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Medicine » Ophthalmology » "Ophthalmology - Current Clinical and Research Updates", book edited by Pinakin Davey, ISBN 978-953-51-1721-6, Published: September 3, 2014 under CC BY 3.0 license. © The Author(s).

Chapter 18

Advances in Pathogenesis of Behcet’s Disease and Vogt- Koyanagi-Harada Syndrome

By Peizeng Yang, Chaokui Wang, Shengping Hou, Bo Lei, Aize Kijlstra and De-Quan Li
DOI: 10.5772/57586

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Advances in Pathogenesis of Behcet’s Disease and Vogt-Koyanagi-Harada Syndrome

Peizeng Yang1, Chaokui Wang1, Shengping Hou1, Bo Lei1, Aize Kijlstra2 and De-Quan Li3

1. Introduction

Uveitis is one of the leading causes of blindness in the world. It is estimated that uveitis accounts for 10%-15% of the blindness in the western world [1]. More importantly, the blindness caused by uveitis is mostly permanent and irreversible since the retina and optic nerve are damaged by inflammation.

Uveitis was previously defined as inflammation of the uveal tract, which is classically composed of the iris, ciliary body and choroid. Yet in common practice, uveitis refers to inflammation involving any intraocular structure and therefore carries the following names: iritis, iridocyclitis, parsplanitis, posterior uveitis, choroiditis, retinitis and retinal vasculitis. It is usually classified into infectious and noninfectious origins on the basis of predominant etiological characteristics. Behcet’s disease (BD) is thought to be an autoinflammatory disease, while Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disease. Therefore, we chose BD and VKH, which are two important representative entities among the noninfectious uveitis class, to discuss the recent advances in our knowledge on the pathogenesis of uveitis.

BD is a chronic systemic autoinflammatory disease, characterized by recurrent uveitis, skin lesions, oral and genital mucous ulcers, as well as some complications in central nervous system, gastrointestinal tract and thrombotic events [2]. A high prevalence of BD has been reported along the ancient Silk Road [3], from Asia to the Mediterranean basin countries, such as Turkey, Iraq, Iran, Korea and Japan. The clinical features of BD have been well documented in publications originating from the high incidence countries. Our research group has evaluated the clinical characteristics and associated ocular complications in a large group of consecutive Chinese BD patients and found that most patients presented a bilateral nongranulomatous anterior, posterior, or panuveitis with a chronic and relapsing course. Uveitis occurred mostly in male patients and in the age group from the second to fifth decade of life. Oral aphthae (100%), skin lesions (78%), and genital ulcers (57.9%) were the typical extraocular findings in patients with BD [4].

VKH syndrome is a well-established immune-mediated multi-organ disorder characterized by a bilateral granulomatous panuveitis frequently associated with extraocular findings including poliosis, vitiligo, alopecia, and central nervous system and auditory signs [5]. It is an autoimmune disease against melanocyte-associated antigens in genetically susceptible individuals. VKH mainly affects certain pigmented races, such as Asians and Native Americans [5-6]. Four clinical stages of uveitis could be developed in patients with VKH syndrome: prodromal, acute, convalescent, and chronic recurrent stages. A clinical analysis based on a large group (n=410) of uveitis patients with VKH syndrome performed by our group showed that the disease was diagnosed most often in young people without a gender predisposition. The intraocular manifestations typically began with choroiditis or chorioretinitis, serous retinal detachment, and optic disc edema, and then proceeded to anterior uveitis if appropriate treatment was not given during the first 2 weeks. Eventually, the eyes developed a recurrent generalized granulomatous uveitis. With regard to the extraocular manifestations, meningismus signs, tinnitus, and abnormal touch sensitivity of the hair frequently occurred before or concurrently with ocular involvement, whereas vitiligo and poliosis usually appear after the uveitis attack [7]. This is possibly due to the autoimmune attack against melanocytes at different sites of the body.

Although the etiology and pathogenesis of BD and VKH syndrome is not completely known, it is hypothesized that abnormalities in the regulation of the immune system and an immunogenetic predisposition are involved in the development of these diseases. Deregulation of Th1, Th17 and regulatory T cells and abnormalities in the associated molecules were found to be involved in the development of these diseases. Recently, two large genome-wide association studies (GWAS) from Japan and Turkey reported an association between single nucleotide polymorphism (SNP) of IL-10, IL-23R/IL-12RB2 gene and BD [8-9]. HLA-DR4 and HLA-DRw53 were reported to be highly associated with VKH syndrome [10], implicating that genetic factors contributed to the pathogenesis of BD and VKH syndrome. The aim of this chapter is to expound the pathogenesis of BD and VKH syndrome with emphasis on new insights in the area of immunoregulation and immunogenetics.

2. Th1 cells and cytokines in Behcet’s disease and VKH syndrome

Th1 cells were the first subtype of T help cells that was reported to be involved in the pathogenesis of autoimmune diseases. IFN-γ is the hallmark cytokine of Th1 cells. A number of studies have determined the role of the Th1 cell and its specific cytokine repertoire in the pathogenesis of BD and VKH syndrome. The increased levels of IFN-γ and T-bet, which is considered as the critical transcriptional factor for Th1 cells, have been observed in the peripheral blood of the patients with active uveitis of BD and VKH syndrome [11-14]. Our study found that S-Ag specific T cells may be involved in the pathogenesis of BD via the production of Th1-dominant cytokines, but not Th17 cytokines [15]. The increased levels of Th1 cell specific cytokines and chemokines in the cerebrospinal fluid (CSF) of VKH patients and in the lesions of active BD patients were also reported [16-17]. El-Asrar et al found an increased levels of IFN-γ in the aqueous humor samples of uveitis from BD, VKH syndrome and HLA-B27-associated uveitis as compared with normal controls; and importantly, the levels of IFN-γ were higher in BD patients than in VKH and HLA-B27-associated uveitis [18], which suggests that IFN-γ may play more important role in the pathogenesis of BD.

In the murine uveitis models, previous reports suggested that Th1 played a pathogenic role during experimental autoimmune uveitis (EAU) development. It was shown that mice neutralized with monoclonal antibodies to IL-12, which drives Th1 differentiation, did not develop EAU [19]. In order to detect whether constitutive ocular expression of IFN-γ influences the course of EAU, Egwuagu et al generated transgenic rats with targeted expression of IFN-γ in the eye and found that IFN-γ markedly accelerated the onset and exacerbated the severity of rat EAU [20]. However, it has been reported that IFN-γ can also provide a protective role in this model. Genetic deletion or neutralization with antibodies against endogenous IFN-γ did not lead to a resistance of EAU induction and development, but rather aggravated the severity of uveitis [21-22]. Mice treated with IL-12 during the first week after immunization appeared to protect the animals from EAU through an IFN-γ-dependent mechanism. It has now been demonstrated that the role of IFN-γ in the development of uveitis is dependent on the stage of disease and the model of EAU that is being studied. IFN-γ confers protection when it is produced during the early stage of the disease. Th1 cells play an essential pathogenic role in the induction of the so called dendritic cell (DC) EAU model, which is induced by the infusion of uveitogenic interphotoreceptor retinoid-binding protein (IRBP) peptide-pulsed DCs. On the other hand, Th17 cells are essential to the induction of classical EAU, which is induced by the immunization with IRBP in the presence of strong adjuvants such as complete Freund's adjuvant and B. pertusis [23].

3. Th17 cells and cytokines in Behcet’s disease and VKH syndrome

Th17 cells, characterized by their production of IL-17, have been reported be associated with the pathogenesis of many autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE). Th17 cells preferentially produce IL-17A, IL-17F, IL-21, and IL-22 [24]. IL-17A, also commonly called IL-17, plays a critical role in the development of allergy and autoimmune responses. IL-17F is mainly involved in mucosal host defense mechanisms, while not required for the induction of experimental autoimmune encephalomyelitis (EAE) and Collagen-induced arthritis (CIA) [25]. As yet no reports have appeared on the role of IL-17F in the pathogenesis of uveitis, thus, whether IL-17F is involved in human uveitis and EAU needs further investigation. This section aims to review studies regarding Th17 cells and related cytokines in the development of BD and VKH syndrome.

Various studies have shown that Th17 cells contribute to the pathogenesis of BD and VKH syndrome. The previous reports from ours and others have shown that the level of IL-17 by polyclonally stimulated peripheral blood mononuclear cells (PBMCs) and CD4+T cells, and the frequency of IL-17–producing CD4+T cells in PBMCs was higher in patients with active BD or VKH syndrome than the controls [11-12, 26]. Geri et al reported an increase of Th17 cells in peripheral blood and in CSF from active BD patients [27]. Animal studies showed that IL-17 may play a major role in the pathogenesis of EAU. The neutralization of IL-17 by monoclonal antibodies prevented or reversed the intraocular inflammation in the EAU model [28-30]. Adoptive transfer of Th17 cells could induce EAU in the absence of INF-γ [29]. These results indicate that IL-17 plays a proinflammatory and pathogenic role in autoimmune uveitis, and the blockade of IL-17 signaling may represent a therapeutic target in BD and VKH syndrome as well as in other Th17 cell-mediated autoimmune diseases.

IL-21, a member of the IL-2 family of cytokines, can drive Th17 differentiation in an autocrine manner [31-32]. We recently reported a higher level of serum IL-21 and IL-21 mRNA in PBMCs from patients having chronic or recurrent active VKH syndrome as compared with patients having inactive VKH syndrome or healthy controls. Moreover, in vitro experiments showed that IL-21 significantly increased IL-17 production, but had no influence on IFN-γ production by PBMCs or CD4+T cells obtained from either patients or healthy controls [33]. Geri et al observed higher levels of serum IL-21 and IL-21-producing CD4+T cells in BD patients. IL-21 was found to be able to drive Th1 and Th17 differentiation and suppressed the frequency of Treg cells. More importantly, they demonstrated the presence of IL-21-producing T cells in the CSF, choroid plexus, brain parenchyma inflammatory infiltrates and intracerebral blood vessels in active BD with CNS involvement [27]. These results suggest that IL-21 may be involved in the pathogenesis of BD and VKH syndrome and may represent a novel therapeutic target for these diseases. The pathogenic role of IL-21 in autoimmune uveitis is supported by animal models. IL-21R-deficient mice are resistant to EAU, and adoptive transfer of IL-21R-/-T cells reduced the EAU severity. Increased IL-21 in lymph nodes and spleens has been reported during the development of EAU [34-35]. All these findings provide evidence for a role of IL-21 in the pathogenesis of uveitis by promoting Th1 and Th17 cell responses and inhibiting Treg cell development.

IL-22, a member of the IL-10 cytokine family, has recently been reported to be involved in a number of human diseases, including mucosal-associated infections and inflammatory disorders of the intestine, skin and joints. In view of the biological function, controversial effects of IL-22 have been observed in different animal models and human disease. IL-22 seems to play a pathogenic role in experimental arthritis and dermatitis, whereas a protective effect was found in inflammatory bowel disease, experimental hepatitis and collagen-induced arthritis [36-37]. Sugita et al showed that the frequency of IL-22-producing T cell clones from aqueous humor of Behcet’s uveitis was higher than that from normal controls. Furthermore, they demonstrated that CD4+T cells from PBMCs secrete increased amounts of IL-22 in BD patients with active uveitis. Higher IL-22 levels in the supernatants of stimulated PBMCs and CD4+T cells and an increased frequency of IL-22-producing CD4+T cells in BD patients with active uveitis were also reported by our group. In addition, increased IL-22 mRNA expression was found in erythema nodosum (EN) skin lesions, and positively correlated with the presence of EN [38]. The group of Nussenblatt reported an upregulated expression of IL-22 in PBMCs of clinical uveitis patients. IL-22 was shown to damage the physiological integrity of primary fetal retinal epithelium cells and induced their apoptosis [39]. These results suggest that an increased IL-22 may also be involved in the pathogenesis of BD. However, studies in a mouse model of uveitis showed that IL-22 can protect mice from the development of uveitis by inducing the generation of regulatory CD11b+antigen-presenting cells, which were able to convert pathogenic T cells into regulatory T cells [40]. As mentioned, the role of IL-22 in human clinical uveitis and animal models remains controversial and needs further investigation.

4. Molecules modulating Th1 or Th17 cells in Behcet’s disease and VKH syndrome

The induction and maintenance of Th1 and Th17 cells requires a large set of molecules. The differentiation of Th17 cells from naïve CD4+T cells is regulated by cytokines [41]. Transforming growth factor-β (TGF-β) and IL-6, broadly expressed by many cell types in the body, including dendritic and epithelial cells, are dominant in the initiation of Th17 cell differentiation [42-45]; IL-23, IL-1β and IL-21, which are products of activated DCs, macrophages, activated T cell or inflamed epithelial cells, possibly expand and maintain the differentiated Th17 cells in the presence of IL-6 and TGF-β1 [31-32, 43, 46-47]. Furthermore, signal transducer and activator of transcription 3 (STAT3) has been found to mediate the initiation of Th17 cell differentiation by these inducing cytokines [48]. IL-12 is an important cytokine responsible for Th1 cell differentiation. IL-27 can induce Tr1 cell differentiation while inhibiting Th17 cell differentiation.

IL-6 has been shown to be a critical mediator of the autoimmune response and inflammation. Various studies have demonstrated that IL-6 was associated with disease activity in BD [49-50]. Studies by Norose et al showed that the level of IL-6 was significantly increased and correlated with the number of lymphocytes in aqueous humor from VKH patients [51]. The infiltrated T cells in the aqueous humor or PBMCs obtained from VKH patients showed an enhanced capability to secrete IL-6 as compared to normal controls [51-52]. Ozdamar et al found that serum levels of IL-6 were higher in BD patients with active uveitis than in those without uveitis [53]. A higher level of IL-6 was also reported in the CSF of patients with active BD with nervous system involvement [54-55]. A case report by Hirano et al showed that tocilizumab, a humanized anti-interleukin 6 receptor antibody, could suppress the clinical manifestations in a patient with refractory BD [56]. Consistent with observations in clinical uveitis, IL-6-deficient mice were not able to generate Th17 cells and were resistant to EAU. Systemic administration of anti-IL-6 receptor antibody ameliorated EAU by suppressing both systemic and regional Th17 responses [57-58]. Taken together, these findings suggest that IL-6 is involved in the pathogenesis of BD and VKH syndrome, and IL-6 blockade may provide a therapeutic efficacy in treating ocular inflammation in patients with BD or VKH syndrome.

IL-23, which is composed of a unique p19 subunit and a shared p40 subunit of IL-12, is essential in the survival and maintenance of pathogenic Th17 cells. Our earlier studies provided evidence for the involvement of IL-23 in the occurrence of uveitis in BD and VKH syndrome. Active uveitis in both diseases showed a higher level of IL-23 in the serum and supernatants of PBMCs as compared to inactive patients and normal controls [11-12]. IL-23p19 mRNA expression was increased in the EN-like skin lesions from BD patients [59]. Studies by Habibagahi et al showed that the IL-23 expression was strongly associated with the disease activity of uveitis with BD [60]. These results suggest that IL-23 may be a biomarker in the course of BD and VKH syndrome. Animal studies have shown that IL-23 is necessary for the induction of EAU due to its capacity to promote a Th17 effector response. It has been shown that IL-23KO mice are resistant to EAU and specific anti-IL-23 antibody prevented EAU induction [29]. These findings support the hypothesis that the IL-23/IL-17 pathway is involved in the pathogenesis of intraocular inflammation in BD and VKH syndrome.

IL-1β is a key proinflammatory cytokine that promotes Th17 cell differentiation. We recently observed a higher IL-1β production by peptidoglycan (PGN)/lipopolysaccharide (LPS)–induced monocyte-derived macrophages from active ocular BD patients [61]. Pay et al showed a significantly increased level of IL-1β in synovial fluid from BD patients as compared to that from osteoarthritis patients [62]. These results suggest that IL-1β may play a critical role in the pathogenesis of BD. The pathogenic role of IL-1β in uveitis was also proven directly by the observation that IL-1 receptor deficient mice were completely resistant to EAU [63].

IL-12, a heterodimeric cytokine composed of the subunits p40 andp35, is known to induce the differentiation of naïve CD4+T cells into Th1 cells. Studies on the role of IL-12 in clinical uveitis have shown that IL-12 levels in plasma and PBMC culture supernatants were higher in BD with active uveitis [64-65]. Actual measurements of IL-12 in VKH syndrome have not yet been reported. Many studies have shown that Th1 cells are involved in VKH syndrome [13-14], which makes it likely that IL-12 is involved in the pathogenesis.

IL-27, a member of the IL-12 family of cytokines, has been shown to be able to inhibit Th17 cells and that it can induce regulatory Tr1 cells. IL-27 is composed of a unique p28 subunit and a shared EBI3 subunit with IL-35. Our studies on VKH found a decreased IL-27P28 mRNA expression by PBMCs and the lower IL-27 levels in the serum and supernatants of PBMCs in active VKH patients as compared to the inactive patients and normal controls, while the shared EBI3 mRNA expression was not different between the three groups. Furthermore, IL-27 was shown to inhibit the Th17 cell response in a direct manner on CD4+T cells as well as by modulating DCs. Treatment with corticosteroids has been shown to upregulate IL-27 production in vivo and in vitro [66]. An increased levels of IL-27 have been reported in the serum of uveitis patients with BD [67]. Various animal models have been used to examine the role of IL-27 in autoimmune disease and found that the presence of IL-27 could protect mice from EAE and CIA [68-69]. In the EAU model, an increased expression of IL-27 was observed at the peak of EAU, and further experiments showed that IL-27 could suppress the expansion of Th17 cells in the retina [70]. These observations suggest that an upregulated IL-27 response may contribute to the self-limited inflammation seen in the EAU model. Further clinical studies are needed in clinical uveitis and EAU to obtain further support whether IL-27 may be a potential therapeutic target for BD and VKH syndrome.

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a significant role in the pathogenesis of many inflammatory and autoimmune diseases. It has been reported that the level of TNF-α was increased in the ocular fluids, serum and in the supernatants of stimulated CD4+T cells from active uveitis patients with BD. Furthermore, TNF-α could induce the polarization of Th17 cells in BD patients [71-72]. A similar result was seen in the aqueous humor of VKH patients concerning the expression of TNF-α [18]. In the animal models of EAU it was shown that TNFR1-deficient mice were resistant to EAU through a TNFR1-dependent deficit in macrophage migration to the inflammatory site [73]. Treatment with systemic or local TNF-α inhibition with etanercept in the induction phase of EAU could effectively alleviate the severity of uveitis [74]. The pathogenic role of TNF-α in uveitis was also supported by experiments that showed that TNF-α could disrupt morphologic and functional barrier properties of polarized retinal pigment epithelium cells [75]. Thus, these results also indicate that TNF-α plays an important role in the pathogenesis of uveitis and has provided the basis as a major target for treating inflammatory and autoimmune eye diseases. In clinical trials, a number of reports have shown encouraging results in treating BD and VKH syndrome with anti-TNF-α antibody, such as infliximab [76-77].

A number of other immune-related molecules were also found to be associated with the pathogenesis of BD or VKH syndrome. Our most recent studies have revealed that other proinflammatory mediators, such as osteopontin (OPN), IL-7 and leptin, were also involved in the pathogenesis of BD and/or VKH syndrome. We observed the increased serum levels of OPN, IL-7 and leptin in patients with active BD and/or VKH syndrome, which may promote both Th1 and/or Th17 polarization [78-81]. Consistent with our findings, it has been shown that OPN aggravated the severity of EAU, and blockade of OPN with siRNA prevented the uveitis development [82-83]. IL-7 and leptin have been reported to be involved in the induction and progress of EAE, a model that shares many immunopathogenic mechanisms with EAU [84-85].

Other regulatory molecules may also play a critical role in controlling autoimmunity. 1,25-Dihydroxyvitamin D, miRNA155, IFN-α and IFN-β have all been shown to have an anti-inflammatory role in autoimmune disease. Levels of 1,25-Dihydroxyvitamin D3 and miRNA155 have been shown to be decreased in BD and VKH syndrome. Furthermore, 1,25-Dihydroxyvitamin D3 and miRNA155 were shown to inhibit Th17 cell responses [86-87], supporting its protective role in both BD and VKH syndrome. IFN-α has been effective in treating uveitis in patients with BD and our studies on the possible mechanisms showed that it could inhibit the Th17 cell response and was able to induce the expression of the regulatory cytokine IL-10 [88]. Studies in the animal model of uveitis showed that IFN-β exerted its inhibitory effect on EAU by inhibiting the Th1 and Th17 cell response [89], suggesting a protective role in uveitis.

5. Treg cells in Behcet’s disease and VKH syndrome

Treg cells maintain the immune balance between effector and tolerogenic immune responses. It is well documented that a deficiency in Treg cells can result in the development of autoimmune disease and adoptive transfer of Treg cells effectively prevented and suppressed the severity of inflammation and/or autoimmune disease. Up to now, several subsets of Treg cells have been identified, such as the TGF-β-secreting Th3 regulatory cells [90], CD8+CD28-T cells [91] and NKT regulatory cells [92]. However, the best characterized subsets of CD4+regulatory T cells are CD4+CD25+FoxP3+Tregs and Tr1 cells that secrete IL-10 and lack FoxP3 expression. The important protective role played by these T-regulatory cells in the control of inflammatory and autoimmune disease has generated considerable interest in patients with noninfectious uveitis including BD and VKH syndrome.

CD4+CD25+FoxP3+Tregs can be divided into two subpopulations: natural Treg cells (nTreg), which are develop as a distinct lineage of cells in the thymus, and the induced Treg cells (iTreg), which are generated in the periphery from naïve CD4+T cells. They can also be induced in vitro. The difference and relative contributions in immune response of nTreg and iTreg cells are difficult to distinguish. A recent study found that a cell surface molecule neuropilin-1 was expressed on thymus-derived nTreg cells, but not on mucosa-generated Foxp3+iTreg cells [93-94]. This marker can now be used to distinguish the subsets of CD4+CD25+Tregs. Our studies showed a decreased frequency of CD4+CD25+Treg cells and CD4+CD25+Foxp3+Treg cells in the peripheral blood from active VKH patients. CD4+CD25+Treg cells from active VKH patients showed a diminished function in suppressing the proliferation of CD4+CD25-T cells and were less potent in inhibiting the production of IFN-γ and IL-13 by CD4+CD25-Tcells [95]. These results suggest that a decreased frequency and diminished function of CD4+CD25+Treg cells are associated with the active uveitis seen in VKH patients. However, Commodaro et al found no significant differences in the frequency of CD4+Foxp3+and CD25+Foxp3+T cells as well as no reduction in FOXP3 mRNA expression in mononuclear cells from VKH patients with active or inactive uveitis as compared with healthy controls [96]. The discrepancy may be due to the difference in Tregs subtypes investigated in the two studies (iTreg or nTreg). Patients with BD showed a significantly decreased frequency of Treg cells [27, 97], suggesting that the low level of Treg cells may contribute to the pathogenesis of ocular attacks in BD patients.

Tr1 cells are defined by their high expression of IL-10 and their ability to suppress antigen-specific effector T cell. Unlike CD4+CD25+Treg cells, which are present from birth, Tr1 cells are inducible cells and can be generated both in vitro and in vivo. It has been reported that IL-27 or CD46 activation in the presence of IL-2 can induce the differentiation of Tr1 cells [98-99]. A defect of CD46-mediated Tr1 cells has been reported in multiple sclerosis [98]. A study by our group revealed a decreased IL-10 production by naïve CD4+T cells under Tr1 cell polarizing conditions in active VKH patients as compared with inactive VKH patients and healthy controls [66], suggesting that a defect of Tr1 cells might contribute to the pathogenesis of VKH syndrome.

Animal studies showed that Treg cells are involved in the remission of ocular inflammation. nTreg cells and iTreg cells induced by LPS-activated bone marrow dendritic cells inhibited the development of EAU. An increased frequency of CD4+CD25+Treg cells was associated with the EAU activity, and these Treg cells from EAU mice have a stronger ability to inhibit the proliferation of CD4+CD25-T cells and decreased IFN-γ production by CD4+CD25-T cells compared with those obtained from normal control mice. Moreover, transfer of CD4+CD25+Treg cells obtained from EAU mice on day 14 or 28 inhibited EAU induction [100]. These results suggest that the increased frequency and inhibitory effect of CD4+CD25+Treg cells in EAU mice may contribute to the monophasic nature and rapid resolution of EAU. Shao and his colleagues found that the suppressive function of Treg cells from animals with recurrent EAU was weaker than those from animals with the monophasic form, indicating that the dysregulation and malfunction of Treg cells in the eye contributed to disease recurrence [101]. Taken together, these results offer an explanation why the uveitis in the BD and VKH syndrome is recurrent while the uveitis in the EAU model is monophasic. The observations demonstrate the important role of Foxp3+Treg cells in maintaining immune tolerance and preventing autoimmunity. Thus, it could be hypothesized that Treg cells in vitro expansion and adoptive transfer back to the patient might be a potential treatment for BD and VKH syndrome.

6. Genetic factors in Behcet’s disease and VKH syndrome

The majority of BD is sporadic, but its familial aggregation has been reported [102-103]. BD can be found all over the world, however, its prevalence is particularly high in a peculiar region along the Silk Road extending from the Mediterranean basin to China [2, 104]. BD has been shown to be strongly associated with HLA-B51, which has been confirmed in different ethnic groups [105-106]. Previous studies showed that VKH syndrome is more prevalent in particular ethnic groups, particularly in pigmented groups [7] including Latin-American and Asian populations and displays a familial aggregation pattern [107]. Several HLA genes such as HLA-DR4 and HLA-DRw53, were strongly associated with VKH in a variety of ethnic groups [10, 108-109]. The aforementioned evidence as provided a strong genetic basis for BD and VKH confirmed by familial aggregation, geographical ethnic distribution, and strong association with especially Human leukocyte antigen (HLA) antigens. The genes associated with Behcet’s disease and VKH syndrome are summarized in Tables 1 and 2, respectively.

6.1. Risk genes in Th1 cell pathway associated with Behcet’s disease and VKH syndrome

STAT4, a transcription factor belonging to the Signal Transducer and Activator of Transcription protein family, is required for Th1 development of naive CD4+T cells. Our study has identified an associated locus at STAT4 for BD in a Chinese Han population, and indicated that the risk SNP rs897200 in the STAT4 gene played a pathogenic role through an effect on STAT4 transcription and IL-17 production [110]. The association of STAT4 with BD was confirmed in a Turkish population [111], suggesting that STAT4 is a common risk gene for BD in different ethnic cohorts.

C-C chemokine receptor type 1 (CCR1) and CCR3 play important roles in the accumulation and activation of inflammatory cells such as the Th1 cell. Recent studies showed that a locus at CCR1/CCR3 was associated with BD in Chinese Han and Turkish populations [111-112]. Functional studies showed a higher expression of CCR1 and migration of monocytes was found in individuals with the risk genotype [111], suggesting that impaired clearance of pathogens may contribute to the development of BD.

IL-18 is a proinflammatory cytokine that stimulates the production of IFN-γ in collaboration with IL-12 by Th1 cells. Studies from Turkish and Korean populations have shown the consistent association with BD in spite of inconsistent result in Korean cohorts [113].

TNF-α has been implicated in the pathogenesis of BD and anti-TNF-α represents an important treatment modality for BD patients [114]. A meta analysis showed an association of TNF-α gene polymorphisms with BD in various ethnic populations [115-117].

6.2. Risk genes in the Th17 cell pathway associated with Behcet’s disease and VKH syndrome

Accumulative evidence supports the important role of the IL-23/Th17/IL-17 pathway in mediating chronic inflammatory or immune diseases such as BD and VKH syndrome [11, 95] and suggests the involvement of genes related to this pathway such as IL23R-IL12RB2, JAK1, STAT3, IL-1β, IL-6, IL17 and OPN in BD and VKH syndrome. We investigated the association of IL23R genes with BD in the Chinese Han population [118]. The results showed that two SNPs in IL23R were associated with the susceptibility to BD. Genome-wide association studies also confirmed the association of IL23R-IL12RB2 with BD in Japanese, Turkish and Iranian patients [8-9, 119]. Additionally, we identified the association of STAT3, JAK1, MCP-1 genes with BD in a Chinese Han population [120-122]. Other genes in the Th17 pathway such as IL-6 and IL-1β also showed an association with BD [123-124].

OPN, also known as bone sialoprotein I or early T-lymphocyte activation, may enhance T cell survival and proliferation, and promotes the responses of Th1 and Th17 cells during chronic inflammatory or immune mediated diseases. We examined the OPN serum level in VKH syndrome and the association of OPN polymorphisms and its receptors with this disease [80]. The results showed that the OPN level was significantly increased in the serum of active VKH patients and identified an association of this gene with VKH syndrome in a Chinese Han population. Furthermore, we found the association of JAK1, IL17F with VKH syndrome [125-126]. These studies suggest that genetic variants of cytokines associated to the Th17 pathway may play an important role in the development of BD and VKH syndrome.

6.3. Risk genes in the Treg cell pathway associated with Behcet’s disease and VKH syndrome

Mir-146a, one of the miRNAs prevalently expressed in Treg cells, is known as a negative regulator of innate immunity in a variety of immune diseases [127]. We examined the association of polymorphisms in mir-146a with BD and VKH syndrome in a Chinese Han population and found that a polymorphism in this gene was associated with BD but not with VKH syndrome [128].

7. Innate immunity in Behcet’s disease and VKH syndrome

It has been reported that infection may be involved in the pathogenesis of BD and VKH syndrome. Most of the uveitis patients with BD or VKH syndrome have manifestations of a bacterial or viral infection before the prodromal stage [129-130], suggesting that infectious agents may be a triggering factor to the onset of these diseases. DCs serve as professional antigen-presenting cells and provide the first line of defense against pathologic infections. Toll-like receptors (TLRs) expressed on DCs play a critical role in innate immunity against these pathologic infections. Interaction of DCs with TLR ligands results in the secretion of a number of proinflammatory cytokines that can induce the differentiation of naïve CD4+T cells into different CD4+T cells, including Th1, Th17 and Treg cells. Kirino and his colleagues reported that an increased expression of TLR4 is associated with heme oxygenase-1 reduction in PBMCs from patients with BD, leading to augmented inflammatory responses [131]. The study by Do et al showed a higher level of TLR2 and TLR4 in monocytes from active BD patients [132]. Our recent study showed a higher expression of TLR2, TLR3, TLR4 and TLR8 by either PBMCs, CD4+T cells or monocytes obtained from BD patients as compared with controls. Furthermore, significantly higher levels of IL-1β were produced by monocytes from active BD patients stimulated with known TLR ligands such as LPS and PGN [133]. These results suggest that a higher expression of TLR is associated with ocular Behcet’s disease and may partly explain the mechanism by which infection was involved in the pathogenesis. It has been reported that DC deregulation was implicated in the pathogenesis of BD [134]. DCs play a critical role in determining the immune balance between self and non-self and this area is becoming a hotspot for researchers to develop tolerogenic DCs for treating autoimmune disease [135].

8. Summary

With the recent progress in immunology and genetics, environmental triggering factors such as viruses, bacteria or other molecular mimicry are thought to be participated in the outbreak of BD and VKH through interacting with TLRs. The imbalance of pathogenic Th1/Th17 and regulatory T cells and abnormalities in the associated immunoregulatory molecules with the abovementioned T cells are now supposed to be involved in the pathogenesis of these two diseases. The understanding of novel pathogenic mechanisms of both diseases may provide a foundation for developing new strategies to better treat the uveitis.

Genes Odd Ratio 95% Confidence Interval Ethnic References
CCR52.371.1- 5.1Italian[136]
1.451.34-1.58Turkish, Arab, Greek, UK, Korean, Japanese[9]
1.451.32–1.60Japanese, Turkish, Korean[8]
1.350.95–1.91Japanese,Turkish, Korean[8]
1.861.39 -2.49Chinese[118]
m.709G >A1.401.0-1.97Iranian[149]
Protein Z6.82.6-17.9Turkish[157]
PTPN222.41.2 to 4.7UK, Middle East[158]
STAT41.451.3-1.6Chinese[110, 160]
3.081.73-5.47Iranian Azeri Turk[117]

Table 1.

Summary of the associated genes with Behcet’s disease


1 - Wakefield D.,J.H. Chang. Epidemiology of uveitis. Int Ophthalmol Clin 2005; 45(2):1-13.
2 - Sakane T., M. Takeno, N. Suzuki,G. Inaba. Behcet's disease. N Engl J Med 1999; 341(17):1284-91.
3 - Evereklioglu C. Current concepts in the etiology and treatment of Behcet disease. Surv Ophthalmol 2005; 50(4):297-350.
4 - Yang P., W. Fang, Q. Meng, Y. Ren, L. Xing,A. Kijlstra. Clinical features of chinese patients with Behcet's disease. Ophthalmology 2008; 115(2):312-318 e4.
5 - Moorthy R.S., H. Inomata,N.A. Rao. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol 1995; 39(4):265-92.
6 - Murakami S., Y. Inaba, M. Mochizuki, A. Nakajima,A. Urayama. [A nation-wide survey on the occurrence of Vogt-Koyanagi-Harada disease in Japan]. Nihon Ganka Gakkai Zasshi 1994; 98(4):389-92.
7 - Yang P., Y. Ren, B. Li, W. Fang, Q. Meng,A. Kijlstra. Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients. Ophthalmology 2007; 114(3):606-14.
8 - Mizuki N., A. Meguro, M. Ota, S. Ohno, T. Shiota, T. Kawagoe, N. Ito, J. Kera, E. Okada, K. Yatsu, Y.W. Song, E.B. Lee, N. Kitaichi, K. Namba, Y. Horie, M. Takeno, S. Sugita, M. Mochizuki, S. Bahram, Y. Ishigatsubo,H. Inoko. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. Nat Genet 2010; 42(8):703-6.
9 - Remmers E.F., F. Cosan, Y. Kirino, M.J. Ombrello, N. Abaci, C. Satorius, J.M. Le, B. Yang, B.D. Korman, A. Cakiris, O. Aglar, Z. Emrence, H. Azakli, D. Ustek, I. Tugal-Tutkun, G. Akman-Demir, W. Chen, C.I. Amos, M.B. Dizon, A.A. Kose, G. Azizlerli, B. Erer, O.J. Brand, V.G. Kaklamani, P. Kaklamanis, E. Ben-Chetrit, M. Stanford, F. Fortune, M. Ghabra, W.E. Ollier, Y.H. Cho, D. Bang, J. O'Shea, G.R. Wallace, M. Gadina, D.L. Kastner,A. Gul. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat Genet 2010; 42(8):698-702.
10 - Islam S.M., J. Numaga, Y. Fujino, R. Hirata, K. Matsuki, H. Maeda,K. Masuda. HLA class II genes in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 1994; 35(11):3890-6.
11 - Chi W., P. Yang, B. Li, C. Wu, H. Jin, X. Zhu, L. Chen, H. Zhou, X. Huang,A. Kijlstra. IL-23 promotes CD4+T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol 2007; 119(5):1218-24.
12 - Chi W., X. Zhu, P. Yang, X. Liu, X. Lin, H. Zhou, X. Huang,A. Kijlstra. Upregulated IL-23 and IL-17 in Behcet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49(7):3058-64.
13 - Li B., P. Yang, H. Zhou, X. Huang, H. Jin, L. Chu, Y. Gao, L. Zhu,A. Kijlstra. Upregulation of T-bet expression in peripheral blood mononuclear cells during Vogt-Koyanagi-Harada disease. Br J Ophthalmol 2005; 89(11):1410-2.
14 - Liu X., P. Yang, X. Lin, X. Ren, H. Zhou, X. Huang, W. Chi, A. Kijlstra,L. Chen. Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome. Clin Immunol 2009; 131(2):333-42.
15 - Zhao C., P. Yang, H. He, X. Lin, L. Du, H. Zhou,A. Kijlstra. Retinal S-antigen Th1 cell epitope mapping in patients with Behcet's disease. Graefes Arch Clin Exp Ophthalmol 2009; 247(4):555-60.
16 - Ben Ahmed M., H. Houman, M. Miled, K. Dellagi,H. Louzir. Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behcet's disease. Arthritis Rheum 2004; 50(7):2291-5.
17 - Miyazawa I., T. Abe, K. Narikawa, J. Feng, T. Misu, I. Nakashima, J. Fujimori, M. Tamai, K. Fujihara,Y. Itoyama. Chemokine profile in the cerebrospinal fluid and serum of Vogt-Koyanagi-Harada disease. J Neuroimmunol 2005; 158(1-2):240-4.
18 - El-Asrar A.M., S. Struyf, D. Kangave, S.S. Al-Obeidan, G. Opdenakker, K. Geboes,J. Van Damme. Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. Clin Immunol 2011; 139(2):177-84.
19 - Yokoi H., K. Kato, T. Kezuka, J. Sakai, M. Usui, H. Yagita,K. Okumura. Prevention of experimental autoimmune uveoretinitis by monoclonal antibody to interleukin-12. Eur J Immunol 1997; 27(3):641-6.
20 - Egwuagu C.E., J. Sztein, R.M. Mahdi, W. Li, C. Chao-Chan, J.A. Smith, P. Charukamnoetkanok,A.B. Chepelinsky. IFN-gamma increases the severity and accelerates the onset of experimental autoimmune uveitis in transgenic rats. J Immunol 1999; 162(1):510-7.
21 - Caspi R.R., C.C. Chan, B.G. Grubbs, P.B. Silver, B. Wiggert, C.F. Parsa, S. Bahmanyar, A. Billiau,H. Heremans. Endogenous systemic IFN-gamma has a protective role against ocular autoimmunity in mice. J Immunol 1994; 152(2):890-9.
22 - Fukushima A., T. Yamaguchi, W. Ishida, K. Fukata, K. Udaka,H. Ueno. Mice lacking the IFN-gamma receptor or fyn develop severe experimental autoimmune uveoretinitis characterized by different immune responses. Immunogenetics 2005; 57(5):337-43.
23 - Damsker J.M., A.M. Hansen,R.R. Caspi. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 2010; 1183:211-21.
24 - Korn T., E. Bettelli, M. Oukka,V.K. Kuchroo. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27:485-517.
25 - Iwakura Y., H. Ishigame, S. Saijo,S. Nakae. Functional specialization of interleukin-17 family members. Immunity 2011; 34(2):149-62.
26 - Hamzaoui K., E. Bouali, I. Ghorbel, M. Khanfir, H. Houman,A. Hamzaoui. Expression of Th-17 and RORgammat mRNA in Behcet's Disease. Med Sci Monit 2011; 17(4):CR227-34.
27 - Geri G., B. Terrier, M. Rosenzwajg, B. Wechsler, M. Touzot, D. Seilhean, T.A. Tran, B. Bodaghi, L. Musset, V. Soumelis, D. Klatzmann, P. Cacoub,D. Saadoun. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behcet disease. J Allergy Clin Immunol 2011; 128(3):655-64.
28 - Peng Y., G. Han, H. Shao, Y. Wang, H.J. Kaplan,D. Sun. Characterization of IL-17+interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 2007; 48(9):4153-61.
29 - Luger D., P.B. Silver, J. Tang, D. Cua, Z. Chen, Y. Iwakura, E.P. Bowman, N.M. Sgambellone, C.C. Chan,R.R. Caspi. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med 2008; 205(4):799-810.
30 - Zhang R., J. Qian, J. Guo, Y.F. Yuan,K. Xue. Suppression of experimental autoimmune uveoretinitis by Anti-IL-17 antibody. Curr Eye Res 2009; 34(4):297-303.
31 - Nurieva R., X.O. Yang, G. Martinez, Y. Zhang, A.D. Panopoulos, L. Ma, K. Schluns, Q. Tian, S.S. Watowich, A.M. Jetten,C. Dong. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007; 448(7152):480-3.
32 - Korn T., E. Bettelli, W. Gao, A. Awasthi, A. Jager, T.B. Strom, M. Oukka,V.K. Kuchroo. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448(7152):484-7.
33 - Li F., P. Yang, X. Liu, C. Wang, S. Hou,A. Kijlstra. Upregulation of interleukin 21 and promotion of interleukin 17 production in chronic or recurrent Vogt-Koyanagi-Harada disease. Arch Ophthalmol 2010; 128(11):1449-54.
34 - Wang L., C.R. Yu, H.P. Kim, W. Liao, W.G. Telford, C.E. Egwuagu,W.J. Leonard. Key role for IL-21 in experimental autoimmune uveitis. Proc Natl Acad Sci U S A 2011; 108(23):9542-7.
35 - Liu L., Y. Xu, J. Wang,H. Li. Upregulated IL-21 and IL-21 receptor expression is involved in experimental autoimmune uveitis (EAU). Mol Vis 2009; 15:2938-44.
36 - Sarkar S., X. Zhou, S. Justa,S.R. Bommireddy. Interleukin-22 reduces the severity of collagen-induced arthritis in association with increased levels of interleukin-10. Arthritis Rheum 2013; 65(4):960-71.
37 - Sanjabi S., L.A. Zenewicz, M. Kamanaka,R.A. Flavell. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 2009; 9(4):447-53.
38 - Cai T., Q. Wang, Q. Zhou, C. Wang, S. Hou, J. Qi, A. Kijlstra,P. Yang. Increased expression of IL-22 is associated with disease activity in Behcet's disease. PLoS One 2013; 8(3):e59009.
39 - Li Z., B. Liu, A. Maminishkis, S.P. Mahesh, S. Yeh, J. Lew, W.K. Lim, H.N. Sen, G. Clarke, R. Buggage, S.S. Miller,R.B. Nussenblatt. Gene expression profiling in autoimmune noninfectious uveitis disease. J Immunol 2008; 181(7):5147-57.
40 - Ke Y., D. Sun, G. Jiang, H.J. Kaplan,H. Shao. IL-22-induced regulatory CD11b+APCs suppress experimental autoimmune uveitis. J Immunol 2011; 187(5):2130-9.
41 - Zheng X., F. Bian, P. Ma, C.S. De Paiva, M. Stern, S.C. Pflugfelder,D.Q. Li. Induction of Th17 differentiation by corneal epithelial-derived cytokines. J Cell Physiol 2010; 222(1):95-102.
42 - Zhou L., Ivanov, II, R. Spolski, R. Min, K. Shenderov, T. Egawa, D.E. Levy, W.J. Leonard,D.R. Littman. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007; 8(9):967-74.
43 - Veldhoen M., R.J. Hocking, C.J. Atkins, R.M. Locksley,B. Stockinger. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24(2):179-89.
44 - Mangan P.R., L.E. Harrington, D.B. O'Quinn, W.S. Helms, D.C. Bullard, C.O. Elson, R.D. Hatton, S.M. Wahl, T.R. Schoeb,C.T. Weaver. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441(7090):231-4.
45 - Bettelli E., Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner,V.K. Kuchroo. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441(7090):235-8.
46 - Manel N., D. Unutmaz,D.R. Littman. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9(6):641-9.
47 - Hunter C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005; 5(7):521-31.
48 - Yang X.O., A.D. Panopoulos, R. Nurieva, S.H. Chang, D. Wang, S.S. Watowich,C. Dong. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007; 282(13):9358-63.
49 - Adam B.,E. Calikoglu. Serum interleukin-6, procalcitonin and C-reactive protein levels in subjects with active Behcet's disease. J Eur Acad Dermatol Venereol 2004; 18(3):318-20.
50 - Nalbant S., B. Sahan, M. Durna, D. Ersanli, M. Kaplan, O. Karabudak,M. Unal. Cytokine profile in Behcet uveitis. Bratisl Lek Listy 2008; 109(12):551-4.
51 - Norose K., A. Yano, X.C. Wang, T. Tokushima, J. Umihira, A. Seki, M. Nohara,K. Segawa. Dominance of activated T cells and interleukin-6 in aqueous humor in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 1994; 35(1):33-9.
52 - Norose K.,A. Yano. Melanoma specific Th1 cytotoxic T lymphocyte lines in Vogt-Koyanagi-Harada disease. Br J Ophthalmol 1996; 80(11):1002-8.
53 - Ozdamar Y., N. Berker, G. Bahar, E. Soykan, T. Bicer, S.S. Ozkan,J. Karakaya. Inflammatory mediators and posterior segment involvement in ocular Behcet disease. Eur J Ophthalmol 2009; 19(6):998-1003.
54 - Akman-Demir G., E. Tuzun, S. Icoz, N. Yesilot, S.P. Yentur, M. Kurtuncu, M. Mutlu,G. Saruhan-Direskeneli. Interleukin-6 in neuro-Behcet's disease: association with disease subsets and long-term outcome. Cytokine 2008; 44(3):373-6.
55 - Wang C.R., C.Y. Chuang,C.Y. Chen. Anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with neuro-Behcet's syndrome. Clin Exp Rheumatol 1992; 10(6):599-602.
56 - Hirano T., N. Ohguro, S. Hohki, K. Hagihara, Y. Shima, M. Narazaki, A. Ogata, K. Yoshizaki, A. Kumanogoh, T. Kishimoto,T. Tanaka. A case of Behcet's disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol 2012; 22(2):298-302.
57 - Hohki S., N. Ohguro, H. Haruta, K. Nakai, F. Terabe, S. Serada, M. Fujimoto, S. Nomura, H. Kawahata, T. Kishimoto,T. Naka. Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses. Exp Eye Res 2010; 91(2):162-70.
58 - Yoshimura T., K.H. Sonoda, N. Ohguro, Y. Ohsugi, T. Ishibashi, D.J. Cua, T. Kobayashi, H. Yoshida,A. Yoshimura. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford) 2009; 48(4):347-54.
59 - Lew W., J.Y. Chang, J.Y. Jung,D. Bang. Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behcet's disease. Br J Dermatol 2008; 158(3):505-11.
60 - Habibagahi Z., M. Habibagahi,M. Heidari. Raised concentration of soluble form of vascular endothelial cadherin and IL-23 in sera of patients with Behcet's disease. Mod Rheumatol 2010; 20(2):154-9.
61 - Liang L., X. Tan, Q. Zhou, Y. Zhu, Y. Tian, H. Yu, A. Kijlstra,P. Yang. IL-1beta triggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behcet's disease. Invest Ophthalmol Vis Sci 2013; 54(1):402-14.
62 - Pay S., H. Erdem, A. Pekel, I. Simsek, U. Musabak, A. Sengul,A. Dinc. Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behcet's disease. Does interleukin-1beta play a major role in Behcet's synovitis? Rheumatol Int 2006; 26(7):608-13.
63 - Su S.B., P.B. Silver, R.S. Grajewski, R.K. Agarwal, J. Tang, C.C. Chan,R.R. Caspi. Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol 2005; 175(10):6303-10.
64 - Guenane H., D. Hartani, L. Chachoua, O.S. Lahlou-Boukoffa, F. Mazari,C. Touil-Boukoffa. [Production of Th1/Th2 cytokines and nitric oxide in Behcet's uveitis and idiopathic uveitis]. J Fr Ophtalmol 2006; 29(2):146-52.
65 - Belguendouz H., D. Messaoudene, D. Hartani, L. Chachoua, M.L. Ahmedi, K. Lahmar-Belguendouz, O. Lahlou-Boukoffa,C. Touil-Boukoffa. [Effect of corticotherapy on interleukin-8 and-12 and nitric oxide production during Behcet and idiopathic uveitis]. J Fr Ophtalmol 2008; 31(4):387-95.
66 - Wang C., Y. Tian, B. Lei, X. Xiao, Z. Ye, F. Li, A. Kijlstra,P. Yang. Decreased IL-27 expression in association with an increased Th17 response in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 2012; 53(8):4668-75.
67 - Shen H., L.P. Xia,J. Lu. Elevated levels of interleukin-27 and effect on production of interferon-gamma and interleukin-17 in patients with Behcet's disease. Scand J Rheumatol 2013; 42(1):48-51.
68 - Fitzgerald D.C., B. Ciric, T. Touil, H. Harle, J. Grammatikopolou, J. Das Sarma, B. Gran, G.X. Zhang,A. Rostami. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol 2007; 179(5):3268-75.
69 - Pickens S.R., N.D. Chamberlain, M.V. Volin, A.M. Mandelin, 2nd, H. Agrawal, M. Matsui, T. Yoshimoto,S. Shahrara. Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum 2011; 63(8):2289-98.
70 - Amadi-Obi A., C.R. Yu, X. Liu, R.M. Mahdi, G.L. Clarke, R.B. Nussenblatt, I. Gery, Y.S. Lee,C.E. Egwuagu. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007; 13(6):711-8.
71 - Sugita S., Y. Kawazoe, A. Imai, Y. Yamada, S. Horie,M. Mochizuki. Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behcet's disease. Arthritis Res Ther 2012; 14(3):R99.
72 - Evereklioglu C., H. Er, Y. Turkoz,M. Cekmen. Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 are increased and associated with elevated lipid peroxidation in patients with Behcet's disease. Mediators Inflamm 2002; 11(2):87-93.
73 - Raveney B.J., D.A. Copland, A.D. Dick,L.B. Nicholson. TNFR1-dependent regulation of myeloid cell function in experimental autoimmune uveoretinitis. J Immunol 2009; 183(4):2321-9.
74 - Busch M., D. Bauer, M. Hennig, S. Wasmuth, S. Thanos,A. Heiligenhaus. Effects of systemic and intravitreal TNF-alpha inhibition in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2013; 54(1):39-46.
75 - Shirasawa M., S. Sonoda, H. Terasaki, N. Arimura, H. Otsuka, T. Yamashita, E. Uchino, T. Hisatomi, T. Ishibashi,T. Sakamoto. TNF-alpha disrupts morphologic and functional barrier properties of polarized retinal pigment epithelium. Exp Eye Res 2013; 110:59-69.
76 - Khalifa Y.M., M.R. Bailony,N.R. Acharya. Treatment of pediatric vogt-koyanagi-harada syndrome with infliximab. Ocul Immunol Inflamm 2010; 18(3):218-22.
77 - Cantini F., L. Niccoli, C. Nannini, O. Kaloudi, E. Cassara, M. Susini,I. Lenzetti. Efficacy of infliximab in refractory Behcet's disease-associated and idiopathic posterior segment uveitis: a prospective, follow-up study of 50 patients. Biologics 2012; 6:5-12.
78 - Liu L., P. Yang, H. He, X. Lin, L. Jiang, W. Chi, C. Zhao,H. Zhou. Leptin increases in Vogt-Koyanagi-Harada (VKH) disease and promotes cell proliferation and inflammatory cytokine secretion. Br J Ophthalmol 2008; 92(4):557-61.
79 - Chu M., P. Yang, S. Hou, F. Li, Y. Chen,A. Kijlstra. Behcet's disease exhibits an increased osteopontin serum level in active stage but no association with osteopontin and its receptor gene polymorphisms. Hum Immunol 2011; 72(6):525-9.
80 - Chu M., P. Yang, R. Hu, S. Hou, F. Li, Y. Chen,A. Kijlstra. Elevated serum osteopontin levels and genetic polymorphisms of osteopontin are associated with Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 2011; 52(10):7084-9.
81 - Yang Y., X. Xiao, F. Li, L. Du, A. Kijlstra,P. Yang. Increased IL-7 expression in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 2012; 53(2):1012-7.
82 - Iwata D., M. Kitamura, N. Kitaichi, Y. Saito, S. Kon, K. Namba, J. Morimoto, A. Ebihara, H. Kitamei, K. Yoshida, S. Ishida, S. Ohno, T. Uede, K. Onoe,K. Iwabuchi. Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA. Exp Eye Res 2010; 90(1):41-8.
83 - Kitamura M., K. Iwabuchi, N. Kitaichi, S. Kon, H. Kitamei, K. Namba, K. Yoshida, D.T. Denhardt, S.R. Rittling, S. Ohno, T. Uede,K. Onoe. Osteopontin aggravates experimental autoimmune uveoretinitis in mice. J Immunol 2007; 178(10):6567-72.
84 - Liu X., S. Leung, C. Wang, Z. Tan, J. Wang, T.B. Guo, L. Fang, Y. Zhao, B. Wan, X. Qin, L. Lu, R. Li, H. Pan, M. Song, A. Liu, J. Hong, H. Lu,J.Z. Zhang. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med 2010; 16(2):191-7.
85 - Matarese G., A. Di Giacomo, V. Sanna, G.M. Lord, J.K. Howard, A. Di Tuoro, S.R. Bloom, R.I. Lechler, S. Zappacosta,S. Fontana. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 2001; 166(10):5909-16.
86 - Tian Y., C. Wang, Z. Ye, X. Xiao, A. Kijlstra,P. Yang. Effect of 1,25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behcet's disease. Invest Ophthalmol Vis Sci 2012; 53(10):6434-41.
87 - Zhou Q., X. Xiao, C. Wang, X. Zhang, F. Li, Y. Zhou, A. Kijlstra,P. Yang. Decreased microRNA-155 expression in ocular Behcet's disease but not in Vogt Koyanagi Harada syndrome. Invest Ophthalmol Vis Sci 2012; 53(9):5665-74.
88 - Liu X., P. Yang, C. Wang, F. Li,A. Kijlstra. IFN-alpha blocks IL-17 production by peripheral blood mononuclear cells in Behcet's disease. Rheumatology (Oxford) 2011; 50(2):293-8.
89 - Sun M., Y. Yang, P. Yang, B. Lei, L. Du,A. Kijlstra. Regulatory effects of IFN-beta on the development of experimental autoimmune uveoretinitis in B10RIII mice. PLoS One 2011; 6(5):e19870.
90 - Weiner H.L. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001; 182:207-14.
91 - Najafian N., T. Chitnis, A.D. Salama, B. Zhu, C. Benou, X. Yuan, M.R. Clarkson, M.H. Sayegh,S.J. Khoury. Regulatory functions of CD8+CD28-T cells in an autoimmune disease model. J Clin Invest 2003; 112(7):1037-48.
92 - Taniguchi M., M. Harada, S. Kojo, T. Nakayama,H. Wakao. The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol 2003; 21:483-513.
93 - Weiss J.M., A.M. Bilate, M. Gobert, Y. Ding, M.A. Curotto de Lafaille, C.N. Parkhurst, H. Xiong, J. Dolpady, A.B. Frey, M.G. Ruocco, Y. Yang, S. Floess, J. Huehn, S. Oh, M.O. Li, R.E. Niec, A.Y. Rudensky, M.L. Dustin, D.R. Littman,J.J. Lafaille. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+T reg cells. J Exp Med 2012; 209(10):1723-42, S1.
94 - Yadav M., C. Louvet, D. Davini, J.M. Gardner, M. Martinez-Llordella, S. Bailey-Bucktrout, B.A. Anthony, F.M. Sverdrup, R. Head, D.J. Kuster, P. Ruminski, D. Weiss, D. Von Schack,J.A. Bluestone. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 2012; 209(10):1713-22, S1-19.
95 - Chen L., P. Yang, H. Zhou, H. He, X. Ren, W. Chi, L. Wang,A. Kijlstra. Diminished frequency and function of CD4+CD25high regulatory T cells associated with active uveitis in Vogt-Koyanagi-Harada syndrome. Invest Ophthalmol Vis Sci 2008; 49(8):3475-82.
96 - Commodaro A.G., J.P. Peron, J. Genre, C. Arslanian, L. Sanches, C. Muccioli, L.V. Rizzo,R. Belfort, Jr. IL-10 and TGF-beta immunoregulatory cytokines rather than natural regulatory T cells are associated with the resolution phase of Vogt-Koyanagi-Harada (VKH) syndrome. Scand J Immunol 2010; 72(1):31-7.
97 - Nanke Y., S. Kotake, M. Goto, H. Ujihara, M. Matsubara,N. Kamatani. Decreased percentages of regulatory T cells in peripheral blood of patients with Behcet's disease before ocular attack: a possible predictive marker of ocular attack. Mod Rheumatol 2008; 18(4):354-8.
98 - Astier A.L., G. Meiffren, S. Freeman,D.A. Hafler. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J Clin Invest 2006; 116(12):3252-7.
99 - Murugaiyan G., A. Mittal, R. Lopez-Diego, L.M. Maier, D.E. Anderson,H.L. Weiner. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+T cells. J Immunol 2009; 183(4):2435-43.
100 - Sun M., P. Yang, L. Du, H. Zhou, X. Ren,A. Kijlstra. Contribution of CD4+CD25+T cells to the regression phase of experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2010; 51(1):383-9.
101 - Ke Y., G. Jiang, D. Sun, H.J. Kaplan,H. Shao. Ocular regulatory T cells distinguish monophasic from recurrent autoimmune uveitis. Invest Ophthalmol Vis Sci 2008; 49(9):3999-4007.
102 - Berman L., B. Trappler,T. Jenkins. Behcet's syndrome: a family study and the elucidation of a genetic role. Ann Rheum Dis 1979; 38(2):118-21.
103 - Gul A., M. Inanc, L. Ocal, O. Aral,M. Konice. Familial aggregation of Behcet's disease in Turkey. Ann Rheum Dis 2000; 59(8):622-5.
104 - Verity D.H., J.E. Marr, S. Ohno, G.R. Wallace,M.R. Stanford. Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 1999; 54(3):213-20.
105 - de Menthon M., M.P. Lavalley, C. Maldini, L. Guillevin,A. Mahr. HLA-B51/B5 and the risk of Behcet's disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum 2009; 61(10):1287-96.
106 - Hou S., P. Yang, L. Du, H. Zhou, X. Lin, X. Liu,A. Kijlstra. SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease. Clin Immunol 2008; 129(1):170-5.
107 - Rutzen A.R., G. Ortega-Larrocea, I.R. Schwab,N.A. Rao. Simultaneous onset of Vogt-Koyanagi-Harada syndrome in monozygotic twins. Am J Ophthalmol 1995; 119(2):239-40.
108 - Zhao M., Y. Jiang,I.W. Abrahams. Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Arch Ophthalmol 1991; 109(3):368-70.
109 - Zhang X.Y., X.M. Wang,T.S. Hu. Profiling human leukocyte antigens in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1992; 113(5):567-72.
110 - Hou S., Z. Yang, L. Du, Z. Jiang, Q. Shu, Y. Chen, F. Li, Q. Zhou, S. Ohno, R. Chen, A. Kijlstra, J.T. Rosenbaum,P. Yang. Identification of a susceptibility locus in STAT4 for Behcet's disease in Han Chinese in a genome-wide association study. Arthritis Rheum 2012; 64(12):4104-13.
111 - Kirino Y., G. Bertsias, Y. Ishigatsubo, N. Mizuki, I. Tugal-Tutkun, E. Seyahi, Y. Ozyazgan, F.S. Sacli, B. Erer, H. Inoko, Z. Emrence, A. Cakar, N. Abaci, D. Ustek, C. Satorius, A. Ueda, M. Takeno, Y. Kim, G.M. Wood, M.J. Ombrello, A. Meguro, A. Gul, E.F. Remmers,D.L. Kastner. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 2013; 45(2):202-7.
112 - Hou S., X. Xiao, F. Li, Z. Jiang, A. Kijlstra,P. Yang. Two-stage association study in Chinese Han identifies two independent associations in CCR1/CCR3 locus as candidate for Behcet's disease susceptibility. Hum Genet 2012; 131(12):1841-50.
113 - Jang W.C., S.B. Park, Y.H. Nam, S.S. Lee, J.W. Kim, I.S. Chang, K.T. Kim,H.K. Chang. Interleukin-18 gene polymorphisms in Korean patients with Behcet's disease. Clin Exp Rheumatol 2005; 23(4 Suppl 38):S59-63.
114 - Arida A., K. Fragiadaki, E. Giavri,P.P. Sfikakis. Anti-TNF agents for Behcet's disease: analysis of published data on 369 patients. Semin Arthritis Rheum 2011; 41(1):61-70.
115 - Touma Z., C. Farra, A. Hamdan, W. Shamseddeen, I. Uthman, H. Hourani,T. Arayssi. TNF polymorphisms in patients with Behcet disease: a meta-analysis. Arch Med Res 2010; 41(2):142-6.
116 - Radouane A., M. Oudghiri, A. Chakib, S. Bennani, I. Touitou,M. Barat-Houari. SNPs in the TNF-alpha gene promoter associated with Behcet's disease in Moroccan patients. Rheumatology (Oxford) 2012; 51(9):1595-9.
117 - Bonyadi M., Z. Jahanafrooz, M. Esmaeili, S. Kolahi, A. Khabazi, A.A. Ebrahimi, M. Hajialilo,S. Dastgiri. TNF-alpha gene polymorphisms in Iranian Azeri Turkish patients with Behcet's Disease. Rheumatol Int 2009; 30(2):285-9.
118 - Jiang Z., P. Yang, S. Hou, L. Du, L. Xie, H. Zhou,A. Kijlstra. IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population. Ann Rheum Dis 2010; 69(7):1325-8.
119 - Xavier J.M., F. Shahram, F. Davatchi, A. Rosa, J. Crespo, B.S. Abdollahi, A. Nadji, G. Jesus, F. Barcelos, J.V. Patto, N.M. Shafiee, F. Ghaderibarim,S.A. Oliveira. Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behcet's disease. Arthritis Rheum 2012; 64(8):2761-72.
120 - Hou S., J. Qi, Q. Zhang, D. Liao, Q. Li, K. Hu, Y. Zhou, A. Kijlstra,P. Yang. Genetic variants in the JAK1 gene confer higher risk of Behcet's disease with ocular involvement in Han Chinese. Hum Genet 2013.
121 - Hu K., S. Hou, Z. Jiang, A. Kijlstra,P. Yang. JAK2 and STAT3 polymorphisms in a Han Chinese population with Behcet's disease. Invest Ophthalmol Vis Sci 2012; 53(1):538-41.
122 - Hou S., P. Yang, L. Du, Z. Jiang, L. Mao, Q. Shu, H. Zhou,A. Kijlstra. Monocyte chemoattractant protein-1-2518 A/G single nucleotide polymorphism in Chinese Han patients with ocular Behcet's disease. Hum Immunol 2010; 71(1):79-82.
123 - Ozcimen A.A., K. Dilek, U. Bingol, H. Saricaoglu, A. Sarandol, O. Taskapilioglu, M. Yurtkuran, M.A. Yurtkuran,H.B. Oral. IL-1 cluster gene polymorphisms in Turkish patients with Behcet's disease. Int J Immunogenet 2011; 38(4):295-301.
124 - Chang H.K., W.C. Jang, S.B. Park, S.M. Han, Y.H. Nam, S.S. Lee, J.U. Kim,H.S. Lee. Association between interleukin 6 gene polymorphisms and Behcet's disease in Korean people. Ann Rheum Dis 2005; 64(2):339-40.
125 - .Hu K., S. Hou, F. Li, Q. Xiang, A. Kijlstra,P. Yang. JAK1, but not JAK2 and STAT3, confers susceptibility to Vogt-Koyanagi-Harada (VKH) syndrome in a Han Chinese population. Invest Ophthalmol Vis Sci 2013; 54(5):3360-5.
126 - Shu Q., P. Yang, S. Hou, F. Li, Y. Chen, L. Du,Z. Jiang. Interleukin-17 gene polymorphism is associated with Vogt-Koyanagi-Harada syndrome but not with Behcet's disease in a Chinese Han population. Hum Immunol 2010; 71(10):988-91.
127 - Tang Y., X. Luo, H. Cui, X. Ni, M. Yuan, Y. Guo, X. Huang, H. Zhou, N. de Vries, P.P. Tak, S. Chen,N. Shen. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 2009; 60(4):1065-75.
128 - Zhou Q., S. Hou, L. Liang, X. Li, X. Tan, L. Wei, B. Lei, A. Kijlstra,P. Yang. MicroRNA-146a and Ets-1 gene polymorphisms in ocular Behcet's disease and Vogt-Koyanagi-Harada syndrome. Ann Rheum Dis 2012.
129 - Sugita S., H. Takase, T. Kawaguchi, C. Taguchi,M. Mochizuki. Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by T cells from patients with Vogt-Koyanagi-Harada disease. Int Ophthalmol 2007; 27(2-3):87-95.
130 - Narikawa S., Y. Suzuki, M. Takahashi, A. Furukawa, T. Sakane,Y. Mizushima. Streptococcus oralis previously identified as uncommon 'Streptococcus sanguis' in Behcet's disease. Arch Oral Biol 1995; 40(8):685-90.
131 - Kirino Y., M. Takeno, R. Watanabe, S. Murakami, M. Kobayashi, H. Ideguchi, A. Ihata, S. Ohno, A. Ueda, N. Mizuki,Y. Ishigatsubo. Association of reduced heme oxygenase-1 with excessive Toll-like receptor 4 expression in peripheral blood mononuclear cells in Behcet's disease. Arthritis Res Ther 2008; 10(1):R16.
132 - Do J.E., S.Y. Kwon, S. Park,E.S. Lee. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008; 47(6):840-8.
133 - Liu X., C. Wang, Z. Ye, A. Kijlstra,P. Yang. Higher expression of Toll-like receptors 2, 3, 4 and 8 in ocular Behcet's disease. Invest Ophthalmol Vis Sci 2013.
134 - Pay S., I. Simsek, H. Erdem,A. Dinc. Immunopathogenesis of Behcet's disease with special emphasize on the possible role of antigen presenting cells. Rheumatol Int 2007; 27(5):417-24.
135 - Harry R.A., A.E. Anderson, J.D. Isaacs,C.M. Hilkens. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis 2010; 69(11):2042-50.
136 - Atzeni F., L. Boiardi, B. Casali, E. Farnetti, D. Nicoli, P. Sarzi-Puttini, N. Pipitone, I. Olivieri, F. Cantini, F. Salvi, R. La Corte, G. Triolo, D. Filippini, G. Paolazzi,C. Salvarani. CC chemokine receptor 5 polymorphism in Italian patients with Behcet's disease. Rheumatology (Oxford) 2012; 51(12):2141-5.
137 - Chen F., S. Hou, Z. Jiang, Y. Chen, A. Kijlstra, J.T. Rosenbaum,P. Yang. CD40 gene polymorphisms confer risk of Behcet's disease but not of Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Rheumatology (Oxford) 2012; 51(1):47-51.
138 - Fei Y., R. Webb, B.L. Cobb, H. Direskeneli, G. Saruhan-Direskeneli,A.H. Sawalha. Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study. Arthritis Res Ther 2009; 11(3):R66.
139 - Oksel F., G. Keser, M. Ozmen, K. Aksu, G. Kitapcioglu, A. Berdeli,E. Doganavsargil. Endothelial nitric oxide synthase gene Glu298Asp polymorphism is associated with Behcet's disease. Clin Exp Rheumatol 2006; 24(5 Suppl 42):S79-82.
140 - Kim J.U., H.K. Chang, S.S. Lee, J.W. Kim, K.T. Kim, S.W. Lee,W.T. Chung. Endothelial nitric oxide synthase gene polymorphisms in Behcet's disease and rheumatic diseases with vasculitis. Ann Rheum Dis 2003; 62(11):1083-7.
141 - Ben Dhifallah I., H. Houman, M. Khanfir,K. Hamzaoui. Endothelial nitric oxide synthase gene polymorphism is associated with Behcet's disease in Tunisian population. Hum Immunol 2008; 69(10):661-5.
142 - Li K., M. Zhao, S. Hou, L. Du, A. Kijlstra,P. Yang. Association between polymorphisms of FCRL3, a non-HLA gene, and Behcet's disease in a Chinese population with ophthalmic manifestations. Mol Vis 2008; 14:2136-42.
143 - Ben Dhifallah I., E.F. Karray, F. Sassi,K. Hamzaoui. Intercellular adhesion molecule 1 K469E gene polymorphism is associated with presence of skin lesions in Tunisian Behcet's disease patients. Tissue Antigens 2010; 75(1):74-8.
144 - Boiardi L., C. Salvarani, B. Casali, I. Olivieri, G. Ciancio, F. Cantini, F. Salvi, R. Malatesta, M. Govoni, F. Trotta, D. Filippini, G. Paolazzi, D. Nicoli, E. Farnetti,L. Macchioni. Intercellular adhesion molecule-1 gene polymorphisms in Behcet's Disease. J Rheumatol 2001; 28(6):1283-7.
145 - Oral H.B., K. Dilek, A.A. Ozcimen, O. Taskapilioglu, U. Bingol, A. Sarandol, H. Saricaoglu, M. Yurtkuran,M.A. Yurtkuran. Interleukin-4 gene polymorphisms confer Behcet's disease in Turkish population. Scand J Immunol 2011; 73(6):594-601.
146 - Yanagihori H., N. Oyama, K. Nakamura, N. Mizuki, K. Oguma,F. Kaneko. Role of IL-12B promoter polymorphism in Adamantiades-Behcet's disease susceptibility: An involvement of Th1 immunoreactivity against Streptococcus Sanguinis antigen. J Invest Dermatol 2006; 126(7):1534-40.
147 - Htoon J., A. Nadig, T. Hughes, S. Yavuz, H. Direskeneli, G. Saruhan-Direskeneli,A.H. Sawalha. IL18 polymorphism is associated with Behcet's disease but not lupus in patients from Turkey. J Rheumatol 2011; 38(5):962-3.
148 - Lee Y.J., S.W. Kang, J.K. Song, H.J. Baek, H.J. Choi, Y.D. Bae, H.J. Ryu, E.Y. Lee, E.B. Lee,Y.W. Song. Associations between interferon regulatory factor-1 polymorphisms and Behcet's disease. Hum Immunol 2007; 68(9):770-8.
149 - Xavier J.M., N.M. Shafiee, F. Ghaderi, A. Rosa, B.S. Abdollahi, A. Nadji, F. Shahram, F. Davatchi,S.A. Oliveira. Association of mitochondrial polymorphism m.709G>A with Behcet's disease. Ann Rheum Dis 2010; 70(8):1514-6.
150 - Rustemoglu A., U. Gul, G. Gumus-Akay, M. Gonul, S. Yigit, N. Bozkurt, A. Karadag, E. Piskin, A. Sunguroglu,A. Kadikiran. MDR1 gene polymorphisms may be associated with Behcet's disease and its colchicum treatment response. Gene 2012; 505(2):333-9.
151 - Zheng X., D. Wang, S. Hou, C. Zhang, B. Lei, X. Xiao, A. Kijlstra,P. Yang. Association of macrophage migration inhibitory factor gene polymorphisms with Behcet's disease in a Han Chinese population. Ophthalmology 2012; 119(12):2514-8.
152 - Park K.S., Y. Min, S.R. Park, E.H. Kim, D.J. Lee, D. Bang,E.S. Lee. Matrix metalloproteinase-2,-9,-12, and tissue inhibitor of metalloproteinase 2 gene polymorphisms and cutaneous expressions in patients with Behcet's disease. Tissue Antigens 2012; 79(5):333-9.
153 - Lee Y.J., S.W. Kang, H.J. Baek, H.J. Choi, Y.D. Bae, E.H. Kang, E.Y. Lee, E.B. Lee,Y.W. Song. Association between matrix metalloproteinase 9 promoter polymorphisms and Behcet's disease. Hum Immunol 2010; 71(7):717-22.
154 - Karakus N., S. Yigit, G. Kalkan, A. Rustemoglu, A. Inanir, U. Gul, G.S. Pancar, S. Akkanet,O. Ates. Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet's disease. Mol Vis 2012; 18:1696-700.
155 - Ates O., L. Dalyan, G. Hatemi, V. Hamuryudan,A. Topal-Sarikaya. Genetic susceptibility to Behcet's syndrome is associated with NRAMP1 (SLC11A1) polymorphism in Turkish patients. Rheumatol Int 2009; 29(7):787-91.
156 - Hou S., X. Xiao, Y. Zhou, X. Zhu, F. Li, A. Kijlstra,P. Yang. Genetic variant on PDGFRL associated with Behcet disease in Chinese Han populations. Hum Mutat 2013; 34(1):74-8.
157 - Demir H.D., F.N. Yalcindag, A. Ozturk,N. Akar. Intron F G79A polymorphism of the protein Z gene in Turkish Behcet patients. Curr Eye Res 2012; 37(7):630-2.
158 - Baranathan V., M.R. Stanford, R.W. Vaughan, E. Kondeatis, E. Graham, F. Fortune, W. Madanat, C. Kanawati, M. Ghabra, P.I. Murray,G.R. Wallace. The association of the PTPN22 620W polymorphism with Behcet's disease. Ann Rheum Dis 2007; 66(11):1531-3.
159 - Kim S.K., W.C. Jang, S.B. Park, D.Y. Park, K.T. Bang, S.S. Lee, J.B. Jun, D.H. Yoo,H.K. Chang. SLC11A1 gene polymorphisms in Korean patients with Behcet's disease. Scand J Rheumatol 2006; 35(5):398-401.
160 - Hou S., A. Kijlstra,P. Yang. The genetics of Behcet's disease in a Chinese population. Front Med 2012; 6(4):354-9.
161 - Park G., H.S. Kim, J.Y. Choe,S.K. Kim. SUMO4 C438T polymorphism is associated with papulopustular skin lesion in Korean patients with Behcet's disease. Rheumatol Int 2012; 32(10):3031-7.
162 - Kamoun M., I. Ben Dhifallah, E. Karray, L. Zakraoui,K. Hamzaoui. Association of small ubiquitin-like modifier 4 (SUMO4) polymorphisms in a Tunisian population with Behcet's disease. Clin Exp Rheumatol 2010; 28(4 Suppl 60):S45-9.
163 - Chen Y., P. Yang, F. Li, S. Hou, Z. Jiang, Q. Shu,A. Kijlstra. Association analysis of TGFBR3 gene with Vogt-Koyanagi-Harada disease and Behcet's disease in the Chinese Han population. Curr Eye Res 2012; 37(4):312-7.
164 - Horie Y., A. Meguro, M. Ota, N. Kitaichi, Y. Katsuyama, Y. Takemoto, K. Namba, K. Yoshida, Y.W. Song, K.S. Park, E.B. Lee, H. Inoko, N. Mizuki,S. Ohno. Association of TLR4 polymorphisms with Behcet's disease in a Korean population. Rheumatology (Oxford) 2009; 48(6):638-42.
165 - Meguro A., M. Ota, Y. Katsuyama, A. Oka, S. Ohno, H. Inoko,N. Mizuki. Association of the toll-like receptor 4 gene polymorphisms with Behcet's disease. Ann Rheum Dis 2008; 67(5):725-7.
166 - Li H., Q. Liu, S. Hou, L. Du, Q. Zhou, Y. Zhou, A. Kijlstra, Z. Li,P. Yang. TNFAIP3 gene polymorphisms confer risk for Behcet's disease in a Chinese Han population. Hum Genet 2013; 132(3):293-300.
167 - Jung E.S., S.W. Kim, C.M. Moon, D.J. Shin, N.H. Son, E.S. Kim, H.J. Lee, S.P. Hong, T.I. Kim, W.H. Kim,J.H. Cheon. Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and inflammatory bowel diseases in the Korean population. Life Sci 2011; 89(9-10):289-94.
168 - Hou S., Q. Shu, Z. Jiang, Y. Chen, F. Li, F. Chen, A. Kijlstra,P. Yang. Replication study confirms the association between UBAC2 and Behcet's disease in two independent Chinese sets of patients and controls. Arthritis Res Ther 2012; 14(2):R70.
169 - Karray E.F., I. Ben Dhifallah, K. Ben Abdelghani, I. Ben Ghorbel, M. Khanfir, H. Houman, K. Hamzaoui,L. Zakraoui. Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behcet's disease in Tunisians. Joint Bone Spine 2012; 79(2):144-8.
170 - Nam E.J., S.W. Han, S.U. Kim, J.H. Cho, K.H. Sa, W.K. Lee, J.Y. Park,Y.M. Kang. Association of vascular endothelial growth factor gene polymorphisms with behcet disease in a Korean population. Hum Immunol 2005; 66(10):1068-73.
171 - Du L., P. Yang, S. Hou, X. Lin, H. Zhou, X. Huang, L. Wang,A. Kijlstra. Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome. Clin Immunol 2008; 127(1):43-8.
172 - Hu K., P. Yang, Z. Jiang, S. Hou, L. Du,F. Li. STAT4 polymorphism in a Chinese Han population with Vogt-Koyanagi-Harada syndrome and Behcet's disease. Hum Immunol 2010; 71(7):723-6.
173 - Li H., Q. Liu, S. Hou, L. Du, Q. Zhou, Y. Zhou, A. Kijlstra,P. Yang. TNFAIP3 gene polymorphisms in a Chinese Han population with Vogt-Koyanagi-Harada syndrome. PLoS One 2013; 8(3):e59515.