Pathogenesis of Behçet's Disease

**37**

**2.1 HLA**

**Chapter 3**

**Abstract**

**1. Introduction**

Genetics of Behçet's Disease

**Keywords:** Behçet's disease, genetic, HLA region, interleukin family,

categorized genes associated with BD reported from 1973 to January 2019.

HLA genes are among the most polymorphic genes in the human genome, and they are associated with almost all autoimmune diseases. HLA-B51 is the strongest risk allele for BD, which has been replicated in almost all studied populations [12–22]. The population attributable risk (PAR) of HLA-B5/B51 was estimated as 52.2% for BD

**2. HLA and HLA-related genes**

inflammation and autoimmunity, transcriptional activation

Behçet's disease (BD) is a chronic refractory multi-system autoimmune disorder with a strong genetic component. Like many other human complex diseases, multiple genes with polymorphisms have been associated with BD. These genes encode proteins involved mainly in immune regulation and inflammation and some in transcriptional activation and post-translational modification. Understanding the genetic association of these genes with BD may provide insight into the pathogenesis and for development of new, targeted therapies for this human complex disease.

Behçet's disease (BD) is a chronic inflammatory disorder with unclear etiology. It can affect a variety of organs characterized by refractory ulcers in genitals and mouth, uveitis, skin lesions, and manifestations in joints, gastrointestinal tract, kidneys, lungs, and cardiovascular and central nervous systems [1]. BD has distinctive geographical distribution, and it is found primarily in populations along the ancient Silk Route from the Mediterranean region transiting through Central Asia to East Asia [2]. The reported prevalence of BD varies between Western (0.12–7.5 per 100,000) [3] and Eastern countries (6.3–14 per 100,000) [4]. Turkey has the highest incidence of BD in general population (80–420 per 100,000) [5–7]. A family history of BD significantly increases the risk at a rate of 31.2% [8], which indicates a strong genetic contribution to the disease by comparing to general population. Men are more commonly affected in Middle Eastern countries, but that appears opposite in USA, Brazil, Israel, and Korea [9]. The first reported genetic association of BD was found in the human leukocyte antigen (HLA) region, or the major histocompatibility complex (MHC) on chromosome 6 [10]. HLA-B51 confers the strongest genetic risk to BD [11]. Multiple other genetic factors outside the HLA region have also been identified. The following are the

*Xiaodong Zhou and Yan Deng*

## **Chapter 3** Genetics of Behçet's Disease

*Xiaodong Zhou and Yan Deng*

#### **Abstract**

Behçet's disease (BD) is a chronic refractory multi-system autoimmune disorder with a strong genetic component. Like many other human complex diseases, multiple genes with polymorphisms have been associated with BD. These genes encode proteins involved mainly in immune regulation and inflammation and some in transcriptional activation and post-translational modification. Understanding the genetic association of these genes with BD may provide insight into the pathogenesis and for development of new, targeted therapies for this human complex disease.

**Keywords:** Behçet's disease, genetic, HLA region, interleukin family, inflammation and autoimmunity, transcriptional activation

#### **1. Introduction**

Behçet's disease (BD) is a chronic inflammatory disorder with unclear etiology. It can affect a variety of organs characterized by refractory ulcers in genitals and mouth, uveitis, skin lesions, and manifestations in joints, gastrointestinal tract, kidneys, lungs, and cardiovascular and central nervous systems [1]. BD has distinctive geographical distribution, and it is found primarily in populations along the ancient Silk Route from the Mediterranean region transiting through Central Asia to East Asia [2]. The reported prevalence of BD varies between Western (0.12–7.5 per 100,000) [3] and Eastern countries (6.3–14 per 100,000) [4]. Turkey has the highest incidence of BD in general population (80–420 per 100,000) [5–7]. A family history of BD significantly increases the risk at a rate of 31.2% [8], which indicates a strong genetic contribution to the disease by comparing to general population. Men are more commonly affected in Middle Eastern countries, but that appears opposite in USA, Brazil, Israel, and Korea [9]. The first reported genetic association of BD was found in the human leukocyte antigen (HLA) region, or the major histocompatibility complex (MHC) on chromosome 6 [10]. HLA-B51 confers the strongest genetic risk to BD [11]. Multiple other genetic factors outside the HLA region have also been identified. The following are the categorized genes associated with BD reported from 1973 to January 2019.

#### **2. HLA and HLA-related genes**

#### **2.1 HLA**

HLA genes are among the most polymorphic genes in the human genome, and they are associated with almost all autoimmune diseases. HLA-B51 is the strongest risk allele for BD, which has been replicated in almost all studied populations [12–22]. The population attributable risk (PAR) of HLA-B5/B51 was estimated as 52.2% for BD patients in Southern Europe, 49.9% in Middle East/North Africa, 44.4% in East Asia, and 31.7% in Northern Europe [23]. Other HLA alleles including BD-risk HLA-A02, -A24, -A26, -A31, -B27, -B57, and BD-protective HLA-A03, -B15, -B35, -B49, -B58 were reported in different populations [22, 24–29].

Certain HLA alleles were also associated with clinical outcomes of BD. BD patients carrying HLA-A26:01 have a poor visual prognosis in Japan [30] and a high incidence of posterior uveitis in Korea [31]. Some HLA alleles were associated with lesions of specific organs in the Korean and Japanese patients, such as HLA-A26:01 with uveitis, HLA-A02:07 with skin lesions and arthritis, and -A30:04 with vascular lesions, genital ulcers, and a positive pathergy test [32]. These findings suggest that specific HLA alleles are likely used as genetic markers for subclassification and/or prognostic evaluation of BD patients.

#### **2.2 CIITA**

The class II major histocompatibility complex transactivator (CIITA) is a transcriptional activator that acts as a master regulator of the HLA class II genes and some other immune-mediating genes [33, 34]. A single nucleotide polymorphism (SNP) of the CIITA gene rs12932187 withG allele and GG genotype appeared to be a risk factor to Chinese BD, and the GG carriers were correlated with a higher expression of the CIITA gene, and with a lower level of IL-10 protein from the peripheral blood mononuclear cells (PBMC) in response to lipopolysaccharide (LPS) [35].

#### **2.3 ERAP1**

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential enzyme to trim peptides in the ER for optimized binding by MHC class I molecules. The association between ERAP1 and BD was first reported in a Turkish population and was replicated in a Chinese cohort, in which the SNPs rs10050860 and rs17482078 of the ERAP1 gene encoding variants of amino acids Asp575Asn and Arg725Gln, respectively, conferred risk to BD [36, 37]. Further analysis of the association indicated that the ERAP1 variant Arg725Gln may interact with the HLA-B51 protein to confer susceptibility to BD [36, 38]. Moreover, the expression of ERAP1 was found to be significantly lower in active BD patients [37], and the patients carrying AA and CC genotype of the ERAP1 SNP rs1065407 and rs10050860, respectively, showed a higher expression level of the ERAP1 gene than the patients carrying AC or CC and CT or TT genotypes of the SNPs, respectively, in response to LPS [37, 38].

#### **2.4 MICA**

The major histocompatibility complex class I chain-related gene A (MICA), located on the centromeric side of the HLA-B gene on chromosome 6, is highly polymorphic [39]. It functions in immune activation under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [40]. There have been more than 100 MICA alleles identified according to its overall sequence variations. In addition, the codon 295 of the MICA gene has a tri-nucleotide microsatellite polymorphism (GCT)n that is designated as An (A4, A5, A6, A9) allele, and a five repetition of GCT may coexist with a guanosine insertion that is designated as A5.1 [41].

MICA\*009 and \*019 alleles were associated with BD in a Spanish population [42], and MICA-A6 allele with Japanese and Korean BD patients [43–45]. The latter appeared to be independent from the potential linkage disequilibrium (LD) effect of HLA-B51 according to the Korean study [45].

**39**

**3.3 IL-33**

**4.1 MEFV**

*Genetics of Behçet's Disease*

**3.1 IL-10**

*DOI: http://dx.doi.org/10.5772/intechopen.87080*

neurological and intestinal involvement [47].

Turkey, Japanese, and Korean cohorts [51–53].

was found in the Turkish and European cohorts [36, 57].

Iranian [64], Western Algeria [65], and Korean [66].

role in neutrophil inflammation and in autoimmune diseases [60].

with higher IL-33 expression in the PBMC of the BD patients [68].

**4. Genes involved in inflammation and autoimmunity**

**3.2 IL-12A, IL-23R, and IL-12RB2**

**3. Interleukin (IL) family genes**

On the other hand, MICA-A5.1 demonstrated a negative correlation with ocular

IL-10 is a cytokine with anti-inflammatory properties, which plays critical roles in modulating immune response and preventing inflammatory and autoimmune pathologies [48, 49]. The SNP rs1800871 of the IL10 promoter region was first found in an association with BD in the UK and Middle Eastern (ME) cohorts [50]. The genome-wide association studies (GWAS) revealed multiple BD-associated SNPs (rs1518111, rs1554286, rs1800871, and rs1800872) of the IL-10 in Chinese,

IL-12A is a gene which encodes for IL-35 that is a subunit of the heterodimeric cytokines IL-12 (encoded by IL-12B) and IL-35. IL-35 binds to a heterodimeric IL-12 receptor (IL-12R) that consists of IL-12Rβ1 (encoded by IL-12RB1) and IL-12Rβ2 (encoded by IL-12RB2) [54], and it impacts on activation of NK cells and polarization of the Th1 pathway through differentiation from naïve CD4+ T cells [55, 56]. The association of the IL-12A variants rs1780546 and rs17810458 with BD

IL-23 is a member of the IL-12 cytokine family. It plays crucial roles in the development process of the Th17 cells [58]. The receptor for IL-23 is composed of two subunits encoded by the IL-23R and the IL-12RB1 genes [59], and it plays a key

A significant association (reaching a GWAS p value) of the IL-23R gene with BD was found at the SNP rs11209026 (Gly149Arg) in Japanese, and at the SNP rs76418789 (Arg381Gln) in Turkish cohort [61]. The association between BD and the IL-23R/IL-12RB2 genes appeared to be consistent in multiple reports with different populations including Turkey [52], Japanese [53], Han Chinese [62, 63],

IL-33 is a member of the IL-1 family that drives production of Th2-associated cytokines [67]. A small Iranian cohort of BD patients showed a significantly higher prevalence of the IL-33 SNP rs1342326T/G, and this genotype was also associated

The Mediterranean fever (MEFV) protein, also named pyrin is an important

regulator of innate immunity [69]. Of noting, familial Mediterranean fever and BD share inflammatory nature and high prevalence in Middle Eastern and

lesions and iridocyclitis in BD patients [45, 46]. MICA-A9 was associated with BD patients who had less severe complications including uveitis, thrombosis, and

On the other hand, MICA-A5.1 demonstrated a negative correlation with ocular lesions and iridocyclitis in BD patients [45, 46]. MICA-A9 was associated with BD patients who had less severe complications including uveitis, thrombosis, and neurological and intestinal involvement [47].

### **3. Interleukin (IL) family genes**

#### **3.1 IL-10**

*Different Aspects of Behçet's Disease*

reported in different populations [22, 24–29].

prognostic evaluation of BD patients.

**2.2 CIITA**

**2.3 ERAP1**

**2.4 MICA**

patients in Southern Europe, 49.9% in Middle East/North Africa, 44.4% in East Asia, and 31.7% in Northern Europe [23]. Other HLA alleles including BD-risk HLA-A02, -A24, -A26, -A31, -B27, -B57, and BD-protective HLA-A03, -B15, -B35, -B49, -B58 were

Certain HLA alleles were also associated with clinical outcomes of BD. BD patients carrying HLA-A26:01 have a poor visual prognosis in Japan [30] and a high incidence of posterior uveitis in Korea [31]. Some HLA alleles were associated with lesions of specific organs in the Korean and Japanese patients, such as HLA-A26:01 with uveitis, HLA-A02:07 with skin lesions and arthritis, and -A30:04 with vascular lesions, genital ulcers, and a positive pathergy test [32]. These findings suggest that specific HLA alleles are likely used as genetic markers for subclassification and/or

The class II major histocompatibility complex transactivator (CIITA) is a transcriptional activator that acts as a master regulator of the HLA class II genes and some other immune-mediating genes [33, 34]. A single nucleotide polymorphism (SNP) of the CIITA gene rs12932187 withG allele and GG genotype appeared to be a risk factor to Chinese BD, and the GG carriers were correlated with a higher expression of the CIITA gene, and with a lower level of IL-10 protein from the peripheral blood mononuclear cells (PBMC) in response to lipopolysaccharide (LPS) [35].

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential enzyme to trim peptides in the ER for optimized binding by MHC class I molecules. The association between ERAP1 and BD was first reported in a Turkish population and was replicated in a Chinese cohort, in which the SNPs rs10050860 and rs17482078 of the ERAP1 gene encoding variants of amino acids Asp575Asn and Arg725Gln, respectively, conferred risk to BD [36, 37]. Further analysis of the association indicated that the ERAP1 variant Arg725Gln may interact with the HLA-B51 protein to confer susceptibility to BD [36, 38]. Moreover, the expression of ERAP1 was found to be significantly lower in active BD patients [37], and the patients carrying AA and CC genotype of the ERAP1 SNP rs1065407 and rs10050860, respectively, showed a higher expression level of the ERAP1 gene than the patients carrying AC or CC and

CT or TT genotypes of the SNPs, respectively, in response to LPS [37, 38].

sine insertion that is designated as A5.1 [41].

of HLA-B51 according to the Korean study [45].

The major histocompatibility complex class I chain-related gene A (MICA), located on the centromeric side of the HLA-B gene on chromosome 6, is highly polymorphic [39]. It functions in immune activation under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [40]. There have been more than 100 MICA alleles identified according to its overall sequence variations. In addition, the codon 295 of the MICA gene has a tri-nucleotide microsatellite polymorphism (GCT)n that is designated as An (A4, A5, A6, A9) allele, and a five repetition of GCT may coexist with a guano-

MICA\*009 and \*019 alleles were associated with BD in a Spanish population [42], and MICA-A6 allele with Japanese and Korean BD patients [43–45]. The latter appeared to be independent from the potential linkage disequilibrium (LD) effect

**38**

IL-10 is a cytokine with anti-inflammatory properties, which plays critical roles in modulating immune response and preventing inflammatory and autoimmune pathologies [48, 49]. The SNP rs1800871 of the IL10 promoter region was first found in an association with BD in the UK and Middle Eastern (ME) cohorts [50]. The genome-wide association studies (GWAS) revealed multiple BD-associated SNPs (rs1518111, rs1554286, rs1800871, and rs1800872) of the IL-10 in Chinese, Turkey, Japanese, and Korean cohorts [51–53].

#### **3.2 IL-12A, IL-23R, and IL-12RB2**

IL-12A is a gene which encodes for IL-35 that is a subunit of the heterodimeric cytokines IL-12 (encoded by IL-12B) and IL-35. IL-35 binds to a heterodimeric IL-12 receptor (IL-12R) that consists of IL-12Rβ1 (encoded by IL-12RB1) and IL-12Rβ2 (encoded by IL-12RB2) [54], and it impacts on activation of NK cells and polarization of the Th1 pathway through differentiation from naïve CD4+ T cells [55, 56]. The association of the IL-12A variants rs1780546 and rs17810458 with BD was found in the Turkish and European cohorts [36, 57].

IL-23 is a member of the IL-12 cytokine family. It plays crucial roles in the development process of the Th17 cells [58]. The receptor for IL-23 is composed of two subunits encoded by the IL-23R and the IL-12RB1 genes [59], and it plays a key role in neutrophil inflammation and in autoimmune diseases [60].

A significant association (reaching a GWAS p value) of the IL-23R gene with BD was found at the SNP rs11209026 (Gly149Arg) in Japanese, and at the SNP rs76418789 (Arg381Gln) in Turkish cohort [61]. The association between BD and the IL-23R/IL-12RB2 genes appeared to be consistent in multiple reports with different populations including Turkey [52], Japanese [53], Han Chinese [62, 63], Iranian [64], Western Algeria [65], and Korean [66].

#### **3.3 IL-33**

IL-33 is a member of the IL-1 family that drives production of Th2-associated cytokines [67]. A small Iranian cohort of BD patients showed a significantly higher prevalence of the IL-33 SNP rs1342326T/G, and this genotype was also associated with higher IL-33 expression in the PBMC of the BD patients [68].

#### **4. Genes involved in inflammation and autoimmunity**

#### **4.1 MEFV**

The Mediterranean fever (MEFV) protein, also named pyrin is an important regulator of innate immunity [69]. Of noting, familial Mediterranean fever and BD share inflammatory nature and high prevalence in Middle Eastern and

Mediterranean populations. Genetically, the MEFV SNPs rs61752717 Met694Val, rs28940580 Met680Ile, and rs3743930 Glu148Gln confer risk to both diseases [61, 70–74]. Moreover, Met694Val and Met680Ile of the MEFV gene were also associated with greater responsiveness to bacterial products [72, 73].

#### **4.2 IRF8**

Interferon regulatory factor (IRF) 8 is a member of the interferon (IFN) regulatory factor (IRF) family, and it acts as a transcription factor to regulate the development and function of a variety of immune cells. In particular, it regulates expression of type I IFN stimulated genes [75], and interacts with the Th17 master transcription factor, ROR-γt to inhibit Th17 cell differentiation [76]. In a study with Chinese cohort, the IRF8 SNPs rs17445836 and rs11642873 were associated with BD, and they appeared to regulate IRF8 expression and corresponding cytokine production [77]. In another study with multiple cohorts including Turkish, Iranian, and Japanese patients, three other BD-associated SNPs (rs11117433, rs142105922 and rs7203487) of the IRF8 gene were reported [78].

#### **4.3 TNFAIP3**

TNF-α-induced protein 3 (TNFAIP3) is a ubiquitin-modifying enzyme A20 that regulates inflammation through NF-κB signaling pathway, and it can be induced by TNF, Toll-like receptors (TLRs), IL-1R, and NOD2 signaling [79–82]. The reports of genetic association between TNFAIP3 and BD appeared conflict in studies of Chinese and European populations. In the former, the TNFAIP3 SNPs (rs9494885, rs10499194 and rs7753873) were associated with BD [83], but were not replicated in the latter [84]. On the other hand, a Japanese study of familial BD indicated that a missense mutation C243Y in A20/TNFAIP3 was likely responsible for an increased production of some inflammatory cytokines by reduced suppression of NF-κB activation [85].

#### **4.4 REL**

The REL gene encodes for c-Rel, a member of the NF-κB family of transcription factors. It may play important roles in regulation of immune activity [86, 87]. A Chinese study indicated that the REL SNPs rs842647 may confer susceptibility to BD, and the allele C of this SNP was also associated with skin lesions in BD patients [88].

#### **4.5 TLR2 and TLR4**

Toll-like receptors (TLR) are transmembrane proteins that mediate innate immunity by recognizing pathogen molecules [89]. TLR2 and TLR4 are two members of the TLR, and they may transduce response to different types of pathogens (e.g., in macrophages, the former mainly for Gram-positive bacteria and the latter for Gram-negative). The TLR2 SNP rs2289318 (C allele and genotype CC) and rs3804099 (CT genotype) were associated with ocular BD in a Chinese cohort [90]. The associations of the TLR4 gene with BD are conflict in different reports. It was found in Japanese [91], Korea [92] and Turkish cohorts [66], but not in Italian [93], Tunisian [94], and Chinese cohorts [95]. Of note, two BD protective TLR4 variants identified in the Turkish cohort, p.Asp299Gly (rs4986790) and p.Thr399Ile (rs4986791) were associated with hyporesponsiveness to endotoxin [96].

**41**

*Genetics of Behçet's Disease*

**4.6 NOD1 and NOD2**

**4.7 CCR1 and CCR3**

**4.8 GIMAP**

**4.9 KLRC4**

**5.1 STAT4**

*DOI: http://dx.doi.org/10.5772/intechopen.87080*

NOD2 rs2066844 was also protective from BD [61, 99, 100].

reduced along with a weaker activity of monocyte chemotaxis [36].

replication study of European cohort [107].

GTPase of the immunity-associated protein (GIMAP) family is a group of newly identified proteins. Although their functions are still poorly characterized, it is believed that they are lymphocyte signaling molecules, and they are also involved in survival and apoptosis of T cells and some other cell types [104, 105]. A GIMAP cluster including SNPs in GIMAP1 (rs2286900), GIMAP2 (rs10266069 and rs10256482), and GIMAP4 (rs1916012, rs1522596, and rs1608157) was associated with BD in a study of Korean and Japanese populations [106], but it failed in a

Killer cell lectin-like receptor subfamily C, member 4 (KLRC4) is a member of NKG2 receptor family that regulates NK cell function. The association of the KLRC4 gene and BD was first suggested in the GWAS of Turkish and Japanese cohorts [36],

and then replicated in the independent study of an Iranian cohort [103].

**5. Genes involved in transcriptional activation of immune regulation**

Signal transducer and activator of transcription-4 (STAT4) is a transcription factor that activates gene expression involved in functional regulation and differentiation of T-helper cells, natural killer (NK) cells, mast cells, and dendritic cells [108]. It modulates differentiation of naïve T cells into Th1 and Th17 cells [56, 109, 110]. The association between the STAT4 gene and BD appeared to be consistent in multiple independent studies including Han Chinese [107], Korean, Turkish, and

Nucleotide-binding oligomerization domain (NOD)-like receptors are intracellular proteins that regulate innate immune response. NOD1 and NOD2 proteins are two members of the NOD family, and they play important roles in initiating inflammation in response to microbial components [97, 98]. In a Chinese report, the minor allele (G) of the NOD1 SNP rs2075818 was protective from BD [35]. Multiple studies indicated that a Crohn's disease-associated polymorphism, Arg702Trp of the

CCR1 and CCR3 proteins are two C-C motif chemokine receptor (CCR) family members. They mediate signal transduction within cells in response to pathogens, and they are critical for the recruitment of effector immune cells to the site of inflammation, and for maintaining homeostasis of the immune system [101]. The CCR1 and 3 genes are clustered together on chromosome 3p. The Several SNPs at CCR1-CCR3 locus were associated with BD including rs7616215 in Turkish [40] and rs13084057, rs13092160 and rs13075270 in Chinese Cohorts [102]. In addition, the CCR1 gene was individually associated with BD in multiple cohorts including Turkish, Japanese, and Iranian cohorts [36, 103]. Functional studies indicated that CCR1 gene expression in primary human monocytes carrying the BD-risk allele was

#### **4.6 NOD1 and NOD2**

*Different Aspects of Behçet's Disease*

**4.2 IRF8**

**4.3 TNFAIP3**

activation [85].

patients [88].

**4.5 TLR2 and TLR4**

ness to endotoxin [96].

**4.4 REL**

Mediterranean populations. Genetically, the MEFV SNPs rs61752717 Met694Val, rs28940580 Met680Ile, and rs3743930 Glu148Gln confer risk to both diseases [61, 70–74]. Moreover, Met694Val and Met680Ile of the MEFV gene were also

Interferon regulatory factor (IRF) 8 is a member of the interferon (IFN) regulatory factor (IRF) family, and it acts as a transcription factor to regulate the development and function of a variety of immune cells. In particular, it regulates expression of type I IFN stimulated genes [75], and interacts with the Th17 master transcription factor, ROR-γt to inhibit Th17 cell differentiation [76]. In a study with Chinese cohort, the IRF8 SNPs rs17445836 and rs11642873 were associated with BD, and they appeared to regulate IRF8 expression and corresponding cytokine production [77]. In another study with multiple cohorts including Turkish, Iranian, and Japanese patients, three other BD-associated SNPs (rs11117433, rs142105922 and

TNF-α-induced protein 3 (TNFAIP3) is a ubiquitin-modifying enzyme A20 that regulates inflammation through NF-κB signaling pathway, and it can be induced by TNF, Toll-like receptors (TLRs), IL-1R, and NOD2 signaling [79–82]. The reports of genetic association between TNFAIP3 and BD appeared conflict in studies of Chinese and European populations. In the former, the TNFAIP3 SNPs (rs9494885, rs10499194 and rs7753873) were associated with BD [83], but were not replicated in the latter [84]. On the other hand, a Japanese study of familial BD indicated that a missense mutation C243Y in A20/TNFAIP3 was likely responsible for an increased production of some inflammatory cytokines by reduced suppression of NF-κB

The REL gene encodes for c-Rel, a member of the NF-κB family of transcription factors. It may play important roles in regulation of immune activity [86, 87]. A Chinese study indicated that the REL SNPs rs842647 may confer susceptibility to BD, and the allele C of this SNP was also associated with skin lesions in BD

Toll-like receptors (TLR) are transmembrane proteins that mediate innate immunity by recognizing pathogen molecules [89]. TLR2 and TLR4 are two members of the TLR, and they may transduce response to different types of pathogens (e.g., in macrophages, the former mainly for Gram-positive bacteria and the latter for Gram-negative). The TLR2 SNP rs2289318 (C allele and genotype CC) and rs3804099 (CT genotype) were associated with ocular BD in a Chinese cohort [90]. The associations of the TLR4 gene with BD are conflict in different reports. It was found in Japanese [91], Korea [92] and Turkish cohorts [66], but not in Italian [93], Tunisian [94], and Chinese cohorts [95]. Of note, two BD protective TLR4 variants identified in the Turkish cohort, p.Asp299Gly (rs4986790) and p.Thr399Ile (rs4986791) were associated with hyporesponsive-

associated with greater responsiveness to bacterial products [72, 73].

rs7203487) of the IRF8 gene were reported [78].

**40**

Nucleotide-binding oligomerization domain (NOD)-like receptors are intracellular proteins that regulate innate immune response. NOD1 and NOD2 proteins are two members of the NOD family, and they play important roles in initiating inflammation in response to microbial components [97, 98]. In a Chinese report, the minor allele (G) of the NOD1 SNP rs2075818 was protective from BD [35]. Multiple studies indicated that a Crohn's disease-associated polymorphism, Arg702Trp of the NOD2 rs2066844 was also protective from BD [61, 99, 100].

#### **4.7 CCR1 and CCR3**

CCR1 and CCR3 proteins are two C-C motif chemokine receptor (CCR) family members. They mediate signal transduction within cells in response to pathogens, and they are critical for the recruitment of effector immune cells to the site of inflammation, and for maintaining homeostasis of the immune system [101]. The CCR1 and 3 genes are clustered together on chromosome 3p. The Several SNPs at CCR1-CCR3 locus were associated with BD including rs7616215 in Turkish [40] and rs13084057, rs13092160 and rs13075270 in Chinese Cohorts [102]. In addition, the CCR1 gene was individually associated with BD in multiple cohorts including Turkish, Japanese, and Iranian cohorts [36, 103]. Functional studies indicated that CCR1 gene expression in primary human monocytes carrying the BD-risk allele was reduced along with a weaker activity of monocyte chemotaxis [36].

#### **4.8 GIMAP**

GTPase of the immunity-associated protein (GIMAP) family is a group of newly identified proteins. Although their functions are still poorly characterized, it is believed that they are lymphocyte signaling molecules, and they are also involved in survival and apoptosis of T cells and some other cell types [104, 105]. A GIMAP cluster including SNPs in GIMAP1 (rs2286900), GIMAP2 (rs10266069 and rs10256482), and GIMAP4 (rs1916012, rs1522596, and rs1608157) was associated with BD in a study of Korean and Japanese populations [106], but it failed in a replication study of European cohort [107].

#### **4.9 KLRC4**

Killer cell lectin-like receptor subfamily C, member 4 (KLRC4) is a member of NKG2 receptor family that regulates NK cell function. The association of the KLRC4 gene and BD was first suggested in the GWAS of Turkish and Japanese cohorts [36], and then replicated in the independent study of an Iranian cohort [103].

#### **5. Genes involved in transcriptional activation of immune regulation**

#### **5.1 STAT4**

Signal transducer and activator of transcription-4 (STAT4) is a transcription factor that activates gene expression involved in functional regulation and differentiation of T-helper cells, natural killer (NK) cells, mast cells, and dendritic cells [108]. It modulates differentiation of naïve T cells into Th1 and Th17 cells [56, 109, 110].

The association between the STAT4 gene and BD appeared to be consistent in multiple independent studies including Han Chinese [107], Korean, Turkish, and Iranians [36, 103]. Functional studies indicated that the risk allele A of the STAT4 SNP rs897200 was correlated with the increased mRNA level of the STAT4 gene, and with the increased gene and protein expression of IL-17, as well as with BD patients who have a higher clinical severity score [111].

#### **5.2 NCOA5**

Nuclear receptor coactivator-5 (NCOA5) protein regulates nuclear receptor subfamily 1 group D member 2 (NR1D2) and estrogen receptor 1 and 2 (ESR1 and ESR2) [112, 113]. The NCOA5 gene SNP rs2903908 was associated with BD patients, especially those affected with genital ulceration and uveitis in the Finland and the Turkish cohorts [114].

#### **5.3 FOXP3**

FOXP3 (forkhead box P3), also known as scurfin, is a member of the FOX protein family of transcription factors. It regulates the development and function of T regulatory (Treg) cells [115, 116]. The FOXP3 SNP rs3761548 was associated with BD in the North-Western Iranian population [117]. In addition, a low copy number variant (CNV) of the FOXP3 gene was reported to confer risk to female BD patients in a Chinese cohort [118].

#### **6. Other genes**

#### **6.1 PSORS1C1**

Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is poorly characterized in terms of its biological function. It is initially recognized as a susceptibility locus to psoriasis [119] and psoriatic arthritis [120]. Recent studies indicated that it is also a shared genetic factor, especially with SNP rs12525170, in other autoimmune diseases including systemic sclerosis [121], Crohn's disease [122], and BD [122]. Therefore, it may play important roles in the pathogenesis of autoimmunity [123, 124].

#### **6.2 FUT2**

Fucosyltransferase 2 (FUT2) is involved in synthesis of the H antigen, the precursor of the ABO-histo-blood group antigen in body fluids, and on the intestinal mucosa [125]. The association between the FUT2 gene (rs632111, rs601338, rs602662, rs492602, rs681343, and rs281377) and BD was reported in Iranian and Turkish populations [126].

#### **6.3 UBAC2**

Ubiquitin-associated domain containing 2 (UBAC2) is another poorly characterized protein, but its gene variants are strongly associated with BD. Limited studies suggest that it may function in protein localization in the endoplasmic reticulum [127]. The association of the UBAC2 gene with BD was found in Turkish, Chinese, Italian, and Japanese populations [128–131]. Functionally, the presence of BD-risk rs9517723 allele was correlated with an increased expression of the UBAC2 gene.

**43**

**7. Conclusion**

*Genetics of Behçet's Disease*

**6.4 SUMO4**

**6.5 LACC1**

*DOI: http://dx.doi.org/10.5772/intechopen.87080*

vascular involvement of BD patients [135, 136].

Japanese, and Chinese cohorts [78, 138].

**6.6 Loci at ADO-EGR2 and CEBPB-PTPN1**

Small ubiquitin-like modifier 4 (SUMO4) is a member of the SUMO family that

post-transcriptionally sumoylates the targeted proteins to regulate their subcellular localization and/or enhance their stability and activity [132]. It is involved in immune regulation by negatively controlling NFκB activity [133]. The genetic association between the SUMO4 (SNPs rs237024, rs237026) and BD was first reported in a Chinese cohort, and that appeared independent from HLA-B51 [134]. The association was replicated in Tunisian and Korean cohorts [135, 136], in which specific polymorphisms were also associated with disease severity, skin lesions, and

LACC1 encodes an oxidoreductase that promotes fatty-acid oxidation. It also functions in activation of inflammasome, bactericidal activity of macrophages, and production of mitochondrial and NADPH-oxidase-dependent reactive oxygen species [137]. SNP rs9316059 of the LACC1 was associated with BD in Turkish,

Two genetic loci between the ADO and the EGR2 genes and the CEBPB and the PTPN1 genes were associated with BD in the Turkish, Iranian, and Japanese cohorts [78]. The ADO encodes cysteamine (2-aminoethanethiol) dioxygenase that is involved in amino acid metabolism [139]. The EGR2 encodes early growth response protein 2 that is a transcription factor, and highly expressed in a population of migrating neural crest cells [140]. CEBPB encodes CCAAT/enhancer binding protein beta, a member of the CCAAT/enhancer binding protein family of basic leucine zipper transcription factors. It functions in controlling cell differentiation, proliferation, and inflammation [141]. The PTPN1 gene encodes protein tyrosine phosphatase, nonreceptor type 1 that functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signaling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors [142].

It is worth noting that these BD-linked loci do not directly reflect the association of the corresponding genes, but may be suggestive for further investigation of these

Multiple genes have been associated with BD, and many of them are involved in immune activation and regulation that may suggest their potential biological relevance to chronic inflammatory nature of BD. However, exact pathogenic mechanisms of BD on these genes are still unclear. Like many other immune-regulatory diseases, this multigenic feature of BD underlies complex pathogenesis. Some of the reported associations, for example, TNFAIP3 and TLR4, appeared to be conflict in different study cohorts and/or populations, which suggests that the BD-associated polymorphisms of the genes may be ethnic specific, or sample selection bias may have occurred and further verification may be warranted. In addition, some of the BD-associated genes, for example, HLA-B, ERAP1, MICA, and IL family, have also been reported in other immune-mediated diseases, which supports the shared

genes in terms of their genetic and functional importance to BD.

#### **6.4 SUMO4**

*Different Aspects of Behçet's Disease*

**5.2 NCOA5**

**5.3 FOXP3**

Turkish cohorts [114].

in a Chinese cohort [118].

**6. Other genes**

**6.1 PSORS1C1**

nity [123, 124].

Turkish populations [126].

**6.2 FUT2**

**6.3 UBAC2**

of the UBAC2 gene.

Iranians [36, 103]. Functional studies indicated that the risk allele A of the STAT4 SNP rs897200 was correlated with the increased mRNA level of the STAT4 gene, and with the increased gene and protein expression of IL-17, as well as with BD

Nuclear receptor coactivator-5 (NCOA5) protein regulates nuclear receptor subfamily 1 group D member 2 (NR1D2) and estrogen receptor 1 and 2 (ESR1 and ESR2) [112, 113]. The NCOA5 gene SNP rs2903908 was associated with BD patients, especially those affected with genital ulceration and uveitis in the Finland and the

FOXP3 (forkhead box P3), also known as scurfin, is a member of the FOX protein family of transcription factors. It regulates the development and function of T regulatory (Treg) cells [115, 116]. The FOXP3 SNP rs3761548 was associated with BD in the North-Western Iranian population [117]. In addition, a low copy number variant (CNV) of the FOXP3 gene was reported to confer risk to female BD patients

Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is poorly characterized in terms of its biological function. It is initially recognized as a susceptibility locus to psoriasis [119] and psoriatic arthritis [120]. Recent studies indicated that it is also a shared genetic factor, especially with SNP rs12525170, in other autoimmune diseases including systemic sclerosis [121], Crohn's disease [122], and BD [122]. Therefore, it may play important roles in the pathogenesis of autoimmu-

Fucosyltransferase 2 (FUT2) is involved in synthesis of the H antigen, the precursor of the ABO-histo-blood group antigen in body fluids, and on the intestinal mucosa [125]. The association between the FUT2 gene (rs632111, rs601338, rs602662, rs492602, rs681343, and rs281377) and BD was reported in Iranian and

Ubiquitin-associated domain containing 2 (UBAC2) is another poorly characterized protein, but its gene variants are strongly associated with BD. Limited studies suggest that it may function in protein localization in the endoplasmic reticulum [127]. The association of the UBAC2 gene with BD was found in Turkish, Chinese, Italian, and Japanese populations [128–131]. Functionally, the presence of BD-risk rs9517723 allele was correlated with an increased expression

patients who have a higher clinical severity score [111].

**42**

Small ubiquitin-like modifier 4 (SUMO4) is a member of the SUMO family that post-transcriptionally sumoylates the targeted proteins to regulate their subcellular localization and/or enhance their stability and activity [132]. It is involved in immune regulation by negatively controlling NFκB activity [133]. The genetic association between the SUMO4 (SNPs rs237024, rs237026) and BD was first reported in a Chinese cohort, and that appeared independent from HLA-B51 [134]. The association was replicated in Tunisian and Korean cohorts [135, 136], in which specific polymorphisms were also associated with disease severity, skin lesions, and vascular involvement of BD patients [135, 136].

#### **6.5 LACC1**

LACC1 encodes an oxidoreductase that promotes fatty-acid oxidation. It also functions in activation of inflammasome, bactericidal activity of macrophages, and production of mitochondrial and NADPH-oxidase-dependent reactive oxygen species [137]. SNP rs9316059 of the LACC1 was associated with BD in Turkish, Japanese, and Chinese cohorts [78, 138].

#### **6.6 Loci at ADO-EGR2 and CEBPB-PTPN1**

Two genetic loci between the ADO and the EGR2 genes and the CEBPB and the PTPN1 genes were associated with BD in the Turkish, Iranian, and Japanese cohorts [78]. The ADO encodes cysteamine (2-aminoethanethiol) dioxygenase that is involved in amino acid metabolism [139]. The EGR2 encodes early growth response protein 2 that is a transcription factor, and highly expressed in a population of migrating neural crest cells [140]. CEBPB encodes CCAAT/enhancer binding protein beta, a member of the CCAAT/enhancer binding protein family of basic leucine zipper transcription factors. It functions in controlling cell differentiation, proliferation, and inflammation [141]. The PTPN1 gene encodes protein tyrosine phosphatase, nonreceptor type 1 that functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signaling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors [142].

It is worth noting that these BD-linked loci do not directly reflect the association of the corresponding genes, but may be suggestive for further investigation of these genes in terms of their genetic and functional importance to BD.

#### **7. Conclusion**

Multiple genes have been associated with BD, and many of them are involved in immune activation and regulation that may suggest their potential biological relevance to chronic inflammatory nature of BD. However, exact pathogenic mechanisms of BD on these genes are still unclear. Like many other immune-regulatory diseases, this multigenic feature of BD underlies complex pathogenesis. Some of the reported associations, for example, TNFAIP3 and TLR4, appeared to be conflict in different study cohorts and/or populations, which suggests that the BD-associated polymorphisms of the genes may be ethnic specific, or sample selection bias may have occurred and further verification may be warranted. In addition, some of the BD-associated genes, for example, HLA-B, ERAP1, MICA, and IL family, have also been reported in other immune-mediated diseases, which supports the shared

genetic effects among these diseases. Moreover, specific gene polymorphisms were associated with clinical presentation of BD, for example, HLA-A02:07 with skin lesions and arthritis, HLA-A\*26:01 with uveitis, HLA-A\*30:04 with vascular lesions and genital ulcers, MICA-A5.1 with ocular lesions, and MICA-A9 with neurological and intestinal involvement. Thus, these specific genotypes may be further explored as potential biomarkers for diagnostic or prognostic classification of BD patients.

While the genetic studies have supported multigenic contribution to susceptibility to BD, epigenetic alternations including DNA methylation, histone modifications, and microRNAs regulation have also been reported in BD [143]. Furthermore, there is appealing evidence indicating environmental factors, especially that microorganisms may trigger the disease [144]. Understanding the genetics of BD in conjunction with epigenetics and environmental triggers of BD will provide insights into pathogenesis of the disease and an opportunity to interrogate candidate genes in potential diagnostic and therapeutic applications.

#### **Author details**

Xiaodong Zhou1 \* and Yan Deng2

1 Department of Internal Medicine/Rheumatology, University of Texas Health Science Center at Houston McGovern Medical School, USA

2 The Second Affiliated Hospital of Nanchang University, Nanchang, China

\*Address all correspondence to: xiaodong.zhou@uth.tmc.edu and zhouxd@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**45**

*Genetics of Behçet's Disease*

Diseases. 2012;**12**(7):20

1999;**54**:213-220

2009;**61**:600-604

1988;**15**:820-822

2002;**9**:325-331

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.87080*

clinical characteristics of Behçet's disease? Acta Dermatovenerologica Croatica. 2013;**21**(3):168-173

[9] Davatchi F, Shahram F, Chams-Davatchi C, Sadeghi Abdollahi B, Shams H, Nadji A, et al. Behçet's disease: Is there a gender influence on clinical manifestations? International Journal of Rheumatic Diseases. 2012;**15**:306-314

[10] Ono S, Aoki K, Sugiura S, Nakayama E, Letter IK. HL-A5 and Behçet's disease. Lancet.

[11] Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet's disease. Archives of Ophthalmology. 1982;**100**:1455-1458

[12] Saadoun D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura Z, Resche-Rigon M, et al. Mortality in Behçet's disease. Arthritis and Rheumatism.

[13] Demirseren DD, Ceylan GG, Akoglu G, Emre S, Erten S, Arman A, et al. HLA-B51 subtypes in Turkish patients with Behçet's disease and their correlation with clinical manifestations. Genetics and Molecular Research.

[14] Hamzaoui A, Houman MH, Massouadia M, Ben Salem T, Khanfir MS, Ben Ghorbel I, et al. Contribution of Hla-B51 in the susceptibility and specific clinical features of Behçet's disease in Tunisian patients. European

Journal of Internal Medicine.

[15] Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G, Cantini F, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet's disease. Journal of Rheumatology.

1973;**2**:1383-1384

2010;**62**:2806-2812

2014;**13**:4788-4796

2012;**23**(4):347-349

2001;**28**:1867-1870

[1] Saadoun D, Wechsler B. Behçet's disease. Orphanet Journal of Rare

[2] Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR. Behçet's disease, the silk road and HLA-B51: Historical and geographical perspectives. Tissue Antigens.

[3] Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. HLA and non-HLA genes in Behçet's disease: A multicentric study in the Spanish population: A population-based study. Arthritis and Rheumatism.

[4] Shahram F, Jamshidi AR, Hirbod-Mobarakeh A, Habibi G, Mardani A, Ghaemi M. Scientometric analysis and mapping of scientific articles on Behçet's disease. International Journal of Rheumatic Diseases. 2013;**16**:185-192

[5] Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, et al. Prevalence of Behçet's disease in Istanbul. Turkey International Journal of Dermatology. 2003;**42**:803-806

[6] Yurdakul S, Günaydin I, Tüzün Y, Tankurt N, Pazarli H, Ozyazgan Y, et al. The prevalence of Behçet's syndrome in a rural area in northern Turkey. The Journal of Rheumatology.

[7] Idil A, Gurler A, Boyvat A, Caliskan D, Ozdemir O, Isik A, et al. The prevalence of Behçet's disease above the age of 10 years. The results of a pilot study conducted at the Park primary health care center in Ankara, Turkey. Ophthalmic Epidemiology.

[8] Ozyurt K, Colgecen E, Baykan H. Does familial occurrence or family history of recurrent oral ulcers influence

### **References**

*Different Aspects of Behçet's Disease*

genetic effects among these diseases. Moreover, specific gene polymorphisms were associated with clinical presentation of BD, for example, HLA-A02:07 with skin lesions and arthritis, HLA-A\*26:01 with uveitis, HLA-A\*30:04 with vascular lesions and genital ulcers, MICA-A5.1 with ocular lesions, and MICA-A9 with neurological and intestinal involvement. Thus, these specific genotypes may be further explored as potential biomarkers for diagnostic or prognostic classification of BD patients. While the genetic studies have supported multigenic contribution to susceptibility to BD, epigenetic alternations including DNA methylation, histone modifications, and microRNAs regulation have also been reported in BD [143]. Furthermore, there is appealing evidence indicating environmental factors, especially that microorganisms may trigger the disease [144]. Understanding the genetics of BD in conjunction with epigenetics and environmental triggers of BD will provide insights into pathogenesis of the disease and an opportunity to interrogate

candidate genes in potential diagnostic and therapeutic applications.

**44**

**Author details**

Xiaodong Zhou1

and zhouxd@hotmail.com

provided the original work is properly cited.

\* and Yan Deng2

Science Center at Houston McGovern Medical School, USA

\*Address all correspondence to: xiaodong.zhou@uth.tmc.edu

1 Department of Internal Medicine/Rheumatology, University of Texas Health

2 The Second Affiliated Hospital of Nanchang University, Nanchang, China

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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[3] Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. HLA and non-HLA genes in Behçet's disease: A multicentric study in the Spanish population: A population-based study. Arthritis and Rheumatism. 2009;**61**:600-604

[4] Shahram F, Jamshidi AR, Hirbod-Mobarakeh A, Habibi G, Mardani A, Ghaemi M. Scientometric analysis and mapping of scientific articles on Behçet's disease. International Journal of Rheumatic Diseases. 2013;**16**:185-192

[5] Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, et al. Prevalence of Behçet's disease in Istanbul. Turkey International Journal of Dermatology. 2003;**42**:803-806

[6] Yurdakul S, Günaydin I, Tüzün Y, Tankurt N, Pazarli H, Ozyazgan Y, et al. The prevalence of Behçet's syndrome in a rural area in northern Turkey. The Journal of Rheumatology. 1988;**15**:820-822

[7] Idil A, Gurler A, Boyvat A, Caliskan D, Ozdemir O, Isik A, et al. The prevalence of Behçet's disease above the age of 10 years. The results of a pilot study conducted at the Park primary health care center in Ankara, Turkey. Ophthalmic Epidemiology. 2002;**9**:325-331

[8] Ozyurt K, Colgecen E, Baykan H. Does familial occurrence or family history of recurrent oral ulcers influence clinical characteristics of Behçet's disease? Acta Dermatovenerologica Croatica. 2013;**21**(3):168-173

[9] Davatchi F, Shahram F, Chams-Davatchi C, Sadeghi Abdollahi B, Shams H, Nadji A, et al. Behçet's disease: Is there a gender influence on clinical manifestations? International Journal of Rheumatic Diseases. 2012;**15**:306-314

[10] Ono S, Aoki K, Sugiura S, Nakayama E, Letter IK. HL-A5 and Behçet's disease. Lancet. 1973;**2**:1383-1384

[11] Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet's disease. Archives of Ophthalmology. 1982;**100**:1455-1458

[12] Saadoun D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura Z, Resche-Rigon M, et al. Mortality in Behçet's disease. Arthritis and Rheumatism. 2010;**62**:2806-2812

[13] Demirseren DD, Ceylan GG, Akoglu G, Emre S, Erten S, Arman A, et al. HLA-B51 subtypes in Turkish patients with Behçet's disease and their correlation with clinical manifestations. Genetics and Molecular Research. 2014;**13**:4788-4796

[14] Hamzaoui A, Houman MH, Massouadia M, Ben Salem T, Khanfir MS, Ben Ghorbel I, et al. Contribution of Hla-B51 in the susceptibility and specific clinical features of Behçet's disease in Tunisian patients. European Journal of Internal Medicine. 2012;**23**(4):347-349

[15] Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G, Cantini F, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet's disease. Journal of Rheumatology. 2001;**28**:1867-1870

[16] Kilmartin DJ, Finch A, Acheson RW. Primary association of HLA-B51 with Behçet's disease in Ireland. British Journal of Ophthalmology. 1997;**81**:649-653

[17] Lennikov A, Alekberova Z, Goloeva R, Kitaichi N, Denisov L, Namba K, et al. Single center study on ethnic and clinical features of Behçet's disease in Moscow, Russia. Clinical Rheumatology. 2015;**34**:321-327

[18] Paul M, Klein T, Krause I, Molad Y, Narinsky R, Weinberger A. Allelic distribution of HLA-B\*5 in HLA-B5-positive Israeli patients with Behçet's disease. Tissue Antigens. 2001;**58**:185-186

[19] Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Shiina T, et al. Sequencing-based typing of HLA-B\*51 alleles and the significant association of HLA-B\*5101 and -B\*5108 with Behçet's disease in Greek patients. Tissue Antigens. 2002;**59**:118-121

[20] Koumantaki Y, Stavropoulos C, Spyropoulou M, Messini H, Papademetropoulos M, Giziaki E, et al. HLA-B5101 in Greek patients with Behçet's disease. Human Immunology. 1998;**59**:250-255

[21] Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Yoshida M, et al. HLA class I genotyping including HLA-B\*51 allele typing in the Iranian patients with Behçet's disease. Tissue Antigens. 2001;**57**:457-462

[22] Ortiz-Fernández L, Carmona FD, Montes-Cano MA, García-Lozano JR, Conde-Jaldón M, Ortego-Centeno N, et al. Genetic analysis with the immunochip platform in Behçet disease. Identification of residues associated in the HLA Class I region and new susceptibility loci. PLoS One. 2016;**11**:e0161305

[23] de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr

A. HLA-B51/B5 and the risk of Behçet's disease: A systematic review and meta-analysis of case-control genetic association studies. Arthritis and Rheumatism. 2009;**61**:1287-1296

[24] Montes-Cano MA, Conde-Jaldón M, García-Lozano JR, et al. HLA and non-HLA genes in Behçet's disease: A multicentric study in the Spanish population. Arthritis Research & Therapy. 2013;**15**:145

[25] Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet's disease: A comprehensive review. Journal of Autoimmunity. 2015;**64**:137-148

[26] Radouane A, Oudghiri M, Chakib A, Naya A, Belhouari A, El Malki A, et al. HLA-B\*27 allele associated to Behçet's disease and to anterior uveitis in Moroccan patients. Annales de Biologie Clinique. 2011;**69**:419-424

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*Different Aspects of Behçet's Disease*

Primary association of HLA-B51 with Behçet's disease in Ireland. British Journal of Ophthalmology.

[17] Lennikov A, Alekberova Z, Goloeva R, Kitaichi N, Denisov L, Namba K, et al. Single center study on ethnic and clinical features of Behçet's disease in Moscow, Russia. Clinical Rheumatology. 2015;**34**:321-327

[18] Paul M, Klein T, Krause I, Molad Y, Narinsky R, Weinberger A. Allelic distribution of HLA-B\*5 in HLA-B5-positive Israeli patients with Behçet's disease. Tissue Antigens.

[19] Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Shiina T, et al. Sequencing-based typing of HLA-B\*51 alleles and the significant association of HLA-B\*5101 and -B\*5108 with Behçet's disease in Greek patients. Tissue Antigens. 2002;**59**:118-121

[20] Koumantaki Y, Stavropoulos C,

[21] Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Yoshida M, et al. HLA class I genotyping including HLA-B\*51 allele typing in the Iranian patients with Behçet's disease. Tissue Antigens.

[22] Ortiz-Fernández L, Carmona FD, Montes-Cano MA, García-Lozano JR, Conde-Jaldón M, Ortego-Centeno N, et al. Genetic analysis with the immunochip platform in Behçet disease. Identification of residues associated in the HLA Class I region and new susceptibility loci. PLoS One.

[23] de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr

Papademetropoulos M, Giziaki E, et al. HLA-B5101 in Greek patients with Behçet's disease. Human Immunology.

Spyropoulou M, Messini H,

1998;**59**:250-255

2001;**57**:457-462

2016;**11**:e0161305

1997;**81**:649-653

2001;**58**:185-186

[16] Kilmartin DJ, Finch A, Acheson RW.

A. HLA-B51/B5 and the risk of Behçet's disease: A systematic review and meta-analysis of case-control genetic association studies. Arthritis and Rheumatism. 2009;**61**:1287-1296

[24] Montes-Cano MA, Conde-Jaldón M, García-Lozano JR, et al. HLA and non-HLA genes in Behçet's disease: A multicentric study in the Spanish population. Arthritis Research &

[26] Radouane A, Oudghiri M, Chakib A, Naya A, Belhouari A, El Malki A, et al. HLA-B\*27 allele associated to Behçet's disease and to anterior uveitis in Moroccan patients. Annales de Biologie

[27] Al Mosawi ZS, Madan W, Fareed E. Pediatric-onset Behçet disease in Bahrain: Report of nine cases and literature review. Archives of Iranian Medicine. 2012;**15**(8):485-487

[28] Meguro A, Inoko H, Ota M, Katsuyama Y, Oka A, Okada E, et al. Genetics of Behçet disease inside and outside the MHC. Annals of the Rheumatic Diseases. 2010;**69**:747-754

[29] Al-Okaily F, Al-Rashidi S, Al-Balawi M, Mustafa M, Arfin M, Al-Asmari A. Genetic association of HLA-A\*26, -A\*31, and -B\*51 with Behçet's disease in Saudi patients. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders.

[30] Kaburaki T, Takamoto M, Numaga J, Kawashima H, Araie M, Ohnogi Y, et al. Genetic association of HLA-A\*2601 with ocular Behçet's disease in Japanese patients. Clinical and Experimental Rheumatology. 2010;**28**:S39-S44

2016;**9**:167-173

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[112] Zervou MI, Goulielmos GN, Castro-Giner F, Boumpas DT, Tosca AD, Krueger-Krasagakis S. A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a southern European population: A casecontrol study. Human Immunology. 2011;**72**:761-765

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[114] Rustemoglu A, Erkol Inal E, Inanir A, Ekinci D, Gul U, Yigit S, et al. Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet's disease. EXCLI Journal. 2017;**16**:609-617

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[117] Hosseini A, Shanehbandi D, Estiar MA, Gholizadeh S, Khabbazi A, Khodadadi H, et al. A single nucleotide polymorphism in the FOXP3 gene associated with Behçet's disease in an Iranian population. Clinical Laboratory. 2015;**61**(12):1897-1903

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[119] Holm SJ, Carlén LM, Mallbris L, Ståhle-Bäckdahl M, O'Brien KP. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Experimental Dermatology. 2003;**12**:435-444

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2007;**56**:2056-2064

2009;**26**:1993-2003

Diseases. 2015;**74**:618-624

2013;**110**:1345-1350

2009;**11**:R66

*DOI: http://dx.doi.org/10.5772/intechopen.87080*

mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genetics.

confirms the association between UBAC2 and Behçet's disease in two independent Chinese sets of patients and controls. Arthritis Research &

Therapy. 2012;**14**:R70

2017;**7**:742-747

2004;**36**:837-841

[131] Yamazoe K, Meguro A, Takeuchi M, Shibuya E, Ohno S, Mizuki N. Comprehensive analysis of the association between UBAC2 polymorphisms and Behçet's disease in a Japanese population. Scientific Reports.

[132] Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D'Arpa P. Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin. The Journal of Biological Chemistry. 2002;**277**:40020-40026

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[134] Hou S, Yang P, Du L, Zhou H, Lin X, Liu X, et al. SUMO4 gene polymorphisms in Chinese Han patients with Behçet's disease. Clinical Immunology. 2008;**129**:170-175

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2010;**28**(Suppl. 60):S45-S49

2012;**32**:3031-3037

[136] Park G, Kim HS, Choe JY, Kim SK. SUMO4 C438T polymorphism is associated with papulopustular skin lesion in Korean patients with Behçet's disease. Rheumatology International.

[137] Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW,

[124] Reich K, Hüffmeier U, König IR, Lascorz J, Lohmann J, Wendler J, et al. TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphism TNF\*- 857 independent of the PSORS1 risk allele. Arthritis and Rheumatism.

[125] Ferrer-Admetlla A, Sikora M, Laayouni H, Esteve A, Roubinet F, Blancher A, et al. A natural history of FUT2 polymorphism in humans. Molecular Biology and Evolution.

[126] Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, et al. FUT2: Filling the gap between genes and environment in Behçet's disease? Annals of the Rheumatic

[127] Olzmann JA, Richter CM, Kopito RR.

Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences of the United States of America.

[128] Fei Y, Webb R, Cobb BL,

Direskeneli H, Saruhan-Direskeneli G, Sawalha AH. Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study. Arthritis Research & Therapy.

[129] Sawalha AH, Hughes T, Nadig A, Yılmaz V, Aksu K, Keser G, et al. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease. Arthritis and Rheumatism. 2011;**63**:3607-3612

[130] Hou S, Shu Q, Jiang Z, Chen Y, Li F, Chen F, et al. Replication study

#### *Genetics of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.87080*

*Different Aspects of Behçet's Disease*

of Sciences of the United States of America. 2002;**99**:12281-12286

MacIsaac KD, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature.

[117] Hosseini A, Shanehbandi D, Estiar MA, Gholizadeh S, Khabbazi A, Khodadadi H, et al. A single nucleotide polymorphism in the FOXP3 gene associated with Behçet's disease in an Iranian population. Clinical Laboratory.

[118] Liao D, Hou S, Zhang J, Fang J, Liu Y, Bai L, et al. Copy number variants and genetic polymorphisms in TBX21, GATA3, Rorc, Foxp3 and susceptibility to Behçet's disease and Vogt-Koyanagi-Harada syndrome. Scientific Reports.

[119] Holm SJ, Carlén LM, Mallbris L, Ståhle-Bäckdahl M, O'Brien KP. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population.

Experimental Dermatology.

Diseases. 2005;**64**:1370-1372

[121] Bossini-Castillo L, Martin JE, Broen J, Simeon CP, Beretta L, Gorlova OY, et al. Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Annals of the Rheumatic Diseases.

[122] Peddle L, Zipperlen K, Melay B, Hefferton D, Rahman P. Association of SEEK1 polymorphisms in Crohn's disease. Human Immunology.

[123] Fan X, Yang S, Huang W, Wang ZM,

Sun LD, Liang YH, et al. Fine

[120] Rahman P, Butt C, Siannis F, Farewell VT, Peddle L, Pellett FJ, et al. Association of SEEK1 and psoriatic arthritis in two distinct Canadian populations. Annals of the Rheumatic

2003;**12**:435-444

2013;**72**:602-607

2004;**65**:706-709

2007;**445**(7130):931-935

2015;**61**(12):1897-1903

2015;**5**:9511

[109] Kim J, Park JA, Lee EY, Lee YJ, Song YW, Lee EB. Imbalance of Th17 to Th1 cells in Behçet's disease. Clinical and Experimental Rheumatology.

[110] Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. Journal of Immunology. 2007;**178**:4901-4907

[111] Hou S, Yang Z, Du L, Jiang Z, Shu Q, Chen Y, et al. Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genomewide association study. Arthritis and Rheumatism. 2012;**64**:4104-4113

[112] Zervou MI, Goulielmos GN, Castro-Giner F, Boumpas DT, Tosca AD, Krueger-Krasagakis S. A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a southern European population: A casecontrol study. Human Immunology.

[113] Böser A, Drexler HC, Reuter H, Schmitz H, Wu G, Schöler HR, et al. SILAC proteomics of planarians identifies NCOA5 as a conserved component of pluripotent stem cells. Cell Reports. 2013;**5**:1142-1155

[114] Rustemoglu A, Erkol Inal E, Inanir A, Ekinci D, Gul U, Yigit S, et al. Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet's disease. EXCLI Journal. 2017;**16**:609-617

[115] Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity.

[116] Marson A, Kretschmer K,

Frampton GM, Jacobsen ES, Polansky JK,

2005;**22**(3):329-341

2010;**28**:S16-S19

2011;**72**:761-765

**52**

mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genetics. 2008;**4**:e1000038

[124] Reich K, Hüffmeier U, König IR, Lascorz J, Lohmann J, Wendler J, et al. TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphism TNF\*- 857 independent of the PSORS1 risk allele. Arthritis and Rheumatism. 2007;**56**:2056-2064

[125] Ferrer-Admetlla A, Sikora M, Laayouni H, Esteve A, Roubinet F, Blancher A, et al. A natural history of FUT2 polymorphism in humans. Molecular Biology and Evolution. 2009;**26**:1993-2003

[126] Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, et al. FUT2: Filling the gap between genes and environment in Behçet's disease? Annals of the Rheumatic Diseases. 2015;**74**:618-624

[127] Olzmann JA, Richter CM, Kopito RR. Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences of the United States of America. 2013;**110**:1345-1350

[128] Fei Y, Webb R, Cobb BL, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH. Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study. Arthritis Research & Therapy. 2009;**11**:R66

[129] Sawalha AH, Hughes T, Nadig A, Yılmaz V, Aksu K, Keser G, et al. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease. Arthritis and Rheumatism. 2011;**63**:3607-3612

[130] Hou S, Shu Q, Jiang Z, Chen Y, Li F, Chen F, et al. Replication study confirms the association between UBAC2 and Behçet's disease in two independent Chinese sets of patients and controls. Arthritis Research & Therapy. 2012;**14**:R70

[131] Yamazoe K, Meguro A, Takeuchi M, Shibuya E, Ohno S, Mizuki N. Comprehensive analysis of the association between UBAC2 polymorphisms and Behçet's disease in a Japanese population. Scientific Reports. 2017;**7**:742-747

[132] Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D'Arpa P. Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin. The Journal of Biological Chemistry. 2002;**277**:40020-40026

[133] Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nature Genetics. 2004;**36**:837-841

[134] Hou S, Yang P, Du L, Zhou H, Lin X, Liu X, et al. SUMO4 gene polymorphisms in Chinese Han patients with Behçet's disease. Clinical Immunology. 2008;**129**:170-175

[135] Kamoun M, Ben Dhifallah I, Karray E, Zakraoui L, Hamzaoui K. Association of small ubiquitin-like modifier 4 (SUMO4) polymorphisms in a Tunisian population with Behçet's disease. Clinical and Experimental Rheumatology. 2010;**28**(Suppl. 60):S45-S49

[136] Park G, Kim HS, Choe JY, Kim SK. SUMO4 C438T polymorphism is associated with papulopustular skin lesion in Korean patients with Behçet's disease. Rheumatology International. 2012;**32**:3031-3037

[137] Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW,

et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology. 2016;**17**:1046-1056

[138] Wu P, Du L, Hou S, Su G, Yang L, Hu J, et al. Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behçet's disease in a Chinese Han population. The British Journal of Ophthalmology. 2018;**102**:1308-1314

[139] Sarkar B, Kulharia M, Mantha AK. Understanding human thiol dioxygenase enzymes: Structure to function, and biology to pathology. International Journal of Experimental Pathology. 2017;**98**:52-66

[140] Wilkinson DG, Bhatt S, Chavrier P, et al. Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Nature. 1989;**337**(6206):461-464

[141] Nerlov C. The C/EBP family of transcription factors: A paradigm for interaction between gene expression and proliferation control. Trends in Cell Biology. 2007;**17**:318-324

[142] Sanford SM, Bottini N. PTPN22: The archetypal non-HLA autoimmunity gene. Nature Reviews Rheumatology. 2014;**10**:602-611

[143] Alipour S, Nouri M, Sakhinia E, Samadi N, Roshanravan N, Ghavami A, et al. Epigenetic alterations in chronic disease focusing on Behçet's disease: Review. Biomedicine & Pharmacotherapy. 2017;**91**:526-533

[144] Hatemi G, Yazici H. Behçet's syndrome and micro-organisms. Best Practice & Research. Clinical Rheumatology. 2011;**25**:389-406

**55**

**Chapter 4**

**Abstract**

**1. Introduction**

bation of BD.

disease [5, 6].

and an autoinflammatory disease.

The Role of Th17 Cells in the

*Yuki Nanke and Shigeru Kotake*

chapter, we review the pathogenic role of Th17 cells in BD.

**Keywords:** IL-17, Th17, Th1, Behçet's disease, regulatory T cells

Pathogenesis of Behçet's Disease

Behçet's disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. BD is now categorized as both autoimmune diseases and auto inflammatory diseases. The pathogenesis of BD is still unclear; however, BD has been thought as a Th1-related disease, with elevating levels of Th1 cytokines such as IFN-γ, TNF-α, and IL-2. Some investigators found that Th17-associated cytokines were elevated in patients with BD; thus, IL-17/IL-23 pathway and Th17 cells may have crucial roles in the pathogenesis of BD. In this

BD is a systemic vasculitis and polysymptomatic [1, 2] and characterized by recurrent aphthous stomatitis, genital ulcers, uveitis, and skin lesions. Arthritis is also a common manifestation of BD, and sometimes inflammation is involved in the gastrointestinal tract as well as vascular and central nervous systems. The cause of BD is not fully understood. BD is now categorized as both an autoimmune disease

The association between carriage of the human leukocyte antigen (HLA) B51 allele and BD has been known in different ethnic groups. Recently, the genomewide studies showed the association of some non-histocompatibility complex (MHC) genes, including IL-23R-IL-12 RB 2 and IL-10 genes [3, 4]. The pathogenesis of BD has not been fully elucidated; in addition to genetic factors, cytokines, viral and bacterial agents, and immune dysfunction are associated with the exacer-

CD4+ T cells and neutrophils play an important role in the pathogenesis of BD. Since IL-12 and IFN-γ from Th1 cells can mediate the inflammatory response between neutrophils and T cells, BD has been considered as a Th1-mediated

Th17 cells play an important role in immunity. Th17 cell differentiation from naïve CD4+ T cells is assisted by IL-6, IL-21, IL-1β, and IL-23. The critical feature of Th17 cells is the expression of IL-17A, IL-17F, IL-22, IL-6, IL-8, and IL-26, and TNF-α expresses RAR-related orphan receptor (ROR) γ. The current studies suggest that Th17 axis plays a pivotal role in BD pathogenesis. IL-17 has been shown to recruit neutrophils to the site of inflammation. Abnormalities in the T cell response cause the hyperreactivity of neutrophils in BD through the production of cytokines,

such as IL-17 [7]. We discuss the pathogenic role of Th17 cells in BD.

#### **Chapter 4**

*Different Aspects of Behçet's Disease*

2016;**17**:1046-1056

et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology.

[138] Wu P, Du L, Hou S, Su G, Yang L, Hu J, et al. Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behçet's disease in a Chinese Han population. The British Journal of Ophthalmology. 2018;**102**:1308-1314

[139] Sarkar B, Kulharia M, Mantha AK.

[140] Wilkinson DG, Bhatt S, Chavrier P, et al. Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Nature.

[141] Nerlov C. The C/EBP family of transcription factors: A paradigm for interaction between gene expression and proliferation control. Trends in Cell

[142] Sanford SM, Bottini N. PTPN22: The archetypal non-HLA autoimmunity gene. Nature Reviews Rheumatology.

[143] Alipour S, Nouri M, Sakhinia E, Samadi N, Roshanravan N, Ghavami A,

et al. Epigenetic alterations in chronic disease focusing on Behçet's disease: Review. Biomedicine & Pharmacotherapy. 2017;**91**:526-533

[144] Hatemi G, Yazici H. Behçet's syndrome and micro-organisms. Best Practice & Research. Clinical Rheumatology. 2011;**25**:389-406

Understanding human thiol dioxygenase enzymes: Structure to function, and biology to pathology. International Journal of Experimental

Pathology. 2017;**98**:52-66

1989;**337**(6206):461-464

Biology. 2007;**17**:318-324

2014;**10**:602-611

**54**

## The Role of Th17 Cells in the Pathogenesis of Behçet's Disease

*Yuki Nanke and Shigeru Kotake*

#### **Abstract**

Behçet's disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. BD is now categorized as both autoimmune diseases and auto inflammatory diseases. The pathogenesis of BD is still unclear; however, BD has been thought as a Th1-related disease, with elevating levels of Th1 cytokines such as IFN-γ, TNF-α, and IL-2. Some investigators found that Th17-associated cytokines were elevated in patients with BD; thus, IL-17/IL-23 pathway and Th17 cells may have crucial roles in the pathogenesis of BD. In this chapter, we review the pathogenic role of Th17 cells in BD.

**Keywords:** IL-17, Th17, Th1, Behçet's disease, regulatory T cells

#### **1. Introduction**

BD is a systemic vasculitis and polysymptomatic [1, 2] and characterized by recurrent aphthous stomatitis, genital ulcers, uveitis, and skin lesions. Arthritis is also a common manifestation of BD, and sometimes inflammation is involved in the gastrointestinal tract as well as vascular and central nervous systems. The cause of BD is not fully understood. BD is now categorized as both an autoimmune disease and an autoinflammatory disease.

The association between carriage of the human leukocyte antigen (HLA) B51 allele and BD has been known in different ethnic groups. Recently, the genomewide studies showed the association of some non-histocompatibility complex (MHC) genes, including IL-23R-IL-12 RB 2 and IL-10 genes [3, 4]. The pathogenesis of BD has not been fully elucidated; in addition to genetic factors, cytokines, viral and bacterial agents, and immune dysfunction are associated with the exacerbation of BD.

CD4+ T cells and neutrophils play an important role in the pathogenesis of BD. Since IL-12 and IFN-γ from Th1 cells can mediate the inflammatory response between neutrophils and T cells, BD has been considered as a Th1-mediated disease [5, 6].

Th17 cells play an important role in immunity. Th17 cell differentiation from naïve CD4+ T cells is assisted by IL-6, IL-21, IL-1β, and IL-23. The critical feature of Th17 cells is the expression of IL-17A, IL-17F, IL-22, IL-6, IL-8, and IL-26, and TNF-α expresses RAR-related orphan receptor (ROR) γ. The current studies suggest that Th17 axis plays a pivotal role in BD pathogenesis. IL-17 has been shown to recruit neutrophils to the site of inflammation. Abnormalities in the T cell response cause the hyperreactivity of neutrophils in BD through the production of cytokines, such as IL-17 [7]. We discuss the pathogenic role of Th17 cells in BD.

#### **2. Th17 in mouse model**

In mice, the combination of IL-6 and TGF-β plays a critical role in the development of Th17 cells from naive T cells. Th17 cells play important roles in the pathogenesis of intraocular inflammation in an animal model of uveitis [8–10]. Anti-mouse IL-17 blocking antibodies are effective for intraocular inflammation in experimental models of uveitis [11].

Inhibition of the expression of TNF-α [12], and the downregulation of IL-6 [13] improved the inflammation in BD mice by the upregulation of Th17 cells. Foxp3 may inhibit Th17 differentiation by antagonizing the function of RORγt, the master transcription factor. It is reported that anti-TNF-α blockade may prevent the differentiation of Th17 cells in animal models for BD [14]. γδ T cells produce IL-17 and may play an important role in experimental uveitis in animal models [10].

#### **3. Th17 in humans**

#### **3.1 Plasma IL-17 levels in BD**

In humans, IL-23 and IL-1β are needed for the development of Th17 cells. IL-17 levels were markedly elevated in BD [15–20]. Some investigators [22, 23] reported that the ability to produce IL-17A and amount of circulating Th17 cells were increased in active BD patients. Increased levels of IL-17 may induce neutrophil activity [22].

It is reported that the ability to produce IL-17A and population of Th17 cells are enhanced in active BD despite the low expression of RORγt mRNA [21]. Chi et al. reported that elevated levels of IL-17A, IL-23, and IFN-γ in the aqueous fluid from the eyes as well as in peripheral blood of BD patients [23, 24].

#### **3.2 Circulating Th17 cell frequencies are correlated with disease activity**

It is reported that the significantly higher frequency of circulating Th17 cells are detected in active BD patients compared with the same patients in remission stages [21]. A positive correlation was seen between the plasma IL-17 level and ESR or CRP in active BD patients [21]. It has been reported that the peripheral blood Th17/Th1 ratio was markedly higher in patients with active BD than the healthy controls [25, 26] and that in BD patients with folliculitis or uveitis, the Th17/Th1 ratio was elevated [23, 24]. Thus, the balance of Th1 and Th17 cells plays an important role in the pathogenesis of BD, especially in the pathogenesis of folliculitis and uveitis. Moreover, the high expression of IL-23p19 mRNA was detected in the erythema nodosum (EN)-like lesion of BD [27].

A significant increase in IL-17- and IFN-γ-expressing CD4+ memory T cells was observed in patients with active BD compared with control groups [28]. Similarly, the levels of IL-17, IL-23, IL-12/IL-23p40, and IFN-γ in serum and supernatants were increased in active BD patients compared with control groups [28]. IFN-γsecreting Th17 cells were elevated in BD patients [27–29]. Touzot M et al. reported that IL-17 was not inhibited by IFN-α in BD and IFN-α increased IFN-γ level in memory CD4+ T cells in BD [31]. Thus, BD is associated with a mixture of TH1/ Th17 cytokine.

Patients with BD in remission expressed low Th17 levels compared to active BD [21, 24, 28]. Thus, the population of Th17 cells is correlated with BD activity [16, 22].

More recently, Lucherini et al. [32] reported that serum amyloid A (SAA) induced Th17 polarization rather than Th1 differentiation from CD4+ T cells in BD

**57**

*The Role of Th17 Cells in the Pathogenesis of Behçet's Disease*

patients. A critical regulation of Th17 may be the functional link between acute SAA

Deniz et al. [33] reported that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in BD. In addition, they speculated that more prominent IL-17 and IFN-γ production by all lymphocyte subsets in BD may be associated with the increased innate responses, early tissue neutrophil infiltrations, and late adaptive

increase and the induction of Th17-mediated inflammatory response in BD.

Recently, it is reported that IL-23R is principal for the differentiation of IL-17-producing effector T cells in vivo [34]. IL-23 was essential to preserve and to generate Th17 cells even in the absence of TGF-β [35]. The IL-23-IL-17 axis is crucial for the inflammation in BD [23]. Elevated levels of IL-23 and IL-17 [21, 28] were seen in peripheral blood mononuclear cells (PBMC) from active BD patients [23]. Recombinant IL-23 stimulated IL-17 in CD4+ T cells in BD patients [15, 23]. Recently, IL-23R, IL-12RB2, and IL-10 were identified as BD susceptibility loci by genetic surveys including GWAS [3, 4]. It is reported that the genetic variation of IL-17F and IL-23 A is associated with BD [36]. Jiang et al. [37] reported that IL-23R gene polymorphism enhanced the expression of the IL-23 R and IL-17 in BD patients.

**3.4 The suppressive effect of IL-27 on Th17 cell differentiation**

IL-27 is a regulator of the proinflammatory T cell response. In mouse, IL-27 plays a negative role in Th17 cell differentiation. It is reported that decreased level of IL-27 in patients with active BD [38] and decreased IL-27 expression was correlated with uveitis activity in patients with BD [38]. IL-27 inhibited human Th17 cell differentiation by upregulation of the expression of interferon regulatory factor (IRF) 8 [38]. Previous

It was reported that the expression of IL-21 was elevated in the serum of active

cerebrospinal fluid and bronchoalveolar lavage fluid in BD patients showed positive

Some investigators reported that IL-17 [15, 41], IL-23, and IFN-γ in the sera and aqueous humor significantly increased in BD patients with active uveitis compared with BD patients without active uveitis and HC [23]. It is also reported that IFN-γproducing and IL-17-producing T cells in BD patients with active uveitis were increased [15, 23, 38]. Thus, the IL-23/IL-17 pathway plays an important role in active uveitis in BD patients. Activated CD4+ T cells obtained from BD patients produce TNF-α in vitro. Chi et al. demonstrated that IL-12 exerted its inhibitory effect on IL-17 through IFN-γ. They also reported that recombinant-IL-23 (rIL-23) can promote the production of IL-17 by CD4+ T cells in BD patients [23]. Jiang et al. reported an association of rs17375018 in the IL-23R gene with uveitis in BD patients [41]. Taken together, elevated levels of IL-17 may

T cells and monocytes promote

studies have shown that the presence of IL-27 limits Th17-mediated uveitis [39].

BD patiens, and that this promoted Th17 differentiation [16]. IL-26 levels in

the generation of Th17 and suppress regulatory T cell cytokines [40].

be associated with the intraocular inflammation of BD patients [15, 23].

correlations with IL-17 level. IL-26-stimulated CD4+

*DOI: http://dx.doi.org/10.5772/intechopen.88361*

immunity in BD.

**3.3 IL-23-IL-17 axis**

**4. IL-21 and IL-26 in BD**

**5. Uveitis in BD**

#### *The Role of Th17 Cells in the Pathogenesis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.88361*

patients. A critical regulation of Th17 may be the functional link between acute SAA increase and the induction of Th17-mediated inflammatory response in BD.

Deniz et al. [33] reported that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in BD. In addition, they speculated that more prominent IL-17 and IFN-γ production by all lymphocyte subsets in BD may be associated with the increased innate responses, early tissue neutrophil infiltrations, and late adaptive immunity in BD.

#### **3.3 IL-23-IL-17 axis**

*Different Aspects of Behçet's Disease*

**2. Th17 in mouse model**

**3. Th17 in humans**

activity [22].

lesion of BD [27].

Th17 cytokine.

**3.1 Plasma IL-17 levels in BD**

experimental models of uveitis [11].

In mice, the combination of IL-6 and TGF-β plays a critical role in the development of Th17 cells from naive T cells. Th17 cells play important roles in the pathogenesis of intraocular inflammation in an animal model of uveitis [8–10]. Anti-mouse IL-17 blocking antibodies are effective for intraocular inflammation in

Inhibition of the expression of TNF-α [12], and the downregulation of IL-6 [13] improved the inflammation in BD mice by the upregulation of Th17 cells. Foxp3 may inhibit Th17 differentiation by antagonizing the function of RORγt, the master transcription factor. It is reported that anti-TNF-α blockade may prevent the differentiation of Th17 cells in animal models for BD [14]. γδ T cells produce IL-17 and

In humans, IL-23 and IL-1β are needed for the development of Th17 cells. IL-17 levels were markedly elevated in BD [15–20]. Some investigators [22, 23] reported that the ability to produce IL-17A and amount of circulating Th17 cells were increased in active BD patients. Increased levels of IL-17 may induce neutrophil

It is reported that the ability to produce IL-17A and population of Th17 cells are enhanced in active BD despite the low expression of RORγt mRNA [21]. Chi et al. reported that elevated levels of IL-17A, IL-23, and IFN-γ in the aqueous fluid from

It is reported that the significantly higher frequency of circulating Th17 cells are detected in active BD patients compared with the same patients in remission stages [21]. A positive correlation was seen between the plasma IL-17 level and ESR or CRP in active BD patients [21]. It has been reported that the peripheral blood Th17/Th1 ratio was markedly higher in patients with active BD than the healthy controls [25, 26] and that in BD patients with folliculitis or uveitis, the Th17/Th1 ratio was elevated [23, 24]. Thus, the balance of Th1 and Th17 cells plays an important role in the pathogenesis of BD, especially in the pathogenesis of folliculitis and uveitis. Moreover, the high expression of IL-23p19 mRNA was detected in the erythema nodosum (EN)-like

A significant increase in IL-17- and IFN-γ-expressing CD4+ memory T cells was observed in patients with active BD compared with control groups [28]. Similarly, the levels of IL-17, IL-23, IL-12/IL-23p40, and IFN-γ in serum and supernatants were increased in active BD patients compared with control groups [28]. IFN-γsecreting Th17 cells were elevated in BD patients [27–29]. Touzot M et al. reported that IL-17 was not inhibited by IFN-α in BD and IFN-α increased IFN-γ level in memory CD4+ T cells in BD [31]. Thus, BD is associated with a mixture of TH1/

Patients with BD in remission expressed low Th17 levels compared to active BD [21, 24, 28]. Thus, the population of Th17 cells is correlated with BD activity [16, 22]. More recently, Lucherini et al. [32] reported that serum amyloid A (SAA) induced Th17 polarization rather than Th1 differentiation from CD4+ T cells in BD

**3.2 Circulating Th17 cell frequencies are correlated with disease activity**

the eyes as well as in peripheral blood of BD patients [23, 24].

may play an important role in experimental uveitis in animal models [10].

**56**

Recently, it is reported that IL-23R is principal for the differentiation of IL-17-producing effector T cells in vivo [34]. IL-23 was essential to preserve and to generate Th17 cells even in the absence of TGF-β [35]. The IL-23-IL-17 axis is crucial for the inflammation in BD [23]. Elevated levels of IL-23 and IL-17 [21, 28] were seen in peripheral blood mononuclear cells (PBMC) from active BD patients [23]. Recombinant IL-23 stimulated IL-17 in CD4+ T cells in BD patients [15, 23]. Recently, IL-23R, IL-12RB2, and IL-10 were identified as BD susceptibility loci by genetic surveys including GWAS [3, 4]. It is reported that the genetic variation of IL-17F and IL-23 A is associated with BD [36]. Jiang et al. [37] reported that IL-23R gene polymorphism enhanced the expression of the IL-23 R and IL-17 in BD patients.

#### **3.4 The suppressive effect of IL-27 on Th17 cell differentiation**

IL-27 is a regulator of the proinflammatory T cell response. In mouse, IL-27 plays a negative role in Th17 cell differentiation. It is reported that decreased level of IL-27 in patients with active BD [38] and decreased IL-27 expression was correlated with uveitis activity in patients with BD [38]. IL-27 inhibited human Th17 cell differentiation by upregulation of the expression of interferon regulatory factor (IRF) 8 [38]. Previous studies have shown that the presence of IL-27 limits Th17-mediated uveitis [39].

#### **4. IL-21 and IL-26 in BD**

It was reported that the expression of IL-21 was elevated in the serum of active BD patiens, and that this promoted Th17 differentiation [16]. IL-26 levels in cerebrospinal fluid and bronchoalveolar lavage fluid in BD patients showed positive correlations with IL-17 level. IL-26-stimulated CD4+ T cells and monocytes promote the generation of Th17 and suppress regulatory T cell cytokines [40].

#### **5. Uveitis in BD**

Some investigators reported that IL-17 [15, 41], IL-23, and IFN-γ in the sera and aqueous humor significantly increased in BD patients with active uveitis compared with BD patients without active uveitis and HC [23]. It is also reported that IFN-γproducing and IL-17-producing T cells in BD patients with active uveitis were increased [15, 23, 38]. Thus, the IL-23/IL-17 pathway plays an important role in active uveitis in BD patients. Activated CD4+ T cells obtained from BD patients produce TNF-α in vitro. Chi et al. demonstrated that IL-12 exerted its inhibitory effect on IL-17 through IFN-γ. They also reported that recombinant-IL-23 (rIL-23) can promote the production of IL-17 by CD4+ T cells in BD patients [23]. Jiang et al. reported an association of rs17375018 in the IL-23R gene with uveitis in BD patients [41]. Taken together, elevated levels of IL-17 may be associated with the intraocular inflammation of BD patients [15, 23].

#### **6. Oral and genital ulcer and articular symptoms**

Alpsoy et al. reported that IL-17 levels of BD patients with active stages of oral and genial ulcers and articular symptoms were higher than BD patients with inactive stages of these symptoms [42]. They also found that the percentage of CD4+ IL-17+, IL-17, and CD4− IL-17+ T cells was significantly elevated after *E. coli* and PHA stimulation in active organ involvement.

#### **7. Skin**

Hamzaoui et al. confirmed that the presence of an important population of IL-17+ cells infiltrates the erythema nodosum-like eruption in BD skin lesions using antibodies to IL-17A [21]. Shimizu et al. demonstrated that IFN-γ + IL-17 + -producing cells were dominant, and some of them were CD4+ cells in BD-EN compared with healthy controls [30]. Th17 cells are elevated in circulation and distribution over the skin lesions of BD patient. Ekinci et al. reported that serum IL-17A levels were markedly elevated in BD patients with active stages of oral ulcers or genital ulcers compared with inactive stage of these symptoms [22]. They also studied the proportion of IL-17-secreting cells in patients with active organ involvement, showing that the percentage of IL-17, CD4− IL-17+ cells, and CD4+ IL-17+ cells was significantly elevated [20, 22]. This finding indicated that Th17 and IL-17 pathway has a crucial role in the acute attack of the disease.

#### **8. Entero-BD**

Gastrointestinal involvement is an important complication of BD. Emmi et al. [43] found that T cells at the intestinal mucosal level produce a high amount of TNF-α and in the early stage of BD. Both Th17 and Th1 cells drive inflammation and mucosal damage though long-lasting cytokine production [44]. Imamura et al. reported the infiltration of CD4+ and CD8+ T cells in the intestine of BD patient, like the expression of mRNAs of proinflammatory and Th1 cytokines/chemokines [45]. Recently, IL-17A, IL-23R, and STAT4 polymorphisms may be involved in the pathogenesis of intestinal involvement in Korean BD patients [46]. On the other hand, Ferrante et al. reported that the serum and mRNA level of IL-23 and IL-17 in entero-BD were not different from those with control groups; thus a Th1 but not a Th17 response occurs with entero-BD [47]. More studies are needed to reveal the role of IL-17 in intestinal involvement of BD.

#### **9. Neuro-BD**

The expression of RAR-related orphan receptor C (RORC), which is the master transcription factor of Th17 cells, was elevated in the cerebrospinal fluid (CSF) of patients with neuro-BD [48]. In the CSF, the Th17/regulatory T cell (Treg) ratio was elevated [49]. It was reported that increased level of IL-17 secretion in the sera of BD patients and the elevated expression of transcription factors for Th17 cells were shown in the CSF were detected with neuro-BD patients [48]. It is reported that IL-17A- and IL-21-producing T cells in the CSF, brain parenchyma inflammatory infiltrates, and intra-cerebral blood vessels from patients with active BD and neuro-BD [16]. The stimulation of CD4+ T cells with IL-21 increased Th1 and Th17 differentiation and decreased the regulatory T cells [16]. Conversely, IL-21 blockade

**59**

*The Role of Th17 Cells in the Pathogenesis of Behçet's Disease*

with an IL21R-Fc restored the Th17 and regulatory T cell homeostasis in BD patients [16]. On the other hand, Saruhan-Direskeneli et al. [49] reported that, both in serum and the CSF, IL-17 was not detectable in BD patients with CNS involvement.

The signaling molecules and Th1- and Th17-related cytokines are involved in the pathogenesis of BD [50–52]. Several reports showed that polymorphisms of Th17 related cytokines and receptors, such as IL-17F, IL-23R, and IL-23 A, were related to BD susceptibility in Korean and Chinese [41, 53, 54]. STAT4 is necessary for the increase of Th17 cells activated by IL-23. Functional studies showed that the risk SNPs in the STAT4 gene took part in BD might affect the expression of STAT4 and production of IL-17 [55]. The haplotype of IL-17A had a relation to the entero-BD risk, where those of IL-23R are protected against disease expansion. The interactions of IL-23R, IL-17A, and STAT4 SNPs modify the susceptibility to intestinal BD, suggesting the crucial role of the IL-17/IL-23 axis in the pathogenesis of intestinal BD [56].

Recently, plasticity of Th17 and Th17 cells means that they can produce Th1 (IFNγ)- or Th2 (IL-4)-type cytokines under inflammation [57, 58]. Th17 cells are able to change IFN-γ-expressing T cells in mouse Th1 disease models, which are named Th17/ Th1 cells, IFN-γ-expressing Th17 cells, or Th1-like cells. The expression of RORC is not fixed in T cells, and the plasticity of Th17 cells was recognized in murine models in vivo [45]; this conception was applied to human diseases [59, 60]. Geri et al. demonstrated that the frequencies of IFN-γ CD4+ T cells and IL-17+ CD4+ T cells were increased in the CSF than in PBMC in BD patients [16]. Th1 and Th17 cells may be complicated at different steps in inflammatory process, and more Th17 cells were generated than Th1 cells during the inflammatory process. The elevated level in Th17/Treg cells and Th17/Th1 ratios is correlated with the expanse of inflammation. In BD, plasticity exists between Th1, Th17, and Treg cells during inflammation at inflammatory sites and in the peripheral circulation [61]. The low levels of Th17 in remission BD compared with active BD may be due to a conversion of Th17 cells into Treg cells. The differentiation of Treg cells into Th17 cells was involved in the downregulation of FoxP3 expression and the suppressor function. Foxp3 inhibits Th17 differentiation by antagonizing the RORγt function [62]. Sonmez et al. [63] reported that IL-17A/F levels increased parallel to IL-23 levels in BD and IL-35 levels were lower in active BD patients than the inactive BD patients, which may be a plasticity between Th17 and Treg cells according to the

CsA is effective for reducing the severity of intraocular inflammation of BD. Chi et al. reported that CsA has an effect on both IFN-γ and IL-17 productions in vitro and in vivo. In vitro, it was shown that CsA inhibited IL-17 production from PBMC of BD patients. In vivo, the improvement of intraocular inflammation in BD was

Thus, the pathogenesis of IL-17 in neuro-BD remains controversial.

*DOI: http://dx.doi.org/10.5772/intechopen.88361*

**10. Polymorphisms**

**11. Plasticity**

state of disease activity.

**12.1 Cyclosporine A (CsA)**

**12. Therapy**

with an IL21R-Fc restored the Th17 and regulatory T cell homeostasis in BD patients [16]. On the other hand, Saruhan-Direskeneli et al. [49] reported that, both in serum and the CSF, IL-17 was not detectable in BD patients with CNS involvement. Thus, the pathogenesis of IL-17 in neuro-BD remains controversial.

#### **10. Polymorphisms**

*Different Aspects of Behçet's Disease*

**7. Skin**

**8. Entero-BD**

**9. Neuro-BD**

**6. Oral and genital ulcer and articular symptoms**

PHA stimulation in active organ involvement.

role of IL-17 in intestinal involvement of BD.

Alpsoy et al. reported that IL-17 levels of BD patients with active stages of oral and genial ulcers and articular symptoms were higher than BD patients with inactive stages of these symptoms [42]. They also found that the percentage of CD4+ IL-17+, IL-17, and CD4− IL-17+ T cells was significantly elevated after *E. coli* and

Hamzaoui et al. confirmed that the presence of an important population of IL-17+ cells infiltrates the erythema nodosum-like eruption in BD skin lesions using antibodies to IL-17A [21]. Shimizu et al. demonstrated that IFN-γ + IL-17 + -producing cells were dominant, and some of them were CD4+ cells in BD-EN compared with healthy controls [30]. Th17 cells are elevated in circulation and distribution over the skin lesions of BD patient. Ekinci et al. reported that serum IL-17A levels were markedly elevated in BD patients with active stages of oral ulcers or genital ulcers compared with inactive stage of these symptoms [22]. They also studied the proportion of IL-17-secreting cells in patients with active organ involvement, showing that the percentage of IL-17, CD4− IL-17+ cells, and CD4+ IL-17+ cells was significantly elevated [20, 22]. This finding indicated that Th17 and IL-17 pathway has a crucial role in the acute attack of the disease.

Gastrointestinal involvement is an important complication of BD. Emmi et al. [43] found that T cells at the intestinal mucosal level produce a high amount of TNF-α and in the early stage of BD. Both Th17 and Th1 cells drive inflammation and mucosal damage though long-lasting cytokine production [44]. Imamura et al. reported the infiltration of CD4+ and CD8+ T cells in the intestine of BD patient, like the expression of mRNAs of proinflammatory and Th1 cytokines/chemokines [45]. Recently, IL-17A, IL-23R, and STAT4 polymorphisms may be involved in the pathogenesis of intestinal involvement in Korean BD patients [46]. On the other hand, Ferrante et al. reported that the serum and mRNA level of IL-23 and IL-17 in entero-BD were not different from those with control groups; thus a Th1 but not a Th17 response occurs with entero-BD [47]. More studies are needed to reveal the

The expression of RAR-related orphan receptor C (RORC), which is the master transcription factor of Th17 cells, was elevated in the cerebrospinal fluid (CSF) of patients with neuro-BD [48]. In the CSF, the Th17/regulatory T cell (Treg) ratio was elevated [49]. It was reported that increased level of IL-17 secretion in the sera of BD patients and the elevated expression of transcription factors for Th17 cells were shown in the CSF were detected with neuro-BD patients [48]. It is reported that IL-17A- and IL-21-producing T cells in the CSF, brain parenchyma inflammatory infiltrates, and intra-cerebral blood vessels from patients with active BD and neuro-BD [16]. The stimulation of CD4+ T cells with IL-21 increased Th1 and Th17 differentiation and decreased the regulatory T cells [16]. Conversely, IL-21 blockade

**58**

The signaling molecules and Th1- and Th17-related cytokines are involved in the pathogenesis of BD [50–52]. Several reports showed that polymorphisms of Th17 related cytokines and receptors, such as IL-17F, IL-23R, and IL-23 A, were related to BD susceptibility in Korean and Chinese [41, 53, 54]. STAT4 is necessary for the increase of Th17 cells activated by IL-23. Functional studies showed that the risk SNPs in the STAT4 gene took part in BD might affect the expression of STAT4 and production of IL-17 [55]. The haplotype of IL-17A had a relation to the entero-BD risk, where those of IL-23R are protected against disease expansion. The interactions of IL-23R, IL-17A, and STAT4 SNPs modify the susceptibility to intestinal BD, suggesting the crucial role of the IL-17/IL-23 axis in the pathogenesis of intestinal BD [56].

#### **11. Plasticity**

Recently, plasticity of Th17 and Th17 cells means that they can produce Th1 (IFNγ)- or Th2 (IL-4)-type cytokines under inflammation [57, 58]. Th17 cells are able to change IFN-γ-expressing T cells in mouse Th1 disease models, which are named Th17/ Th1 cells, IFN-γ-expressing Th17 cells, or Th1-like cells. The expression of RORC is not fixed in T cells, and the plasticity of Th17 cells was recognized in murine models in vivo [45]; this conception was applied to human diseases [59, 60]. Geri et al. demonstrated that the frequencies of IFN-γ CD4+ T cells and IL-17+ CD4+ T cells were increased in the CSF than in PBMC in BD patients [16]. Th1 and Th17 cells may be complicated at different steps in inflammatory process, and more Th17 cells were generated than Th1 cells during the inflammatory process. The elevated level in Th17/Treg cells and Th17/Th1 ratios is correlated with the expanse of inflammation. In BD, plasticity exists between Th1, Th17, and Treg cells during inflammation at inflammatory sites and in the peripheral circulation [61]. The low levels of Th17 in remission BD compared with active BD may be due to a conversion of Th17 cells into Treg cells. The differentiation of Treg cells into Th17 cells was involved in the downregulation of FoxP3 expression and the suppressor function. Foxp3 inhibits Th17 differentiation by antagonizing the RORγt function [62]. Sonmez et al. [63] reported that IL-17A/F levels increased parallel to IL-23 levels in BD and IL-35 levels were lower in active BD patients than the inactive BD patients, which may be a plasticity between Th17 and Treg cells according to the state of disease activity.

#### **12. Therapy**

#### **12.1 Cyclosporine A (CsA)**

CsA is effective for reducing the severity of intraocular inflammation of BD. Chi et al. reported that CsA has an effect on both IFN-γ and IL-17 productions in vitro and in vivo. In vitro, it was shown that CsA inhibited IL-17 production from PBMC of BD patients. In vivo, the improvement of intraocular inflammation in BD was

accompanied by the suppression of both IFN-γ and IL-17 productions after CsA administration [24]. Therefore, it is suggested that the efficacy of CsA on uveitis in BD is through the inhibition of IFN-γ and IL-17 production.

#### **12.2 Antibodies to IFN-α**

Type I IFNs were able to inhibit IL-17 production by PBMC. Recombinant IFN-α has been used to treat BD [57]. Liu et al. reported that significantly higher levels of IL-17 are detected in active BD patients and stimulation with IFN-α decrease IL-17 production [17]. In vitro study showed that IFN-α does not directly regulate the Th1/Th17 balance in BD but rather promotes a regulatory Th1 response through IL-10 secretion [63]. IFN-α activity was mediated via STAT2 phosphorylation [17]. IFN-α upregulates the gene expression of IL-27, a negative regulator of Th17 cells [64].

#### **12.3 Anti-TNF-α therapy**

TNF-α has been detected in patients with BD [5]. Anti-TNF-α blockade can increase Tregs [46] and prevent effector T cell differentiation in BD patients with uveitis [14, 65, 66]. It was demonstrated that the production of IL-17 by polarized Th17 cell lines exposed to infliximab in vitro or fresh CD4+ T cells from BD patients being treated with infliximab was decreased and the RORγt in T cells was also decreased. Therefore, TNF-α is needed for Th17 differentiation in BD. CD4+ T cells exposed to anti-TNF-α blockade may transform into Treg cells. Anti-TNF-α therapy-induced Treg cells from BD patients restrained the activation of target T cells [14]. Anti-TNF-α agents have efficacy for uveitis, neurological and gastrointestinal involvement, and vessel diseases in BD [66]. Taken together, the Th17/Treg cell balance may be crucial for the inflammation in BD [45, 58].

#### **12.4 Antibodies to IL-17A**

IL-17A has a crucial role in deterioration of eye disease and oral ulcers, genital ulcers, and articular symptoms [21–23]. IL-17A from active BD patients can increase the expression of adhesion molecule mRNA. Therapy with antibodies to IL-17A decreased the production of adhesion molecules [21, 67]. Some reported [68–70] that secukinumab improved active mucocutaneous manifestation refractory to previous treatment such as colchicine, conventional DMARDs, and anti-TNF-α agent [69], and refractory oral ulcers [68]. Thus, therapeutic modalities attempting to evaluate new approaches to eliminate the over activities of IL-17A and/or the IL-23/IL-17 pathway may clarify the pathological importance of Il-17A and Th17 cells in BD patients.

#### **13. Other therapeutic strategies**

It is reported that suppression of microRNA-155 reduced the amount of pathogenic IL-17-expressing T cells [71].

#### **13.1 Prognostic biomarker**

The proportion of Th17 cells was increased, which was related with the increasing levels of IL-17, IL-23, and RORγt mRNA expression in BD patients. Ahmadi

**61**

**Author details**

Yuki Nanke1,2\* and Shigeru Kotake2

1 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

2 Division of Rheumatology, First Department of Comprehensive Medicine,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Jichi Medical University Saitama Medical Center, Saitama, Japan

\*Address all correspondence to: ynn@twmu.ac.jp

provided the original work is properly cited.

*The Role of Th17 Cells in the Pathogenesis of Behçet's Disease*

et al. [72] reported that T cell-associated miRNA expression levels, miR-25, miR-106b, miR-326, and miR-93 were significantly unregulated in PBMCs in BD patients; thus the evaluation of immune cells and related miRNA profile may serve

BD is predominated by Th1 and Th17 immune responses. Th17 cells are associated with the active inflammation of BD. Thus, IL-23-IL-17 axis and Th1/Th17-type immune responses are crucial for inflammation and have a pathologic role in BD.

*DOI: http://dx.doi.org/10.5772/intechopen.88361*

as prognostic biomarker.

**14. Conclusion**

**Conflict of interest**

We have no conflict of interest.

**Acronyms and abbreviations**

BD Behçet's disease IL interleukin

TNF tumor necrosis factor

CRP C-reactive protein SAA serum amyloid A IFN interferon

CsA cyclosporine A Th T helper

Treg regulatory T cell

RORC RAR-related orphan receptor C

PBMC peripheral blood mononuclear cells

et al. [72] reported that T cell-associated miRNA expression levels, miR-25, miR-106b, miR-326, and miR-93 were significantly unregulated in PBMCs in BD patients; thus the evaluation of immune cells and related miRNA profile may serve as prognostic biomarker.

### **14. Conclusion**

*Different Aspects of Behçet's Disease*

**12.2 Antibodies to IFN-α**

**12.3 Anti-TNF-α therapy**

Th17 cells [64].

in BD [45, 58].

**12.4 Antibodies to IL-17A**

cells in BD patients.

**13. Other therapeutic strategies**

genic IL-17-expressing T cells [71].

**13.1 Prognostic biomarker**

accompanied by the suppression of both IFN-γ and IL-17 productions after CsA administration [24]. Therefore, it is suggested that the efficacy of CsA on uveitis in

Type I IFNs were able to inhibit IL-17 production by PBMC. Recombinant IFN-α has been used to treat BD [57]. Liu et al. reported that significantly higher levels of IL-17 are detected in active BD patients and stimulation with IFN-α decrease IL-17 production [17]. In vitro study showed that IFN-α does not directly regulate the Th1/Th17 balance in BD but rather promotes a regulatory Th1 response through IL-10 secretion [63]. IFN-α activity was mediated via STAT2 phosphorylation [17]. IFN-α upregulates the gene expression of IL-27, a negative regulator of

TNF-α has been detected in patients with BD [5]. Anti-TNF-α blockade can increase Tregs [46] and prevent effector T cell differentiation in BD patients with uveitis [14, 65, 66]. It was demonstrated that the production of IL-17 by polarized Th17 cell lines exposed to infliximab in vitro or fresh CD4+ T cells from BD patients being treated with infliximab was decreased and the RORγt in T cells was also decreased. Therefore, TNF-α is needed for Th17 differentiation in BD. CD4+ T cells exposed to anti-TNF-α blockade may transform into Treg cells. Anti-TNF-α therapy-induced Treg cells from BD patients restrained the activation of target T cells [14]. Anti-TNF-α agents have efficacy for uveitis, neurological and gastrointestinal involvement, and vessel diseases in BD [66]. Taken together, the Th17/Treg cell balance may be crucial for the inflammation

IL-17A has a crucial role in deterioration of eye disease and oral ulcers, genital ulcers, and articular symptoms [21–23]. IL-17A from active BD patients can increase the expression of adhesion molecule mRNA. Therapy with antibodies to IL-17A decreased the production of adhesion molecules [21, 67]. Some reported [68–70] that secukinumab improved active mucocutaneous manifestation refractory to previous treatment such as colchicine, conventional DMARDs, and anti-TNF-α agent [69], and refractory oral ulcers [68]. Thus, therapeutic modalities attempting to evaluate new approaches to eliminate the over activities of IL-17A and/or the IL-23/IL-17 pathway may clarify the pathological importance of Il-17A and Th17

It is reported that suppression of microRNA-155 reduced the amount of patho-

The proportion of Th17 cells was increased, which was related with the increasing levels of IL-17, IL-23, and RORγt mRNA expression in BD patients. Ahmadi

BD is through the inhibition of IFN-γ and IL-17 production.

**60**

BD is predominated by Th1 and Th17 immune responses. Th17 cells are associated with the active inflammation of BD. Thus, IL-23-IL-17 axis and Th1/Th17-type immune responses are crucial for inflammation and have a pathologic role in BD.

### **Conflict of interest**

We have no conflict of interest.

### **Acronyms and abbreviations**


#### **Author details**

Yuki Nanke1,2\* and Shigeru Kotake2

1 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

2 Division of Rheumatology, First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan

\*Address all correspondence to: ynn@twmu.ac.jp

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[62] Zhou L, Lopes JE, Mark MW, et al. TGF-beta induced Foxp3

10.1038/nature06878

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[63] Sonmez C, Yucel AA, Yesil TH, et al. Correlation between IL-17A/F

Korean population. Life Sciences. 2012;**90**(19-20):740-746. DOI: 10.1016/j. IL-23, IL-35 and IL-12?-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behçet's disease. Clinical Rheumatology.

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secukinumab in refractory

jaut.2018.09.002

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Behçet's syndrome: A preliminary study. Journal of Autoimmunity. 2019;**97**:108-113. DOI: 10.1016/j.

[70] Baerveladt EM, Kappen JH, Thio HB, van Laar JA, van Hagen

2018;**37**(10):2797-2804

2007;**82**(5):1185-1192

2004;**31**(7):1362-1368

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[58] Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunology.

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**66**

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[72] Ahmadi M, Yousefi M, Abbaspour-Aghdam S, Dolati S, Aghebati-Maleki L, Eghbal-Fard S, et al. Disturbed Th17Treg balance, cytokines, and miRNAs in peripheral blood of patients with Behçet's disease. Journal of Cellular Physiology. 2019;**234**(4):3985-3994

**69**

Section 3

Pregnancy and Behçet's

Disease

## Section 3
