overexpressing the IL-23 in mice using mini-circle vector, development of axial and peripheral spondyloarthritis and aortitis was observed. It was maybe due to presence of an IL-23R positive cells population resident in the enthesis, which is one of the key sites where manifestations of AS occur. These resident cells secreted critical cytokines including TNF-α, IL-17 and IL-22 in response to IL-23 stimulation. This may imply that IL-23 is the key cytokine, manipulating the disease symptoms and manifestations in AS [77]. Furthermore, in numerous mouse and rat models of spondyloarthritis, involvement of the IL-23 pathway has been shown [78–81]. Considering these findings, therefore, IL-23 upregulation appears to be causal factor for spondyloarthritis-like phenotype. Recent studies have suggested that IL-17-producing T cells are responsible for many of the inflammatory autoimmune and arthritis settings, and that IL-23 is a critical player in the TH17 cells expansion [82,83]. Inflammatory bowel disease (IBD) animal models have demonstrated a central role of IL-23 in chronic intestinal inflammation [84]. Studies have also established involvement of the IL-23 pathway in the etiopathogenesis of psoriasis [85] and multiple sclerosis [86] and systemic lupus erythematosus [87]. Moreover, polymorphisms in IL12B, namely rs3212227 and rs6887695 were associated with psoriasis and psoriatic arthritis (PsA) [88]. Investigations have associated polymorphisms in the gene encoding IL-23R with susceptibility to spondyloarthropathies (SpA) [89], other than AS. Therefore, IL-23 pathway share a paramount role in SpAs and other inflammatory disorders. IL-1 cluster genes The involvement of IL-1 genes in the pathogenesis of AS had been reported before genome-wide association studies (GWAS) could document any evidence [22,90,91]. However, GWA studies have now indicated the early observation that the IL1R1-IL1R2 locus is associated with AS [28,92]. Involvement of pattern recognition receptors (PRRs) on innate immune cells cause production of pro-IL-1β that is further cleaved to IL-1β through the inflammasome and is then released. Most of the IL-1β responses are mediated by IL1R1, while L1R2 acts as a decoy receptor for IL-1β by competitively binding to the IL-1β and diminishes IL-1β-IL1R1 signaling. A role for IL-1 in AS is supported by the observation that anakinra (recombinant version of the interleukin receptor antagonist 1 (IL1-RA)) alleviates the inflammatory manifestations of AS [93,94]. Gene SNPs of IL-1 family are related with susceptibility to AS [95]. On the contrary, a polymorphism in interleukin-1 receptor 2 (IL1R2), rs2310173, was not associated with risk of AS [96]. Other inflammatory cytokines were also associated with AS. Gene variants in the IL-6 receptor were shown to be related with CRP levels, asthma, and pulmonary function [50,97,98]. IL6R SNPs was then further observed to be associated with AS risk [28,92]. Moreover, a polymorphism within the tumor necrosis factor alpha (TNF-α) gene at -238 plays an important role in AS, in spite of any relation of this polymorphism with HLA-B27 subtypes [99]. Lymphocyte development and activation Several transcription factors involved in the development and activation of lymphocyte including RUNX3, EOMES, ZMIZ1, TBX21, IL7, and IL7R have been associated with AS pathogenesis [28,70,92] (Table 1). RUNX3 plays a role in T cell development in thymus [100] and its variants has been associated with AS. RUNX3 variants alongside with AS-associated variants in IL7R and ZMIZ1, have been observed to be associated with decreased CD8 T cell counts in healthy individuals [50]. RUNX3 knockout mice was observed to spontaneously develop inflammatory bowel disease, providing the important role of the gene in AS-organ specific immune function [101]. RUNX3 stimulates expression of eomesodermin, which is a transcription factor involved in CD8 differentiation and encoded by EOMES gene [102–104]. In case of eomesodermin deficiency, IL-17 expression by CD8 T cells is promoted [105]. IL7R α chain knockout mice lack γσ T cells and are deficient in αβ T cells and B cells, suggesting a role for IL7R involvement in T cell development [106]. Involvement of IL-7R by IL-7 induces RUNX3 expression in developing T-cells in thymus, leading to differentiation towards the CD8-lineage [107]. The transcriptional co-activator of the Protein Inhibitor of Activated STAT (PIAS)-like family, ZMIZ1, impresses signaling of cytokines mediated by STAT. Interaction of ZMIZ1 with activating mutations of NOTCH1 results in induction of T-cell acute lymphoblastic leukemia, implying a role in T-cell differentiation [108]. T-bet is an important transcription factor, encoded by TBX21, in regulation of development and function of T and NK cells. IL-23 regulates T-bet expression [109], which in turn regulates IL-22 secretion by innate lymphoid cells in the gut [110]. It appears that the differentiation of immune cells are paramount in AS pathogenesis, however it is yet ambiguous which of these cells are mainly under impression of the identified genetic variants. The presence of innate lymphoid cell populations, like T [111] and NKp46 IL-22 expressing cells [112] in AS patients demonstrates that these genes are major determinants of differentiation and activation of these cell types, implying that they are contributing factor in AS pathogenesis [111]. Antibodies to CD74 which targets the HLA class II invariant chain peptide has been reported, in early AS [113,114]. Moreover, association of CD74 variants with AS had previously been reported [6]. Considering these findings, a plausible role of CD74 can be implied in AS etiopathology. These data emphasize on B cell role in AS, which is supported by the recent study showing an association of the disease with the B-cell specific transcription factor BACH2. This gene transcribes the BACH2 protein which of great importance in somatic hypermutation and isotype switching during B cell development [115]. The exact mechanisms by which this association plays a role in AS development remain obscure. Programmed cell death-1 (PDCD1), codes an immunoreceptor belonging to the immunoglobulin super family, namely PD-1, which has a cytoplasmic domain containing two tyrosine residues located within immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM), providing a predominantly inhibitory function for PD-1 [116,117]. The PD-1 ligands, PDL1 and PDL2, are commonly expressed on a variety of immune cells such as activated but not resting T cells, B cells, monocytes, and dendritic cells following to pro-inflammatory agents stimulation [118]. The PDCD1 gene has been investigated in Korean AS patients, implying a genetic association between the PD1 polymorphisms and susceptibility to AS [119]. Furthermore, association of two SNPs of the PDCD1 gene, PD-1.3 (G, A) in nucleotide position +7146 of intron 4 and PD-1.9 (C, T) in nucleotide +7625 of exon 5, in Iranian AS population has been established [120]. These findings suggest a conclusion that PDCD1 gene could be considered as a potential candidate gene in AS. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is another inhibitory molecule, expressed by activated T cells and interacts with the B7 molecule on the surface of antigen presenting cells (APCs) to eventuate in reduction of T cell activation [121]. Polymorphism within CTLA4 gene, causing reduction of CTLA-4 expression and therefore autoimmune T cell clonal proliferation, may contribute to the pathogenesis of autoimmune diseases [122]. Polymorphisms of CTLA4 gene at positions +49 (in exon 1), −318, and −1,147 (in the promoter region) have been associated with Iranian AS patients [123]. It appears that gene variations in inhibitory molecules are involved in AS pathogenesis; however, precise underlying molecular mechanisms needs to be further surveyed. G-protein coupled receptors G-protein coupled receptors (GPRs) are known to mediate several cellular signaling [124]. Three GPRs including GPR35, GPR37 and GPR65 have now been observed to be associated with AS [28] (Table 1). GPR35 is primarily expressed in immune cells and gastrointestinal tissues, which are both important cells in AS development [125]. The indoleamine 2,3-dioxygenase (IDO) which is an important immune system mediator, signals by GPR35 recruiting [126]. IDO has role in tolerance in dendritic cells [127] and alterations in the enzyme activity; therefore, it can influence inflammatory disease circumstances. Over-expression of GPR37 results in misfolded protein, and then get accumulated to induce macro-autophagy [128]. This event together with the role of NPEPPS in clearing the accumulated proteins may imply importance of this pathway in AS and IBD [129]. GPR65, also known as T cells death-associated gene 8 (TDAG8), plays an important role in thymocyte apoptosis, suggesting the protein importance in T cell development processes in thymus, which in turn can influence inflammatory disease status [130]. Intergenic regions Two intergenic regions at chromosomes 21q22 (rs2836883) and 2p15 (rs6759298), which are not translated to proteins, have been associated with AS [92]. PSMG1 is the nearest gene, but 82 kb away of the intergenic region at chromosome 21q22, and a study shows that the expression level of this gene is not different in AS patients and controls. In addition, expression of the gene was not relevant to the AS-associated SNPs at this region. Moreover, gene variants of PSMG1 have not been observed to be included in the LD block of AS-associated SNPs at the intergenic region belonging to the chromosome 21q22 [92]. Novel non-coding RNA transcripts have been identified at both regions, suggesting a mechanism by which germline sequence variation influences on non-coding RNA sequence [92]. However, allele and genotypes of rs6759298 polymorphism located on 2p15 were observed to be associated with AS through pilot study in our lab. Moreover, GC and GG genotypes were related with enhanced disease susceptibility in HLA-B27 positive patients [131]. Recently, a concept of “MHCI–opathy” has been introduced, which is originated from the immunopathological links between Behçet disease (BD) and the associated human SpAs encompassing AS and reactive arthritis, PsA. BD, PsA and SpAs could be concertedly considered as “MHCIopathies” due to modified appearance and expression of all these diseases through interactions between tissuespecific factors and MHCI alleles [132]. The concept is based on three main evidence: genetic associations implicating to shared immunopathogenic mechanisms pertaining to MHCIassociated adaptive immunity in BD and SpA; tissuespecific factors (like injury, microorganism-derived damages and impaired barrier function) imply to a role of innate immunity in triggering and initiating the typical inflammatory outcomes in BD and SpA; and investigations suggesting an important role of unconventional lymphocytes, like innate lymphoid cells (ILCs) which are involved in “lymphoid stress surveillance” through the IL23–IL17 axis, at such tissue-specific sites [132,133]. BD as well several clinically distinct spondyloarthropathies including AS are associated with MHC-I alleles like HLA-B51, HLA-C*0602 and HLA-B27 and epistatic ERAP1 interactions, and appear to have a common immunopathogenetic basis [50]. These “MHC-I-opathies” show a differential immunopathology, which maybe reflecting antigenic differences within each target tissues: HLA-B51 is related to ocular and mucocutaneous disorders but not to gut involvement, and HLA-C*0602 is linked to type I psoriasis but not scalp or nail disorders [132]. GWA studies demonstrated that the MHCI associated conditions share an association with ERAP1 polymorphisms [56,134]. Moreover, the neighboring as well as functionally related ERAP2 genes have been documented to be associated with some MHCIopathies [135]. It has been implied that ERAP1 polymorphisms can alter ERAP1 protein function through modifying its peptide preference or catalytic activity, which in turn affects the composition and binding affinity of the HLAinteracting peptidome [136–138]. On the other hand, SNPs in the common p40 subunit of IL12 and IL23, as well as SNPs associated to the IL23R pathway, have been related to the entire spectrum of MHCIopathyrelated SpAs, including psoriasis, PsA, IBD, isolated anterior uveitis, AS and BD [139–141]. Furthermore, MHCIopathies encompassing disorders might share somewhat common genetic background. Those ERAP1 genotypes which have been associated with an increased risk of AS probably have protective effects in HLA-B51 positive BD patients [142]. Evidence around the nuances of the role of the ERAP1 pathway in the MHCIopathies has been initiated to pile up, nonetheless comprehensive elucidation is forthcoming [56,134]. Epigenetics and ankylosing spondylitis According to numerous investigations trying to disclose the etiopathology of AID, it has been suggested that environmental factors play a paramount role in triggering of the AIDs including AS above and beyond genetics [143] (Figure 1). Moreover, epigenetic has been established to be involved in etiopathogenesis of AID [144]. Through animal studies, it has been documented that environmental factors (e.g. physical, chemical and biological agents) can either induce AID or exacerbate the disease circumstance [145]. Needless to say, it is difficult to identify and describe a certain agent for one certain disease, regarding the distinct agent can trigger multiple diseases, and also various factors can manifest the identical clinical features. As a result, it appears to be beneficial to devise a new criteria for environmentally related AID [146]. It is believed nowadays that environmental factors can break tolerance through post-translational modifications as well as molecular mimicry to induce self-antigen modulation then trigger a range of immune responses [147,148]. Considering these surveys, epigenetics is of unique importance to explain the etiology of AS. Figure 1. Open in new tabDownload slide Possible link between genetics and epigenetics in AS. Environmental factors contribute to epigenetically change of AS-involved genes or other genes, including DNMT1, which keep the normal epigenetic status of candidate genes involved in AS. Figure 1. Open in new tabDownload slide Possible link between genetics and epigenetics in AS. Environmental factors contribute to epigenetically change of AS-involved genes or other genes, including DNMT1, which keep the normal epigenetic status of candidate genes involved in AS. Epigenetic mechanisms Epigenetics is typically known as stable but heritable alterations in gene expression without aberration in DNA sequence. The epigenetic phenomenon therefore is of paramount important for controlling the profile of gene expression during the cell cycle, development, and in response to environmental or biological changes. In other words, the concept of epigenetics explains how cells with a limited number of genes can differentiate into several different cell types and how a phenotype can be passed through daughter cells [149]. Epigenetic mechanisms regulating the gene expression include modification of the DNA strand through biochemical alterations mainly through methylation, posttranslational modification of histones proteins by acetylation, methylation and phosphorylation, and ultimately microRNAs. DNA methylation in the promoter region of genes hinders gene transcription, whereas histone acetylation appropriates gene expression condition by resulting in a heterochromatin structure, thereby promotes the availability of DNA regulatory regions to the transcriptional factors or to other DNA binding proteins [150]. DNA methylation In mammalian cells, DNA methylation is an epigenetic mechanism mediated by DNA methyltransferase (DNMT) enzymes, with S-adenosyl-methionine (SAM) as the methyl donor. The methyl group (CH3) is transferred onto the C5 position of cytosines to form the 5-methylcytosine (5mC). DNA methylation usually occurs at four general types according to the target sites: the methylation of CpG islands within promoter region of genes, the methylation of CpG island shores (located up to 2 Kb from CpG islands), the methylation of gene bodies throughout whole gene, and the methylation of repetitive sequences [151]. There are five members of DNMT enzymes, which commonly fall into two major classes: de novo DNMTs (DNMT3a, DNMT3b and DNMT3L) and maintenance DNMTs (DNMT1, DNMT2). The de novo DNMT enzymes are involved particularly in methylation during embryonic development, whereas the maintenance DNMTs methylate the cytosine in the hemimethylated DNA during DNA replication [152]. DNMTs have mutual activities and are involved in both the addition and removal of methyl groups to DNA. In the methylated state of DNA, transcription is repressed through decreased binding of transcription factors and increased binding of methyl-CpG-binding domain (MBD) proteins, and vice versa. DNA methylation affects the chromatin structure and lead to the formation of a co-repressor complex. On the contrary, the unmethylated DNA has a euchromatin structure and allows transcription factors to bind the proper regions [153]. Histone modifications Histones are conserved proteins within nucleosome structure which package and organize DNA. These proteins are categorized into two major groups of core (H2A, H2B, H3 and H4) and linker (H1 and H5) histones. Histone proteins can also undergo a series of posttranslational biochemical modifications such as acetylation, phosphorylation and methylation, deimination, b-N-acetylglucosamine, ubiquitylation, ADP ribosylation, and sumoylation [154]. Unlike acetylation, histone methylation does not alter the charge of histone proteins. Histone methylation mainly occurs at lysine and arginine residues of histones H3 and H4 which can be monomethylated, dimethylated (lysines and arginines) and trimethylated (lysines) [155]. Of these biochemical modifications, histone acetylation is particularly studied widely. Histone acetylation is catalyzed by two enzymes of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs transfer an acetyl group from acetyl CoA to the amino group of lysine side chains. This change neutralizes the positive charge of lysine and weakens the interaction between the histone and the DNA strand, therefore leading to a less integrated and disposable chromatin structure, which in turns increases gene expression. HDACs, on the other side, remove an acetyl group from the acetylated lysine tail of histones, adding a positive charge and leading to a concentrated chromatin configuration, which in turns decrease the gene expression [155,156]. MicroRNAs MicroRNAs (miRNAs) are endogenous non-coding RNAs with typically 18–23 nucleotides that serve as one of the post-translational regulators of gene expression. The pivotal role of miRNAs in cell proliferation, development and differentiation, apoptosis, cell metabolism processes and the pathogenesis of many human diseases has been documented. The function of miRNAs in gene expression alteration is mediated by two pathways. First, miRNAs induces degradation of target mRNA when the sequence of miRNA is matched completely with 3′UTR of target mRNA. On the other hand, preventing of translation occurs when miRNA strand is incompletely matched with 3′UTR of target mRNA. The second way in which miRNAs affect gene expression is by the means of modulating DNA methylation of promoter sites and also histone modifications [157,158]. Epigenetic modifications in ankylosing spondylitis To date, little has been investigated with regard to the DNA methylation modifications in AS. Lai et al. demonstrated that methylation of SOCS-1 could be detected in serum of HLA-B27-positive AS patients but not in B27-positive healthy controls. Methylation level of SOCS-1 was shown to correlate with the degree of inflammation as measured through sacroiliitis, acute phase reactant, erythrocyte sedimentation rate and C-reactive protein, as well as cytokine level of IL-6 and TNF-α [159]. Other two surveys have been carried out at our lab to evaluate DNA methylation alterations in AS patients. In the pilot study, it was observed that CpG sites at the promoter region of DNA methyltransferase 1 (DNMT1) were highly methylated in the PBMCs from AS patients compared with the healthy controls. Alternately, the mRNA expression level of this gene was downregulated in patients, which significantly correlated with higher methylation level in AS patients [160]. As such, expression and methylation level of BCL11B gene were investigated in PBMCs of AS patients and compared with that of healthy individuals. Pilot study revealed that mRNA expression level of BCL11B was downregulated as well in the promoter region was hypermethylated in PBMCs from AS patients compared with healthy subjects [161]. Further surveys would be advantageous to elucidate the exact mechanisms by which both DNMT1 and BCL11B hypermethylation are involved in the etiopathogenesis of AS. In addition, albeit a global DNA hypomethylation and higher expressions of DNMT1 in rheumatoid arthritis (RA) patients [162], to our best knowledge, DNMT1 promoter hypermethylation is specific for AS patients thus far. The interaction between miRNA-130a and its target, mRNA of tumor necrosis factor (TNF)-α, and Histone deacetylase (HDAC) 3 in peripheral blood mononuclear cells (PBMCs) from AS patients have been investigated. Reduced miRNA-130a and increased HDAC3 levels were observed. Knockdown or inhibition of HDAC3 culminated in overexpression of miRNA-130a. The interaction, also, led to HDAC3 recruitment to the promoter region of the gene encoding miRNA-130a. Furthermore, overexpression of miR-130a caused a downregulation of TNF-α mRNA in PBMCs, while miR-130a inhibition led to an overexpression. Additionally, knockdown or inhibition of HDAC3 was revealed to be associated with both upregulation of miR-130a and downregulation of TNF-α. The findings of this survey concluded that HDAC3 through constituting a negative feedback loop with miR-130a as well promotion of TNF-α expression played a role in the molecular etiopathology of AS [163]. Overally, miRNAs have been focused more than others in AS. Three miRNAs with upregulated expression: miR-16, miR-221 and let-7i have been shown in T cells from AS patients. The authors observed that let-7i and miR-221 correlated positively with Bath Ankylosing Spondylitis Radiographic Index (BASRI) for lumbar spine. The study implies that the increased expression of let-7i in AS T cells contributes to the immunopathogenesis of AS via enhancing the Th1 (IFN-γ) inflammatory response [164]. Negative regulation of Dickkopf homolog 1 (Dkk-1) in Wnt signaling might be contributing factor in new bone formation in AS [165]. It was found that miR-29, which directly targets the Dkk-1 mRNA, had upregulated expression in the PBMCs of AS patients in comparison to RA patients and healthy individuals. The study showed no correlation between miR-29a expression in the PBMCs of AS patients and level of ESR and CRP, as well litis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index (BASFI) score of patients. [166]. The binding of miR-21 to programmed cell death 4 (PDCD4) could inhibit the expression of PDCD4 and further induce the activation of osteoclasts [167]. Huang et al. observed a significantly higher levels of miR-21, PDCD4 mRNA, and collagen cross-linked C-telopeptide (CTX) in AS patients. MiR-21 expression was seen to be negatively correlated with PDCD4 mRNA expression in patients with AS who were taking neither NSAID nor DMARD. Furthermore, significantly positive correlations between miR-21 expression with PDCD4 mRNA expression and CTX level were observed in patients with AS who were taking sulfasalazine. Positive correlations of miR-21 and CTX level were also observed in AS patients with disease duration less than 7 years and active disease. It appears that the expression of miR-21 might have a role in the development of AS [168]. MicroRNAs target a vast gamut of mRNAs, which participate in various physiological processes of cells, including cell growth, cell division, differentiation, development, metabolism and apoptosis. As a result, miRNAs seem to be involved and regulate a vast range of cell physiology; hence any aberration in their expression profile can eventuate in detrimental manifests on the normal functioning of the cell. Despite our knowledge of the roles of miRNAs in various immunological disorders has recently been increased, their role in the regulation of physiological function of immune system and in prevention of immune disorders have been implicated. In RA patients, for example, two miRNAs of miR-155 and miR-146 particularly, are markedly upregulated in the synovial fibroblasts and synovial tissues of these patients [169]. Furthermore, relative to healthy controls, in SLE patients miRNA expression pattern examination reveals up-modulation of seven miRNAs (miR-409-3p, miR-141, miR-383, miR-196a, miR-17-5p, miR-112 and miR-184) and down-modulation of nine miRNAs (miR-189, miR-61, miR-142-3p, miR-342, miR-299-3p, miR-198, miR-78, miR-21 and miR-298) [170]. Although specific miRNA expression profile has not been established in AS patients, miR-29a could be regarded as an advantageous diagnostic marker for monitoring the new bone formation in AS and might be a therapeutic approach in the future [166]. However, miR-29a is also not specific for AS and involved in other disorders [171]. Concluding remarks Although a large number of AS susceptibility loci has been discovered over the course of past years, genetic risk of AS cannot be predicted precisely and accurately [172] (Figure 1). Nevertheless, with thank to GWAS, novel pathogenic pathways have been identified. Genetics, on the other hand, do not seem to explain all of the alterations in gene function that underpin AS initiation and development. Correct gene function explanation is contingent upon epigenetic governing, which differs between cell and tissue types as well various environments and life styles. Moreover, twin studies demonstrate a significant discordance rates of AS prevalence between monozygotic twins, implying a remarkable role for environmental factors in AS risk [2,4]. To date, less information has been revealed with regard to the involvement of epigenetic modification in AS. Although the application of epigenetics to answer the uncertainties in AS etiopathology is in its infancy, the data considering this field of research have been started to accumulate. It will be of significant importance for the forthcoming epigenetic surveys in AS to concentrate on the pertinent cell types as well the possibly underlying biological pathways. Conflict of interest This survey was supported by grants from Research Deputy of Tehran University of Medical Sciences (Grant no. 93-01-41-24538). References Schett G Bone formation versus bone resorption in ankylosing spondylitis. In: Molecular Mechanisms of Spondyloarthropathies . Vol. 649 of the series Advances in Experimental Medicine and Biology. Springer ; 2009 : 114 – 21 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Brown MA , Kennedy LG, Macgregor AJ, Darke C, Duncan E, Shatford JL, et al. . Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment . Arthritis Rheum . 1997 ; 40 ( 10 ): 1823 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Hamersma J , Cardon L, Bradbury L, Brophy S, Der Horst-, Bruinsma V, Calin A, et al. . Is disease severity in ankylosing spondylitis genetically determined ? Arthritis Rheum . 2001 ; 44 ( 6 ): 1396 – 400 . Google Scholar Crossref Search ADS PubMed WorldCat Brophy S , Hickey S, Menon A, Taylor G, Bradbury L, Hamersma J, et al. . Concordance of disease severity among family members with ankylosing spondylitis? J Rheumatol . 2004 ; 31 ( 9 ): 1775 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Fallahi S , Mahmoudi M, Nicknam MH, Gharibdoost F, Farhadi E, Saei A, et al. . Effect of HLA-B*27 and its subtypes on clinical manifestations and severity of ankylosing spondylitis in Iranian patients . Iran J Allergy Asthma Immunol . 2013 ; 12 ( 4 ): 321 – 30 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Burton PR , Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. . Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genetics . 2007 ; 39 ( 11 ): 1329 – 37 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Brionez TF , Reveille JD The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis. Curr Opin Rheumatol . 2008 ; 20 ( 4 ): 384 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat Greer JM , McCombe PA The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics . 2012 ; 6 : 307 Google Scholar PubMed OpenURL Placeholder Text WorldCat Fernández-Morera J , Calvanese V, Rodríguez-Rodero S, Menéndez-Torre E, Fraga M. Epigenetic regulation of the immune system in health and disease. Tissue Antigens . 2010 ; 76 ( 6 ): 431 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Sawalha AH Epigenetics and T-cell immunity. Autoimmunity . 2008 ; 41 ( 4 ): 245 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Brown M , Laval S, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis . Ann Rheum Dis . 2000 ; 59 ( 11 ): 883 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Brewerton D , Hart F, Nicholls A, Caffrey M, James D, Sturrock R. Ankylosing spondylitis and HL-A 27. Lancet . 1973 ; 1 ( 7809 ): 904 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Schlosstein L , Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis . N Engl J Med . 1973 ; 288 ( 14 ): 704 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat MacLean I , Iqball S, Woo P, Keat A, Hughes R, Kingsley JG, et al. . HLA-B27 subtypes in the spondarthropathies Clin Exp Immunol . 1993 ; 91 ( 2 ): 214 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat Nicknam MH , Mahmoudi M, Amirzargar AA, Hakemi MG, Khosravi F, Jamshidi AR, et al. . Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis. Iran J Allergy Asthma Immunol . 2008 ; 7 ( 1 ): 19 – 24 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Reveille J , Inman R, Khan M, Yu D, Jin L. Family studies in ankylosing spondylitis: microsatellite analysis of 55 concordant sib pairs. J Rheumatol . 2000 ; 27 ( Suppl 59 ): 5 . Google Scholar OpenURL Placeholder Text WorldCat Lopez-Larrea C , Sujirachato K, Mehra N, Chiewsilp P, Isarangkura D, Kanga U, et al. . HLA‐B27 subtypes in Asian patients with ankylosing spondylitis Evidence for new associations. Tissue Antigens . 1995 ; 45 ( 3 ): 169 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat Gonzalez-Roces S , Alvarez M, Gonzalez S, Dieye A, Makni H, Woodfield D, et al. . HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens . 1997 ; 49 ( 2 ): 116 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Armas JB , Gonzalez S, Martinez- Borra J, Laranjeira F, Ribeiro E, Correia J, et al. . Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles. Tissue Antigens . 1999 ; 53 ( 3 ): 237 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat García R , Rognan D, Lamas J, Marina A, Castro J. An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity. Tissue Antigens . 1998 ; 51 ( 1 ): 1 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat García-Fernández S , Gonzalez S, Mina Blanco A, Martinez-Borra J, Blanco-Gelaz M, López-Vazquez A, et al. . New insights regarding HLA‐B27 diversity in the Asian population. Tissue Antigens . 2001 ; 58 ( 4 ): 259 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Djouadi K , Nedelec B, Tamouza R, Genin E, Ramasawmy R, Charron D, et al. . Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies. Cytokine . 2001 ; 13 ( 2 ): 98 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat Cortes A , Brown MA Promise and pitfalls of the Immunochip. Arthritis Res Ther . 2011 ; 13 ( 1 ): 101 . Google Scholar Crossref Search ADS PubMed WorldCat Robinson WP , Van Der Linden SM, Khan MA, Rentsch HU, Cats A, Russell A, et al. . HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients . Arthritis Rheum . 1989 ; 32 ( 9 ): 1135 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Brown MA , Pile KD, Kennedy LG, Calin A, Darke C, Bell J, et al. . HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheumc Dis . 1996 ; 55 ( 4 ): 268 – 70 . Google Scholar Crossref Search ADS WorldCat Wei J , Tsai W, Lin H, Tsai C, Chou C. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology . 2004 ; 43 ( 7 ): 839 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat Caffrey MF , James D Human lymphocyte antigen association in ankylosing spondylitis. Nature . 1973 ; 242 : 121 . doi: 10.1038/242121a0 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC Consortium IGoAS . Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature Genetics . 2013 ; 45 ( 7 ): 730 – 8 . Crossref Search ADS PubMed WorldCat Lin Z , Bei J-X, Shen M, Li Q, Liao Z, Zhang Y, et al. . A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nature Genetics . 2012 ; 44 ( 1 ): 73 – 7 . Google Scholar Crossref Search ADS WorldCat Yamaguchi A , Tsuchiya N, Mitsui H, Shiota M, Ogawa A, Tokunaga K, et al. . Association of HLA-B39 with HLA-B27-negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in Japanese patients. Evidence for a role of the peptide-anchoring B pocket. Arthritis Rheum . 1995 ; 38 ( 11 ): 1672 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Cortes A , Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, et al. . Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nature Commun . 2015 ; 6 . doi: 10.1038/ncomms8146 . Google Scholar OpenURL Placeholder Text WorldCat Crossref Calin A , Marder A, Becks E, Burns T. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls . Arthritis Rheum . 1983 ; 26 ( 12 ): 1460 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat van der Linden S , Valkenburg H, Cats A The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Rheumatology . 1983 ; 22 ( suppl 2 ): 18 – 19 . Google Scholar Crossref Search ADS WorldCat Pedersen O , Svendsen AJ, Ejstrup L, Skytthe A, Harris J, Junker P. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand J Rheumatol . 2008 ; 37 ( 2 ): 120 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Pickart CM Mechanisms underlying ubiquitination. Annual Rev Biochem . 2001 ; 70 ( 1 ): 503 – 33 . Google Scholar Crossref Search ADS WorldCat Wang S , Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. . A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immunity . 2012 ; 13 ( 5 ): 380 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Genetic Analysis of Psoriasis Consortium and the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature Genetics . 2010 ; 42 ( 11 ): 985 – 90 . Crossref Search ADS PubMed WorldCat Chapman JA , Kirkness EF, Simakov O, Hampson SE, Mitros T, Weinmaier T, et al. . The dynamic genome of Hydra. Nature . 2010 ; 464 ( 7288 ): 592 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Dendrou CA , Fung E, Esposito L, Todd JA, Wicker LS, Plagnol V. Fluorescence intensity normalisation: correcting for time effects in large-scale flow cytometric analysis. Adv Bioinformatics . 2009 ; 2009 . doi: 10.1155/2009/476106 . Google Scholar OpenURL Placeholder Text WorldCat Crossref Mehta AM , Jordanova ES, van Wezel T, Uh HW, Corver WE, Kwappenberg K, et al. . Genetic variation of antigen processing machinery components and association with cervical carcinoma. Genes Chromosomes Cancer . 2007 ; 46 ( 6 ): 577 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Chang S-C , Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA . 2005 ; 102 ( 47 ): 17107 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat York IA , Chang S-C, Saric T, Keys JA, Favreau JM, Goldberg AL, et al. . The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nature Immunol . 2002 ; 3 ( 12 ): 1177 – 84 . Google Scholar Crossref Search ADS WorldCat Choi C-B , Kim T-H, Jun J-B, Lee H-S, Shim SC, Lee B, et al. . ARTS1 polymorphisms are associated with ankylosing pondylitis in Koreans. Ann Rheum Dis . 2010 ; 69 ( 3 ): 582 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Davidson SI , Wu X, Liu Y, Wei M, Danoy PA, Thomas G, et al. . Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population . Arthritis Rheum . 2009 ; 60 ( 11 ): 3263 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Harvey D , Pointon JJ, Karaderi T, Appleton LH, Farrar C, Wordsworth BP. A common functional variant of endoplasmic reticulum aminopeptidase 2 (ERAP2) that reduces major histocompatibility complex class I expression is not associated with ankylosing spondylitis. Rheumatology . 2011 ; 50 ( 9 ): 1720 – 1 . Google Scholar Crossref Search ADS PubMed WorldCat Li C , Lin Z, Xie Y, Guo Z, Huang J, Wei Q, et al. . ERAP1 is associated with ankylosing spondylitis in Han Chinese. J Rheumatol . 2011 ; 38 ( 2 ): 317 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Maksymowych W , Inman R, Gladman D, Reeve J, Pope A, Rahman P. Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis . Arthritis Rheum . 2009 ; 60 ( 5 ): 1317 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Pimentel-Santos F , Ligeiro D, Matos M, Mourao A, Sousa E, Pinto P, et al. . Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population. Clin Exp Rheumatol . 2009 ; 27 : 800 – 6 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Mahmoudi M , Jamshidi AR, Amirzargar AA, Farhadi E, Nourijelyani K, Fallahi S, et al. . Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iran J Allergy Asthma Immunol . 2012 ; 11 ( 4 ): 294 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Evans DM , Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, et al. . Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genetics . 2011 ; 43 ( 8 ): 761 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Evnouchidou I , Momburg F, Papakyriakou A, Chroni A, Leondiadis L, Chang S-C, et al. . The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1. PLoS One . 2008 ; 3 ( 11 ): e3658 . Google Scholar Crossref Search ADS PubMed WorldCat Kochan G , Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, et al. . Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci . 2011 ; 108 ( 19 ): 7745 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat Nguyen TT , Chang S-C, Evnouchidou I, York IA, Zikos C, Rock KL, et al. . Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nature Struct Mol Biol . 2011 ; 18 ( 5 ): 604 – 13 . Google Scholar Crossref Search ADS WorldCat Hammer GE , Gonzalez F, Champsaur M, Cado D, Shastri N. The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nature Immunol . 2006 ; 7 ( 1 ): 103 – 12 . Google Scholar Crossref Search ADS WorldCat García-Medel N , Sanz-Bravo A, Van Nguyen D, Galocha B, Gómez-Molina P, Martín-Esteban A, et al. . Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo. Mol Cell Proteom . 2012 ; 11 ( 11 ): 1416 – 29 . Google Scholar Crossref Search ADS WorldCat Ombrello MJ , Kastner DL, Remmers EF Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics. Curr Opin Rheumatol . 2015 ; 27 ( 4 ): 349 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Kadi A , Izac B, Said-Nahal R, Leboime A, Van Praet L, de Vlam K, et al. . Investigating the genetic association between ERAP1 and spondyloarthritis. Ann Rheum Dis . 2013 ; 72 ( 4 ): 608 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Bettencourt BF , Rocha FL, Alves H, Amorim R, Caetano-Lopes J, Vieira-Sousa E, et al. . Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals. Rheumatology (Oxford) . 2013 ; 52 ( 12 ): 2168 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat Tsui FW , Haroon N, Reveille JD, Rahman P, Chiu B, Tsui HW, et al. . Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis . 2010 ; 69 ( 4 ): 733 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Birtley JR , Saridakis E, Stratikos E, Mavridis IM. The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. Biochemistry . 2011 ; 51 ( 1 ): 286 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Saveanu L , Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, et al. . Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nature Immunol . 2005 ; 6 ( 7 ): 689 – 97 . Google Scholar Crossref Search ADS WorldCat Hinks A , Cobb J, Marion MC, Prahalad S, Sudman M, Bowes J, et al. . Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nature Genetics . 2013 ; 45 ( 6 ): 664 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Tsoi LC , Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. . Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nature Genetics . 2012 ; 44 ( 12 ): 1341 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Andrés AM , Dennis MY, Kretzschmar WW, Cannons JL, Lee-Lin S-Q, Hurle B, et al. . Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet . 2010 ; 6 ( 10 ): e1001157 . Google Scholar Crossref Search ADS PubMed WorldCat Evnouchidou I , Birtley J, Seregin S, Papakyriakou A, Zervoudi E, Samiotaki M, et al. . A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing. J Immunol . 2012 ; 189 ( 5 ): 2383 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat Saveanu L , Carroll O, Weimershaus M, Guermonprez P, Firat E, Lindo V, et al. . IRAP identifies an endosomal compartment required for MHC class I cross-presentation. Science . 2009 ; 325 ( 5937 ): 213 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Menzies FM , Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, et al. . Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genetics . 2010 ; 19 : 4573 – 86 . Google Scholar Crossref Search ADS WorldCat Kudo LC , Parfenova L, Ren G, Vi N, Hui M, Ma Z, et al. . Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAUP301L double-transgenic mice. Hum Mol Genetics . 2011 ; 20 : 1820 – 33 . Google Scholar Crossref Search ADS WorldCat Ciccia F , Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, Giardina A, et al. . Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Anne Rheum Dis . 2014 ; 73 ( 8 ): 1566 – 74 . Google Scholar Crossref Search ADS WorldCat Danoy P , Pryce K, Hadler J, Bradbury LA, Farrar C, Pointon J, et al. . Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PLoS Genet . 2010 ; 6 ( 12 ): e1001195 . Google Scholar Crossref Search ADS PubMed WorldCat Di Meglio P , Di Cesare A, Laggner U, Chu C-C, Napolitano L, Villanova F, et al. . The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PloS One . 2011 ; 6 ( 2 ): e17160 . Google Scholar Crossref Search ADS PubMed WorldCat Sarin R , Wu X, Abraham C Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci . 2011 ; 108 ( 23 ): 9560 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Davidson S , Jiang L, Cortes A, Wu X, Glazov E, Donskoi M, et al. . Brief report: high-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum . 2013 ; 65 ( 7 ): 1747 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Daryabor G , Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N, et al. . Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Network . 2014 ; 25 ( 1 ): 24 – 9 . Google Scholar OpenURL Placeholder Text WorldCat Adamopoulos IE , Tessmer M, Chao C-C, Adda S, Gorman D, Petro M, et al. . IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass . J. Immunol . 2011 ; 187 ( 2 ): 951 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Ciccia F , Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, et al. . Overexpression of interleukin‐23, but not interleukin‐17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum . 2009 ; 60 ( 4 ): 955 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat Sherlock JP , Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, et al. . IL-23 induces spondyloarthropathy by acting on ROR-γt + CD3 + CD4-CD8- entheseal resident T cells. Nature Med . 2012 ; 18 ( 7 ): 1069 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat Boldizsar F , Tarjanyi O, Nemeth P, Mikecz K, Glant TT. Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 mice. Int Immunol . 2009 ; 21 ( 5 ): 511 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat DeLay ML , Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA.. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats . Arthritis Rheum . 2009 ; 60 ( 9 ): 2633 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat Kontoyiannis D , Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, et al. . Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J Exp Med . 2002 ; 196 ( 12 ): 1563 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat Ruutu M , Yadav B, Thomas G, Steck R, Strutton G, Tran A, et al. . Fungal beta-glucan triggers spondyloarthropathy and Crohn’s disease in SKG mice. Arthritis Rheum . 2010 ; 62 ( Suppl 10 ): 1446 . Google Scholar OpenURL Placeholder Text WorldCat D'Elios MM , Del Prete G, Amedei A Targeting IL-23 in human diseases. Expert Opin Therap Targets . 2010 ; 14 ( 7 ): 759 – 74 . Google Scholar Crossref Search ADS WorldCat Lubberts E The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol . 2015 ; 11 ( 7 ): 415 – 29 . Google Scholar Crossref Search ADS PubMed WorldCat Kullberg MC , Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al. . IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med . 2006 ; 203 ( 11 ): 2485 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Kopp T , Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G. IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity . J Immunol . 2003 ; 170 ( 11 ): 5438 – 44 . Google Scholar Crossref Search ADS PubMed WorldCat Crawford MP , Yan SX, Ortega SB, Mehta RS, Hewitt RE, Price DA, et al. . High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood . 2004 ; 103 ( 11 ): 4222 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Sanchez E , Rueda B, Callejas J, Sabio J, Ortego-Centeno N, Jimenez-Alonso J, et al. . Analysis of interleukin‐23 receptor (IL23R) gene polymorphisms in systemic lupus erythematosus. Tissue Antigens . 2007 ; 70 ( 3 ): 233 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu K-J , Zhu C-Y, Shi G, Fan Y-M. Meta-analysis of IL12B polymorphisms (rs3212227, rs6887695) with psoriasis and psoriatic arthritis. Rheumatol Int . 2013 ; 33 ( 7 ): 1785 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Coffre M , Roumier M, Rybczynska M, Sechet E, Law HK, Gossec L, et al. . Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin‐23 signaling pathway in spondyloarthritis. Arthritis Rheum . 2013 ; 65 ( 6 ): 1510 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Sims A-M , Timms AE, Bruges-Armas J, Burgos- Vargas R, Chou C-T, Doan T, et al. . Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis . 2008 ; 67 ( 9 ): 1305 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Van der Paardt M , Crusius J, García-Gonzá lez M, Baudoin P, Kostense P, Alizadeh B, et al. . Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology (Oxford) . 2002 ; 41 ( 12 ): 1419 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Consortium A-A-AS. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nature Genetics . 2010 ; 42 ( 2 ): 123 – 7 . Crossref Search ADS PubMed WorldCat Haibel H , Rudwaleit M, Listing J, Sieper J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis . 2005 ; 64 ( 2 ): 296 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Tan AL , Marzo-Ortega H, O’Connor P, Fraser A, Emery P, McGonagle D. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis . 2004 ; 63 ( 9 ): 1041 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Mahmoudi M , Amirzargar A, Jamshidi A, Farhadi E, Noori S, Avraee M, et al. . Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis. Eur Cytokine Network . 2011 ; 22 ( 4 ): 175 – 80 . Google Scholar OpenURL Placeholder Text WorldCat Momenzadeh P , Mahmoudi M, Beigy M, Garshasbi M, Vodjdanian M, Farazmand A, et al. . Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. Rheumatol Int . 2016 ; 36 : 429 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat Dehghan A , Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. . Meta-analysis of genome-wide association studies in 80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation . 2011 ; 123 ( 7 ): 731 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Wilk JB , Walter RE, Laramie JM, Gottlieb DJ, T O' Connor G. Framingham Heart Study genome-wide association: results for pulmonary function measures. BMC Med Genetics . 2007 ; 8 ( Suppl 1 ): S8 . Google Scholar Crossref Search ADS WorldCat Nicknam MH , Mahmoudi M, Amirzargar AA, Jamshidi AR, Rezaei N, Nikbin B. HLA-B27 subtypes and tumor necrosis factor α promoter region polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Network . 2009 ; 20 ( 1 ): 17 – 20 . Google Scholar OpenURL Placeholder Text WorldCat Park J-H , Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, et al. . Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nature Immunol . 2010 ; 11 ( 3 ): 257 – 64 . Google Scholar Crossref Search ADS WorldCat Brenner O , Levanon D, Negreanu V, Golubkov O, Fainaru O, Woolf E, et al. . Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc Natl Acad Sci USA . 2004 ; 101 ( 45 ): 16016 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Cruz-Guilloty F , Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, et al. . Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med . 2009 ; 206 ( 1 ): 51 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Pearce EL , Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, et al. . Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science . 2003 ; 302 ( 5647 ): 1041 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat Yagi R , Junttila IS, Wei G, Urban JF, Zhao K, Paul WE, et al. . The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma. Immunity . 2010 ; 32 ( 4 ): 507 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Intlekofer AM , Banerjee A, Takemoto N, Gordon SM, DeJong CS, Shin H, et al. . Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science . 2008 ; 321 ( 5887 ): 408 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Candeias S , Peschon J, Muegge K, Durum S. Defective T-cell receptor γ gene rearrangement in interleukin-7 receptor knockout mice. Immunol Lett . 1997 ; 57 ( 1 ): 9 – 14 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Franke A , McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. . Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics . 2010 ; 42 ( 12 ): 1118 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Rakowski LA , Garagiola DD, Li CM, Decker M, Caruso S, Jones M, et al. . Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias. Cancer Res . 2013 ; 73 ( 2 ): 930 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Klose CS , Kiss EA, Schwierzeck V, Ebert K, Hoyler T, d’Hargues Y, et al. . A T-bet gradient controls the fate and function of CCR6-RORγt + innate lymphoid cells. Nature . 2013 ; 494 ( 7436 ): 261 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Sciumé G , Hirahara K, Takahashi H, Laurence A, Villarino AV, Singleton KL, et al. . Distinct requirements for T-bet in gut innate lymphoid cells. J Exp Med . 2012 ; 209 ( 13 ): 2331 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Kenna TJ , Brown MA The role of IL-17-secreting mast cells in inflammatory joint disease. Nature Reviews Rheumatology 2013 ; 9 ( 6 ): 375 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Ciccia F , Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, Peralta S, et al. . Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis . Arthritis Rheum . 2012 ; 64 ( 6 ): 1869 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat Baerlecken N , Nothdorft S, Stummvoll G, Sieper J, Rudwaleit M, Reuter S, et al. . Autoantibodies against CD74 in spondyloarthritis. Ann Rheum Dis . 2014 ; 73 ( 6 ): 1211 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Baraliakos X , Baerlecken N, Witte T, Heldmann F, Braun J. High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann Rheum Dis . 2014 ; 73 ( 6 ): 1079 – 82 . Google Scholar Crossref Search ADS PubMed WorldCat Muto A , Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, et al. . The transcriptional programme of antibody class switching involves the repressor Bach2. Nature . 2004 ; 429 ( 6991 ): 566 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat Okazaki T , Honjo T PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol . 2007 ; 19 ( 7 ): 813 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Keir ME , Francisco LM, Sharpe AH PD-1 and its ligands in T-cell immunity. Curr Opin Immunol . 2007 ; 19 ( 3 ): 309 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Sharpe AH , Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunol . 2007 ; 8 ( 3 ): 239 – 45 . Google Scholar Crossref Search ADS WorldCat Lee S , Lee Y, Woo D, Song R, Park E, Ryu M, et al. . Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population . Arthritis Res Ther . 2006 ; 8 ( 6 ): R163 . Google Scholar Crossref Search ADS PubMed WorldCat Soleimanifar N , Amirzargar AA, Mahmoudi M, Pourfathollah AA, Azizi E, Jamshidi AR, et al. . Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis. Inflammation . 2011 ; 34 ( 6 ): 707 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Harper K , Balzano C, Rouvier E, Mattûi M-G, Luciani M, Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol . 1991 ; 147 ( 3 ): 1037 – 44 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Vaidya B , Imrie H, Perros P, Young ET, Kelly WF, Carr D, et al. . The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. Hum Mol Genetics . 1999 ; 8 ( 7 ): 1195 – 9 . Google Scholar Crossref Search ADS WorldCat Azizi E , Massoud A, Amirzargar AA, Mahmoudi M, Soleimanifar N, Rezaei N, et al. . Association of CTLA4 gene polymorphism in Iranian patients with ankylosing spondylitis . J Clin Immunol . 2010 ; 30 ( 2 ): 268 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat Rosenbaum DM , Rasmussen SG, Kobilka BK The structure and function of G-protein-coupled receptors. Nature . 2009 ; 459 ( 7245 ): 356 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat Wang J , Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, et al. . Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35 . J Biol Chem . 2006 ; 281 ( 31 ): 22021 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Ren G , Su J, Zhang L, Zhao X, Ling W, L' Huillie A, et al. . Species variation in the mechanisms of mesenchymal Stem cell-mediated immunosuppression. Stem Cells . 2009 ; 27 ( 8 ): 1954 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Pallotta MT , Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. . Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nature Immunol . 2011 ; 12 ( 9 ): 870 – 8 . Google Scholar Crossref Search ADS WorldCat Marazziti D , Di Pietro C, Golini E, Mandillo S, Matteoni R, Tocchini-Valentini GP. Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor. FASEB J . 2009 ; 23 ( 6 ): 1978 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat Khor B , Gardet A, Xavier RJ Genetics and pathogenesis of inflammatory bowel disease. Nature . 2011 ; 474 ( 7351 ): 307 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Tosa N , Murakami M, Jia WY, Yokoyama M, Masunaga T, Iwabuchi C, et al. . Critical function of T cell death‐associated gene 8 in glucocorticoid‐induced thymocyte apoptosis. Int Immunol . 2003 ; 15 ( 6 ): 741 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Mahmoudi M , Nicknam MH, Ahmadzadeh N, Jamshidi AR. rs6759298 polymorphism and its interaction with Human Leukocyte Antigene-B27 in Iranian Patients with Ankylosing Spondylitis. Unpublished Data, 2016 . McGonagle D , Aydin SZ, Gul A, Mahr A, Direskeneli H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol . 2015 ; 11 ( 12 ): 731 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat Hayday AC γδ Gammadelta T cells and the lymphoid stress-surveillance response. Immunity . 2009 ; 31 ( 2 ): 184 – 96 . Google Scholar Crossref Search ADS PubMed WorldCat Tran TM , Colbert RA Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation. Curr Opin Rheumatol . 2015 ; 27 ( 4 ): 357 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat Robinson PC , Costello M-E, Leo P, Bradbury LA, Hollis K, Cortes A, et al. . ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis . 2015 ; 74 : 1627 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Guasp P , Alvarez- Navarro C, Gomez- Molina P, Martín- Esteban A, Marcilla M, Barnea E, et al. . The peptidome of the Behçet's disease‐associated HLA‐B* 51: 01 includes two sub‐peptidomes differentially shaped by ERAP1. Arthritis Rheumatol . 2016 ; 68 : 505 – 15 . Google Scholar Crossref Search ADS PubMed WorldCat Costantino F , Talpin A, Evnouchidou I, Kadi A, Leboime A, Said- Nahal R, et al. . ERAP1 gene expression is influenced by nonsynonymous polymorphisms associated with predisposition to spondyloarthritis. Arthritis Rheumatol . 2015 ; 67 ( 6 ): 1525 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Chen L , Fischer R, Peng Y, Reeves E, McHugh K, Ternette N, et al. . Critical role of endoplasmic reticulum aminopeptidase 1 in determining the length and sequence of peptides bound and presented by HLA–B27. Arthritis Rheumatol . 2014 ; 66 ( 2 ): 284 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Remmers EF , Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. . Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nature Genetics . 2010 ; 42 ( 8 ): 698 – 702 . Google Scholar Crossref Search ADS PubMed WorldCat Mizuki N , Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. . Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nature Genetics . 2010 ; 42 ( 8 ): 703 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Chi W , Zhu X, Yang P, Liu X, Lin X, Zhou H, et al. . Upregulated IL-23 and IL-17 in Behçet patients with active uveitis . Invest Ophthalmol Vis Sci . 2008 ; 49 ( 7 ): 3058 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat Kirino Y , Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. . Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nature Genetics . 2013 ; 45 ( 2 ): 202 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Selmi C , Lu Q, Humble MC Heritability versus the role of the environment in autoimmunity. J Autoimmun . 2012 ; 39 ( 4 ): 249 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Aslani S , Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH. Epigenetic alterations underlying autoimmune diseases. Autoimmunity . 2016 ; 49 : 69 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat Germolec D , Kono DH, Pfau JC, Pollard KM. Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS Expert Panel Workshop. J Autoimmun . 2012 ; 39 ( 4 ): 285 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Miller FW , Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, et al. . Criteria for environmentally associated autoimmune diseases. J Autoimmun . 2012 ; 39 ( 4 ): 253 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Ngalamika O , Zhang Y, Yin H, Zhao M, Gershwin ME, Lu Q. Epigenetics, autoimmunity and hematologic malignancies: a comprehensive review. J Autoimmun . 2012 ; 39 ( 4 ): 451 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat Selmi C , Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, et al. . Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun . 2012 ; 39 ( 4 ): 272 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat Waddington CH Canalization of development and the inheritance of acquired characters. Nature . 1942 ; 150 ( 3811 ): 563 – 5 . Google Scholar Crossref Search ADS WorldCat McCarrey JR Epigenetic mechanisms regulating gene expression. In: Krawetz SA, Womble DD editors. Introduction to bioinformatics . Springer ; 2003 : 123 – 39 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Quintero-Ronderos P , Montoya-Ortiz G Epigenetics and autoimmune diseases. Autoimmune Dis . 2012 ; 2012 . doi: 10.1155/2012/593720 . Google Scholar OpenURL Placeholder Text WorldCat Crossref Huang K , Fan G DNA methylation in cell differentiation and reprogramming: an emerging systematic view. Regenerative Med . 2010 ; 5 ( 4 ): 531 – 44 . Google Scholar Crossref Search ADS WorldCat Fan S , Zhang X CpG island methylation pattern in different human tissues and its correlation with gene expression. Biochem Biophys Res Commun . 2009 ; 383 ( 4 ): 421 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Yun M , Wu J, Workman JL, Li B.. Readers of histone modifications. Cell Res . 2011 ; 21 ( 4 ): 564 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat Bannister AJ , Kouzarides T Regulation of chromatin by histone modifications. Cell Res . 2011 ; 21 ( 3 ): 381 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat De Ruijter A , Van Gennip A, Caron H, Kemp S, van Kuilenburg A. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J . 2003 ; 370 : 737 – 49 . Google Scholar Crossref Search ADS PubMed WorldCat Scaria V , Hariharan M, Maiti S, Pillai B, Brahmachari SK. Host-virus interaction: a new role for microRNAs. Retrovirology . 2006 ; 3 ( 1 ): 68 Google Scholar Crossref Search ADS PubMed WorldCat Bartel DP MicroRNAs: genomics, biogenesis, mechanism, and function. Cell . 2004 ; 116 ( 2 ): 281 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat Lai N-S , Chou J-L, Chen GC, Liu S-Q, Lu M-C, Chan MW. Association between cytokines and methylation of SOCS-1 in serum of patients with ankylosing spondylitis . Mol Biol Rep . 2014 ; 41 ( 6 ): 3773 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat Aslani S , Mahmoudi M, Karami J, Jamshidi A, Nicknam MH. Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis. Unpublished Data, 2016 . Karami J , Mahmoudi M, Aslani S, Jamshidi AR, Nicknam MH. Expression and methylation of BCL11B in PBMCs from patients with ankylosing spondylitis. Unpublished Data, 2016 . Liu C-C , Fang T-J, Ou T-T, Wu C-C, Li R-N, Lin Y-C, et al. . Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett . 2011 ; 135 ( 1-2 ): 96 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Jiang Y , Wang L Role of histone deacetylase 3 in ankylosing spondylitis via negative feedback loop with microRNA-130a and enhancement of tumor necrosis factor-1α expression in peripheral blood mononuclear cells. Mol Med Rep . 2016 ; 13 ( 1 ): 35 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat Lai NS , Yu HC, Chen HC, Yu CL, Huang HB, Lu MC. Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis. Clin Exp Immunol . 2013 ; 173 ( 1 ): 47 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat Daoussis D , Andonopoulos AP The emerging role of Dickkopf-1 in bone biology: is it the main switch controlling bone and joint remodeling ? Sem Arthritis Rheumatism . 2011 ; 41 : 170 – 7 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC Huang J , Song G, Yin Z, Luo X, Ye Z. Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis. Modern Rheumatol . 2014 ; 24 ( 2 ): 331 – 4 . Google Scholar Crossref Search ADS WorldCat Sugatani T , Vacher J, Hruska KA A microRNA expression signature of osteoclastogenesis. Blood . 2011 ; 117 ( 13 ): 3648 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat Huang C-H , Wei JC-C, Chang W-C, Chiou S-Y, Chou C-H, Lin Y-J, et al. . Higher expression of whole blood microRNA-21 in patients with ankylosing spondylitis associated with programmed cell death 4 mRNA expression and collagen cross-linked C-telopeptide concentration . J. Rheumatol . 2014 ; 41 ( 6 ): 1104 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Stanczyk J , Pedrioli DML, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, et al. . Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis . Arthritis Rheum . 2008 ; 58 ( 4 ): 1001 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Dai Y , Huang Y-S, Tang M, Lv T-Y, Hu C-X, Tan Y-H, et al. . Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus . 2007 ; 16 ( 12 ): 939 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat Hébert SS , Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. . Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression Proc Natl Acad Sci. USA . 2008 ; 105 ( 17 ): 6415 – 20 . Google Scholar Crossref Search ADS WorldCat Robinson PC , Brown MA Genetics of ankylosing spondylitis. Mol Immunol . 2014 ; 57 ( 1 ): 2 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes * These authors contributed equally to this work. © 2016 Japan College of Rheumatology This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications
JF - Modern Rheumatology
DO - 10.1080/14397595.2016.1206174
DA - 2017-03-04
UR - https://www.deepdyve.com/lp/oxford-university-press/new-insights-toward-the-pathogenesis-of-ankylosing-spondylitis-genetic-14ZQKtcs6h
SP - 198
EP - 209
VL - 27
IS - 2
DP - DeepDyve
ER -