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Journal of Ophthalmic Inflammation and Infection
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Influence of molecular genetics in Vogt-Koyanagi-Harada disease

Journal of Ophthalmic Inflammation and Infection volume 4, Article number: 20 (2014) Cite this article

Abstract

Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes. Recent studies have identified multiple genetic factors that might be associated with the pathogenesis of VKH disease. We performed an electronic database search of PubMed, MEDLINE, and EMBASE, and all relevant papers published up to 13 June 2014 were reviewed. A total of 1,031 publications including articles relevant to the genetics of VKH disease and the references of these articles were reviewed. The review identified a number of genetic factors which might be involved in the pathogenesis of VKH disease, some of which may alter the clinical course of VKH disease. Genes which might be involved in the pathogenesis of VKH disease included genes expressing HLA, complement factor H, interleukins, cytotoxic T-lymphocyte antigen 4 (CTLA-4), killer cell immunoglobulin-like receptors (KIR), programmed cell death 1 (PDCD1), protein tyrosine phosphatase non-receptor 22 (PTPN22), osteopontin, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and other immune response genes. Further studies to explore the correlation among different genotypes and phenotypes of VKH disease will be useful to shed light on the pathogenesis of uveitis in VKH disease and may facilitate the development of new treatment modalities of uveitis in VKH disease.

Review

Introduction

Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes and affects the eyes, skin, ears, and meninges [[1]-[4]]. VKH disease usually occurs more frequently in females with a female-to-male ratio of approximately 2:1 and is one of the top three leading causes of uveitis in China [[4]-[6]]. It is characterized by bilateral granulomatous uveitis and can be classified into four stages: prodromal, uveitic, convalescence, and chronic recurrent [[7]]. In the prodromal and uveitic phases, there are neurological and auditory manifestations, and integumentary findings usually appear in the convalescent and chronic recurrent phases of the disease [[2]]. Together with the absence of past ocular surgery, the ocular, neurological, auditory, and integumentary findings help to establish the diagnosis of VKH disease [[8]]. Treatment for VKH disease generally involves aggressive systemic corticosteroid treatment during the acute stage to reduce the risk of permanent visual loss [[9]-[12]]. Corticosteroid treatment should be tapered off slowly and maintained for at least 6 months as early withdrawal of oral corticosteroid has been found to be a significant risk factor for recurrence of VKH disease and might lead to worse visual outcome [[13]].

The precise etiology of VKH disease is unclear, and it has been postulated that pathogenesis involves an autoimmune process directed against melanocytes triggered by an infectious agent in genetically susceptible individuals [[1]], leading to the loss of melanocytes and subsequent depigmentation [[14],[15]]. The potential role of infection in the pathogenesis of VKH disease is supported by the presence of Epstein-Barr virus DNA in vitreous aspiration of a patient with VKH disease [[16]], and cross-reactions between melanocyte peptides and cytomegalovirus envelope glycoprotein resulting in melanocyte proliferation [[17]]. However, a causative association between viral agents and VKH disease has not yet been established. The autoimmune response against melanocytes is complex and involves innate, humoral, and cellular immunity. CD4+ and CD8+ lymphocytes, as well as Th17 and regulatory T cells, have all been implicated in the pathogenesis [[18]]. High titres of IgG against KU-MEL-1, an antigen expressed by human melanocytes, have been detected in patients with VKH disease [[19]]. Innate immunity may also play an important role in the pathogenesis of VKH disease as evidenced by the presence of histiocytic and multinucleated giant cell infiltrates in enucleated eyes with VKH disease [[14]]. In combination with environmental factors, genetic factors are of paramount importance in various immune processes in VKH disease. This review aims to provide an overview on the role of genetics in the development of VKH disease and the clinical importance and implications of genetics in VKH disease.

Human leukocyte antigen genes

The major histocompatibility complex (MHC) in human is known as human leukocyte antigen (HLA). The MHC region in human is located at 6p21.3 on the short arm of chromosome 6, containing more than 200 genes and over 40 of which are HLA genes [[20]]. The HLA genes encode a wide variety of antigen-presenting molecules on cell surface and proteins with immunological function. The HLA genes involved in immune function are classified into three classes [[20],[21]]: MHC class I region contains genes that encode HLA-A, HLA-B, and HLA-C which form complexes with peptides of antigens and then export these antigens to the cell surface; MHC class II region contains genes encoding HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR which are present in antigen-presenting cells and bind extracellular antigens in order to present them to T cells; and MHC class III region contains genes that play important roles in immune response including several components of complement (C2, C4, and factor B), tumor necrosis factor (tumor necrosis factor-alpha, lymphotoxin alpha, and lymphotoxin beta), and heat shock protein. Both MHC class I and class II are expressed on the cell surface to present antigens to the T lymphocytes in order to initiate immune response.

Among the MHC class II genes, more than 1,500 different alleles have been identified, and studies have provided evidence that MHC class II are associated with various autoimmune diseases [[21]-[23]]. MHC class II genes are expressed on activated T cells and antigen-presenting cells including dendritic cells, macrophages, and B cells. Both the α- and β-chain genes are present in each subregion of DR, DP, and DQ and form a specific MHC class II molecule [[20]]. A number of HLA genotypes have been strongly linked with VKH disease, and these include HLA-DR and HLA-DQ (Tables 1 and 2).

Table 1 Major HLA genotypes associated with VKH disease
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Table 2 Major HLA serotypes associated with VKH disease
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HLA-DQ

Islam et al. conducted a study in Japanese VKH patients and found that HLA-DQ4 and HLA-DQA1*0301 were present in 83% and 100% of VKH patients, respectively, compared with 32% and 67%, respectively, in control subjects, with HLA-DQA1*0301/-DR4 showing the highest risk ratio (Table 1) [[24]]. The study also showed that HLA-DQB1*0604 could not be detected in any VKH patient, and therefore, it might offer some protection against VKH disease by modifying the pathogenesis of VKH [[24]].

HLA-DR

A large number of studies have shown that VKH disease is strongly associated with various HLA-DR alleles (Table 1) [[25]]. HLA-DR4 of MHC class II was first found to be associated with VKH disease in Japanese in 1976 [[26]]. Since then, studies have demonstrated that HLA-DR4 is strongly associated with VKH patients of different ethnic groups (Tables 1 and 2) including North Americans [[27]], Chinese [[25]], Japanese [[28],[29]], Hispanics [[30]-[32]], Italians [[33]], ethnically heterogeneous Brazilian [[34]], Koreans [[35]], and Saudi Arabians [[36]].

Over two decades ago, Goldberg et al. demonstrated that HLA-DRB1*0405 was a major allele responsible for susceptibility to develop VKH disease in Brazilian patients which is a highly admixed population [[34]]. In the study [[34]], the diverse alleles initially suggested to be associated with VKH disease occurred independently, strengthening the significance of HLA-DRB1*0405 in the pathogenesis of VKH. The frequency of HLA-DRB1*0405 was also significantly higher in Japanese patients with prolonged type of VKH disease [[37]]. Further studies have demonstrated that patients with VKH disease who were HLA-DRB1*0405-positive recognized a greater range of melanocyte epitopes than HLA-matched control subjects [[38]], consolidating the influence of HLA-DRB1*0405 in affecting the susceptibility to VKH disease.

In addition to HLA-DRB1*0405 mentioned above, HLA-DRB1*0407 and HLA-DRB1*0410 alleles were also found to have increased frequency in Mestizo patients living in southern California [[32]]. It was also found that the frequency of HLA-DRB1*0410 was increased in Japanese patients with VKH disease [[24],[28],[39]]. Increased frequencies of HLA-DRB1*0405 and HLA-DRB1*0404 were identified in Mexican Mestizo VKH patients with odds ratios of 2.95 and 2.79, respectively [[40]]. The serotype HLA-DR1 has also been suspected as having a possible association with VKH disease [[30]]. However, alleleic analyses did not find a significant association between HLA-DRB1 alleles with VKH disease [[36]].

S57-LLEQRRAA (67-74) located in the third hypervariable region of the HLA-DRB1 molecule is a shared epitope of the two HLA-DRB1*0405 and HLA-DRB1*0410 alleles [[41]]. This shared epitope was found to be linked with VKH disease in Indian patients [[41]]. Results from alleleic and epitopic studies have demonstrated that epitopes may be involved in the immunopathogenesis of VKH disease. However, complex associations between different epitopes and VKH disease are expected due to the high variability of HLA and the differences in genetic profiles across different ethnic populations [[42],[43]].

Although multiple studies have shown that the genetic predisposition to VKH disease is contributed by multiple overlapping factors encoded by the HLA system, the strengths of association between HLA-DRB1*04 subtypes and VKH disease vary among different races, indicating that the pathogenesis of VKH may be multifactorial with additional genetic susceptibility and environmental causes [[32],[34]].

Cytotoxic T-lymphocyte antigen 4 gene

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is located on chromosome 2q33 and is expressed in activated T cells and inhibits T cell activation by CD28 [[44]]. Over 100 single-nucleotide polymorphisms (SNPs) have been identified in CTLA-4 gene regions, and some of these SNPs were found to be related to immune-mediated diseases including type 1 diabetes mellitus [[45]], multiple sclerosis [[46]], systemic lupus erythematosus (SLE) [[47]], rheumatoid arthritis [[48],[49]], Hashimoto's thyroiditis, and Graves' disease [[45]]. However, some of the studies showed conflicting results in the association of CTLA-4 gene polymorphisms and autoimmune diseases [[50]-[52]].

A study of Chinese Han patients with VKH disease provided evidence that the G allele at SNP +49 of CTLA-4 was associated with VKH disease, and the CTLA-4 haplotype −1661A:−318C:+49G:CT60G was also found to confer risk of VKH disease [[53]]. The CTLA-4 haplotype has been shown to be associated with other types of uveitis, and this can be due to differences in the pathogenesis mechanisms among different uveitis entities [[53]].

Complement system

The complement system is an essential component of the primary immune system, and it plays a key role in regulating various immunological and inflammatory responses. It has been demonstrated that experimental autoimmune uveoretinitis (EAAU) can be caused by activation of the complement system, and depletion of the host's complement system can completely inhibit the EAAU [[54],[55]]. Yang et al. have shown that in Chinese females, the 184G rs800292 polymorphism of complement factor H (CFH) gene is a genetic risk marker of anterior uveitis [[56]]. Another study also showed that the carrier frequency of G allele of CFH-rs800292 is increased in patients with non-infectious intermediate and posterior uveitis [[57]]. However, so far, SNPs in CFH that are associated with VKH disease have not yet been discovered.

Interleukin genes

Interleukins (ILs) are produced by leukocytes and are potent inflammatory mediators which are heavily involved in numerous immunological diseases [[58]-[60]] including diverse entities of uveitis [[59],[61]-[63]]. Studies have demonstrated that various interleukins may be associated with VKH disease (Table 3).

Table 3 Interleukin (IL) genes that have been suggested to be associated with VKH disease
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Interleukin-12B gene

Interleukin-12 (IL-12) is critical in the differentiation of naïve T cells into Th1 cells [[64]] and was identified to be involved in the pathogenesis of Behcet's disease [[65],[66]]. Recently, C allele of rs3212227 of the IL-12B gene was shown to be a significant risk factor of VKH disease [[67]].

Interleukin-17 gene

Upregulation of interleukin-17 (IL-17) was identified to be associated with intraocular inflammation in patients of VKH disease and Behçet's disease [[68]]. It was also shown that rs763780 of IL-17F was associated with VKH disease in Chinese Han population, with the TT genotype increasing the susceptibility of VKH disease and the C allele of rs763780 being possibly protective against VKH disease [[69]]. However, since only two SNPs of the IL-17 gene were tested in the study [[69]], further studies are needed to evaluate if the other polymorphisms of the IL-17 gene are also associated with VKH disease.

Interleukin-23 receptor gene

Interleukin-23 (IL-23) was identified to be an important cytokine in the development of autoimmune diseases [[70],[71]]. It enhances the production of IL-17 by CD4+ T cells and contributes to the maintenance of various autoimmune diseases [[72]]. Previous study has found that the levels of IL-23 in the serum of VKH patients with active uveitis were significantly higher than those without active uveitis and normal controls [[68]]. However, no statistical significant association was found in four selected polymorphisms (rs17375018, rs7517847, rs11209032, and rs1343151) of interleukin-23 receptor (IL23R) gene in VKH patients from a Chinese Han population [[73]]. In view of the discrepancy between the SNP analysis and the current understanding in the functions of IL-23 in uveitis, more SNPs in the IL23R gene should be explored to investigate its association with VKH disease.

Interleukin-27 gene

Interleukin-27 (IL-27) is expressed in photoreceptors and retinal ganglion cells [[74]]. It enhances the differentiation of naïve T cells into Th1 cells but suppresses naïve T cells from differentiating into Th17 cells, resulting in mutual antagonism of Th1 and Th17 cells which are both involved in the pathogenesis of uveitis [[75],[76]]. Nonetheless, a previous study by Yang et al. showed no association between the rs4788084 SNP of IL-27 and intermediate uveitis and posterior uveitis [[57]].

Killer cell immunoglobulin-like receptor gene cluster

The killer cell immunoglobulin-like receptor (KIR) genes on chromosome 19 encode inhibitory (3DL1, 3DL2, 3DL3, 2DL1, 2DL2, 2DL3, and 2DL5) and activating (3DS1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5) receptors which are expressed on the majority of natural killer (NK) cells and a small proportion of T cells [[77]]. The inhibitory KIRs recognize distinct HLA class I molecules and stop the effector function of NK cells, thus offering protections to healthy cells. Expression of HLA class I molecules protect healthy cells from surveillance of NK cells [[78]].

KIR2DS3 was found to be more frequent in VKH patients than in the control group in a study performed in Saudi Arabia [[79]]. Another study by Levinson et al. showed that the frequency of KIR gene cluster 3DS1-2DL5-2DS1-2DS5 was higher and increased the susceptibility to VKH disease in Japanese patients [[80]]. Therefore, it was suggested that the KIR genes that encode activating KIR receptors may increase the risk of VKH disease. On the other hand, KIR-HLA interactions might be involved in the protection against VKH disease and might possibly reduce the severity of VKH disease as KIR2DL2/2DL3+HLA-C1 was identified to have a higher frequency in the control group [[79]]. However, the direct role of NK cells in the pathogenesis of VKH disease has not yet been established.

Programmed cell death 1 gene

Programmed cell death 1 (PDCD1) on chromosome 2q37 encodes programmed cell death 1 (PD-1) which induces apoptotic cell death of murine lymphoid cell lines in vitro [[81]]. It has been suggested to suppress the development of inflammatory helper T cells modulating the innate immune system [[82]]. PDCD1 has been shown to be involved in a wide range of autoimmune diseases including Graves' disease [[83]], type I diabetes [[84]], ankylosing spondylitis [[85]], rheumatoid arthritis [[86],[87]], SLE [[88]-[91]], and multiple sclerosis [[92]]. However, several studies have shown contradictory results [[93]-[97]]. In Chinese Han population, the frequency of C allele in PD-1.5 was found to be significantly lower in VKH patients with poliosis or with dysacusis compared with control subjects, suggesting that PD-1.5 may influence the extraocular manifestations among VKH patients [[98]]. In the same study, no association was found among VKH disease and the SNPs PD-1.3 and PD-1.6 [[98]].

Protein tyrosine phosphatase non-receptor 22 gene

Protein tyrosine phosphatase non-receptor 22 (PTPN22) influences the development and activation of lymphocytes, innate cell-mediated immune host defense, formation of tolerance, and regulation of the immune system [[99]]. PTPN22 is located on chromosome 1p13.3 to 1p13.1 and encodes the lymphoid-specific phosphatase known as Lyp which plays an essential suppressive role in T cell activation [[100]]. Several studies have demonstrated that a SNP in PTPN22, R620W (rs2476601), predisposes individuals to various autoimmune diseases including insulin-dependent diabetes mellitus [[101]], rheumatoid arthritis [[102],[103]], Graves' disease [[104]], and SLE [[105]]. In a study of 67 Japanese patients with VKH disease [[106]], six SNPs in PTPN22 (rs3811021, rs1217413, rs1237682, rs3761935, rs3789608, and rs2243471) were shown to have no significant association with VKH disease. However, in a study of 1,005 VKH patients and 2,010 healthy controls of Han Chinese population [[107]], significantly increased frequencies of rs2488457 CC genotype and C allele were found in VKH patients. Moreover, there was decreased frequency of rs2488457 GG genotype in patients with VKH disease. No significant association between T cell activation and rs2488457 genotype was observed [[107]]. It was proposed that a functional variant rs2488457 in PTPN22 increases susceptibility to VKH disease via modulating the expression of PTPN22, production of interleukin 10 (IL-10) and proliferation of peripheral blood mononuclear cells [[107]].

Osteopontin gene

The osteopontin (OPN) gene encodes osteopontin which is a pro-inflammatory cytokine involved in chronic inflammatory diseases [[108],[109]]. It was shown that serum levels of OPN were significantly higher in patients with active VKH disease than in patients with inactive VKH disease and in the control group [[110]]. In the same study [[110]], recombinant OPN was shown to induce a significant increase in the proliferation of CD4+ T cells and secretion of interferon gamma and IL-17 in patients with active VKH disease. The frequency of the TT genotype of OPN rs4754 was also shown to be positively correlated with VKH disease in Chinese Han population [[110]].

Tumor necrosis factor, alpha-induced protein 3 gene

Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene encodes the A20 protein which is a cytoplasmic zinc finger protein. The A20 protein prevents the over-reaction of innate immune responses by suppressing TNF-induced signaling and negatively regulating nuclear factor kappa B (NF-κB) responses mediated by innate immune receptors including TNF receptor [[111],[112]]. TNFAIP3 polymorphisms were found to predispose to autoimmune diseases including rheumatoid arthritis [[113],[114]], psoriasis [[115]], and SLE [[116],[117]]. A study by Li et al. in VKH patients has found that the rs9494885 TC genotype and C allele may confer a risk to VKH disease, while the rs9494885 TT genotype and T allele may protect against VKH disease [[118]].

Macrophage migration inhibitory factor gene

The macrophage migration inhibitory factor (MIF) gene on chromosome 22q11.2 plays an important role in the level of MIF expression in macrophages and T cells, as well as release of other inflammatory cytokines [[119]]. SNPs in the MIF gene have been shown to be involved in a number of immunological diseases including psoriasis [[120]], SLE [[121]], ulcerative colitis [[122]], juvenile idiopathic arthritis [[123],[124]], and multiple sclerosis [[125]]. The levels of MIF were also found to be significantly higher in uveitis patients with VKH disease, sarcoidosis, and Behçet's disease [[126],[127]]. In a study by Zhang et al. [[128]], the frequencies of GG genotype and G allele of rs755622 in the MIF gene were found to be significantly lower in VKH patients than in controls. The frequency of T allele of rs2096525 was also significantly lower in patients with headache or vitiligo than in the control group [[128]]. Therefore, the GG genotype and G allele may be protective factors for VKH disease, while the T allele of rs2096525 may be a risk factor for non-ocular manifestation of VKH disease [[128]]. The study also demonstrated that the combined rs755622/rs2096525 CT haplotype confers an increased risk to VKH disease, whereas the GT haplotype reduces the susceptibility to VKH disease [[128]].

Tyrosinase gene family

Tyrosinase gene family is specifically expressed in melanocytes, and it encodes the enzymes that forms melanin [[129]]. Mutations of tyrosinase gene family are related to depigmentation and developmental defects of the eye including oculocutaneous albinism type 1 (OCA1) and microphthalmia [[130]-[133]]. Lymphocytes of patients with VKH disease were shown to be reactive to peptides derived from tyrosinase family proteins, thus it is possible that tyrosinase and tyrosinase-related proteins could be the auto-antigens in VKH disease [[1]]. However, a study evaluating polymorphisms of microsatellites loci in tyrosinase gene family among Japanese VKH patients has failed to find a significant association with VKH disease [[134]].

Interferon gamma gene

Previous studies have demonstrated elevated levels of interferon gamma in the aqueous humor and serum of patients with VKH disease [[135],[136]]. However, a study evaluating gene polymorphism of interferon gamma gene and VKH disease found no significant difference in the frequencies of alleles and genotypes of interferon gamma gene between VKH patients and healthy controls [[137]].

NLR family, pyrin domain containing 1 gene

NLR family, pyrin domain containing 1 (NLRP1) gene on chromosome 17p13 is involved in the primary immune system and was shown to be associated with generalized vitiligo and other autoimmune diseases [[138]-[141]]. Since skin hypopigmentation in VKH disease resembles generalized vitiligo, NLRP1 might be involved in the pathogenesis of VKH. However, a study by Horie et al. has shown that NLRP1 gene polymorphisms related to vitiligo were not associated with the risks or clinical manifestations of VKH disease, and this suggests that the genetic and immune factors associated with VKH disease are likely to be distinct from generalized vitiligo [[142]].

Toll-like receptor 9 gene

Toll-like receptor 9 (TLR9) recognizes unmethylated 2′-deoxyribo(cytidine-phosphate-guanosine) (CpG) dinucleotide motifs in viruses and is of importance in the immunological defense against viral infections [[143]]. TLR9 has been postulated to be one of the candidate genes in the pathogenesis of VKH, but a study by Ito et al. has failed to find a significant association between TLR9 polymorphisms and VKH disease [[144]].

Transforming growth factor β receptor gene

Transforming growth factor β ((TGF-β) influences the differentiation of Th17 [[145]-[147]], and two SNPs of type III TGF-β receptor (rs1805110 and rs2489188) have been investigated to determine their association with VKH disease in Chinese Han population [[148]]. These two SNPs were shown not to be associated with VKH disease, whereas rs2489188 CC genotype of the type III TGF-β receptor was shown to be protective against Behcet's disease [[148]].

Janus kinase 1 gene

Janus kinase 1 (JAK1) is an essential component of the human immune system which regulates cell differentiation of Th1 and Th17 [[149]]. A recent study suggested that three SNPs of the JAK1 gene including GG genotype of rs310230, GG genotype of rs310236, and TT genotype of rs310241 were found to occur in lower frequencies in VKH patients than control subjects [[150]]. However, no significant link between the three SNPs and clinical manifestations of VKH disease was identified, and currently, there is no published data on the functional role of these SNPs of JAK1 [[150]].

Fibroblast growth factor receptor 1 oncogene partner and chemokine (C-C motif) receptor 6 genes

Both fibroblast growth factor receptor 1 oncogene partner (FGFR1OP) and chemokine receptor 6 (CCR6) are encoded by a linkage disequilibrium block located on chromosome 6q27 [[151]], and both have been identified to be associated with susceptibility of vitiligo. Moreover, the two genes have been implicated in the pathogenesis of autoimmune diseases as CCR6 was found to be associated with Crohn's disease [[152]], ulcerative colitis [[153]], and rheumatoid arthritis [[154],[155]], while FGFR1OP was found to be related to Graves' disease [[156]] and myeloproliferative disorders [[157],[158]] and is involved in microtubule anchoring at the centrosome [[159]]. Two independent case-control cohorts of Chinese Han population have shown that the A allele of rs2301436 of FGFR1OP is associated with susceptibility to VKH, whereas no association was found for the four tested CCR6 SNPs including rs3093024, rs6902119, rs3093023, and rs968334 [[160]].

Limitations of genetic studies in VKH disease

Although genetic studies have contributed greatly in identifying mechanisms involved in the pathogenesis of VKH disease, they are not without any limitation. Firstly, there may be linkage disequilibrium in the genetic analysis, i.e., the occurrence of certain combinations of alleles or genetic markers in a population more frequently or less frequently than these would be expected from a totally random formation of haplotypes from alleles based on their original frequencies. Linkage equilibrium occurs when there is non-random correlation among neighboring alleles that descend from single ancestral chromosomes [[161]]. The genetic association found in the different studies may be in linkage disequilibrium with the causative locus, thereby leading to confounding of the results. Secondly, the effects of genotypes on phenotypes found in many of the research are not clearly known, and therefore, exactly how the SNPs affect the inflammatory proteins and their receptor functions remains uncertain. Therefore, whether the manipulations of these inflammatory proteins in patients with certain genotypes would be able to alter the course of VKH disease remain to be seen.

Conclusion

In recent years, advancement in research has shed some light on the genetic basis and mechanisms of uveitis including VKH disease. Multiple studies have demonstrated that genetic polymorphisms may influence the expression of genes or the functions of gene products and affect the susceptibility of VKH disease (Tables 4 and 5). Some of the major genetic factors involved in immune response associated with uveitis include HLA genes and non-HLA genes such as CTLA-4, ILs, and KIR. The autoimmune response against melanocytes in VKH disease involves a large variety of genes including variants of HLA genes, multiple ILs, and other cytokines and genes involved in the immune pathway. Since each individual gene may have an independent but small effect on the susceptibility and clinical manifestations of VKH disease, this increases the challenge of finding the genetic culprit in pathogenesis of VKH disease.

Table 4 Summary of genes that have been shown to be related to increased risk of VKH disease
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Table 5 Summary of genes which have been shown to be unrelated or with uncertain association with VKH disease
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For future directions of genetics study on VKH disease, in-depth genome-wide scans with fine mapping and exomic sequencing with replications in different ethnic groups will be important for revealing novel genetic regions associated with VKH disease. Detailed studies on correlations of various genotypes and phenotypes of VKH disease should also be carried out. These findings will greatly enhance our understanding in the role of genetic factors in the pathogenesis of VKH disease and will be useful in predicting treatment response and developing more targeted treatment and possible gene therapy.

Authors' information

The authors with qualifications are: Joanne YW Ng, MBBS FIona OJ Luk, MRCS Timothy YY Lai, MD, FRCS, FRCOphth Chi-Pui Pang, DPhil.

Acknowledgements

This paper was presented in part in the 2014 World Ophthalmology Congress, Tokyo, Japan, held in April 2014.

Abbreviations

CCR6:

chemokine (C-C Motif) receptor 6

CFH:

complement factor H

CTLA-4:

cytotoxic T-lymphocyte antigen 4

CpG:

cytidine-phosphate-guanosine

EAAU:

experimental autoimmune uveoretinitis

FGFR1OP:

fibroblast growth factor receptor 1 oncogene partner

HLA:

human leukocyte antigens

IL:

interleukin

JAK1:

Janus kinase 1

KIR:

killer cell immunoglobulin-like receptors

MIF:

macrophage migration inhibitory factor

MHC:

major histocompatibility complex

NK:

natural killer

NLRP1:

NLR family, pyrin domain containing 1

OCA1:

oculocutaneous albinism type 1

OPN:

osteopontin

PDCD1:

programmed cell death 1

PTPN22:

protein tyrosine phosphatase non-receptor 22

SLE:

systemic lupus erythematosus

SNPs:

single-nucleotide polymorphisms

TLR9:

toll-like receptor 9

TNFAIP3:

tumor necrosis factor alpha-induced protein 3

TGF-β:

transforming growth factor β

VKH:

Vogt-Koyanagi-Harada

References

  1. Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S: Tyrosinase family proteins are antigens specific to Vogt-Koyanagi-Harada disease. J Immunol 2000, 165: 7323–7329.

    Article  CAS  PubMed  Google Scholar 

  2. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, Pivetti-Pezzi P, Tessler HH, Usui M: Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001, 131: 647–652.

    Article  CAS  PubMed  Google Scholar 

  3. Kitamura M, Takami K, Kitaichi N, Namba K, Kitamei H, Kotake S, Ohno S: Comparative study of two sets of criteria for the diagnosis of Vogt-Koyanagi-Harada's disease. Am J Ophthalmol 2005, 139: 1080–1085. doi:10.1016/j.ajo.2005.01.046

    Article  PubMed  Google Scholar 

  4. Tabbara KF, Chavis PS, Freeman WR: Vogt-Koyanagi-Harada syndrome in children compared to adults. Acta Ophthalmol Scand 1998, 76: 723–726.

    Article  CAS  PubMed  Google Scholar 

  5. Wang Y, Chan CC: Gender differences in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. J Ophthalmol 2014, 2014: 157803. doi:10.1155/2014/157803

    PubMed Central  PubMed  Google Scholar 

  6. Yang P, Zhang Z, Zhou H, Li B, Huang X, Gao Y, Zhu L, Ren Y, Klooster J, Kijlstra A: Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res 2005, 30: 943–948. doi:10.1080/02713680500263606

    Article  PubMed  Google Scholar 

  7. Moorthy RS, Inomata H, Rao NA: Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol 1995, 39: 265–292.

    Article  CAS  PubMed  Google Scholar 

  8. Yamaki K, Hara K, Sakuragi S: Application of revised diagnostic criteria for Vogt-Koyanagi-Harada disease in Japanese patients. Jpn J Ophthalmol 2005, 49: 143–148. doi:10.1007/s10384–004–0165–9

    Article  PubMed  Google Scholar 

  9. Sasamoto Y, Ohno S, Matsuda H: Studies on corticosteroid therapy in Vogt-Koyanagi-Harada disease. Ophthalmologica 1990, 201: 162–167.

    Article  CAS  PubMed  Google Scholar 

  10. Rubsamen PE, Gass JD: Vogt-Koyanagi-Harada syndrome. Clinical course, therapy, and long-term visual outcome. Arch Ophthalmol 1991, 109: 682–687.

    Article  CAS  PubMed  Google Scholar 

  11. Read RW, Yu F, Accorinti M, Bodaghi B, Chee SP, Fardeau C, Goto H, Holland GN, Kawashima H, Kojima E, Lehoang P, Lemaitre C, Okada AA, Pivetti-Pezzi P, Secchi A, See RF, Tabbara KF, Usui M, Rao NA: Evaluation of the effect on outcomes of the route of administration of corticosteroids in acute Vogt-Koyanagi-Harada disease. Am J Ophthalmol 2006, 142: 119–124. doi:10.1016/j.ajo.2006.02.049

    Article  CAS  PubMed  Google Scholar 

  12. Chee SP, Luu CD, Cheng CL, Lim WK, Jap A: Visual function in Vogt-Koyanagi-Harada patients. Graefes Arch Clin Exp Ophthalmol 2005, 243: 785–790. doi:10.1007/s00417–005–1156–3

    Article  PubMed  Google Scholar 

  13. Lai TY, Chan RP, Chan CK, Lam DS: Effects of the duration of initial oral corticosteroid treatment on the recurrence of inflammation in Vogt-Koyanagi-Harada disease. Eye (Lond) 2009, 23: 543–548. doi:10.1038/eye.2008.89

    Article  CAS  Google Scholar 

  14. Rao NA: Pathology of Vogt-Koyanagi-Harada disease. Int Ophthalmol 2007, 27: 81–85. doi:10.1007/s10792–006–9029–2

    Article  PubMed  Google Scholar 

  15. Inomata H, Rao NA: Depigmented atrophic lesions in sunset glow fundi of Vogt-Koyanagi-Harada disease. Am J Ophthalmol 2001, 131: 607–614.

    Article  CAS  PubMed  Google Scholar 

  16. Bassili SS, Peyman GA, Gebhardt BM, Daun M, Ganiban GJ, Rifai A: Detection of Epstein-Barr virus DNA by polymerase chain reaction in the vitreous from a patient with Vogt-Koyanagi-Harada syndrome. Retina 1996, 16: 160–161.

    Article  CAS  PubMed  Google Scholar 

  17. Sugita S, Takase H, Kawaguchi T, Taguchi C, Mochizuki M: Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by T cells from patients with Vogt-Koyanagi-Harada disease. Int Ophthalmol 2007, 27: 87–95. doi:10.1007/s10792–006–9020-y

    Article  PubMed  Google Scholar 

  18. Greco A, Fusconi M, Gallo A, Turchetta R, Marinelli C, Macri GF, De Virgilio A, de Vincentiis M: Vogt-Koyanagi-Harada syndrome. Autoimmun Rev 2013, 12: 1033–1038. doi:10.1016/j.autrev.2013.01.004

    Article  CAS  PubMed  Google Scholar 

  19. Otani S, Sakurai T, Yamamoto K, Fujita T, Matsuzaki Y, Goto Y, Ando Y, Suzuki S, Usui M, Takeuchi M, Kawakami Y: Frequent immune response to a melanocyte specific protein KU-MEL-1 in patients with Vogt-Koyanagi-Harada disease. Br J Ophthalmol 2006, 90: 773–777. doi:10.1136/bjo.2005.086520

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Klein J, Sato A: The HLA system: first of two parts. New Eng J Med 2000, 343: 702–709.

    Article  CAS  PubMed  Google Scholar 

  21. Shiina T, Inoko H, Kulski JK: An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 2004, 64: 631–649. doi:10.1111/j.1399–0039.2004.00327.x

    Article  CAS  PubMed  Google Scholar 

  22. Stastny P: Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978, 298: 869–871. doi:10.1056/nejm197804202981602

    Article  CAS  PubMed  Google Scholar 

  23. McMichael AJ, Sasazuki T, McDevitt HO, Payne RO: Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arthritis Rheum 1977, 20: 1037–1042.

    Article  CAS  PubMed  Google Scholar 

  24. Islam SM, Numaga J, Fujino Y, Hirata R, Matsuki K, Maeda H, Masuda K: HLA class II genes in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 1994, 35: 3890–3896.

    CAS  PubMed  Google Scholar 

  25. Zhang XY, Wang XM, Hu TS: Profiling human leukocyte antigens in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1992, 113: 567–572.

    Article  CAS  PubMed  Google Scholar 

  26. Tagawa Y, Sugiura S, Yakura H, Wakisaka A, Aizawa M: Letter: HLA and Vogt-Koyanagi-Harada syndrome. N Engl J Med 1976, 295: 173.

    CAS  PubMed  Google Scholar 

  27. Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican DC, Palestine AG, Nussenblatt RB: HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology 1990, 97: 1137–1142.

    Article  CAS  PubMed  Google Scholar 

  28. Shindo Y, Inoko H, Yamamoto T, Ohno S: HLA-DRB1 typing of Vogt-Koyanagi-Harada's disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410. Br J Ophthalmol 1994, 78: 223–226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Shindo Y, Ohno S, Yamamoto T, Nakamura S, Inoko H: Complete association of the HLA-DRB1*04 and -DQB1*04 alleles with Vogt-Koyanagi-Harada's disease. Hum Immunol 1994, 39: 169–176.

    Article  CAS  PubMed  Google Scholar 

  30. Weisz JM, Holland GN, Roer LN, Park MS, Yuge AJ, Moorthy RS, Forster DJ, Rao NA, Terasaki PI: Association between Vogt-Koyanagi-Harada syndrome and HLA-DR1 and -DR4 in Hispanic patients living in southern California. Ophthalmology 1995, 102: 1012–1015.

    Article  CAS  PubMed  Google Scholar 

  31. Arellanes-Garcia L, Bautista N, Mora P, Ortega-Larrocea G, Burguet A, Gorodezky C: HLA-DR is strongly associated with Vogt-Koyanagi-Harada disease in Mexican Mestizo patients. Ocul Immunol Inflamm 1998, 6: 93–100.

    Article  CAS  PubMed  Google Scholar 

  32. Levinson RD, See RF, Rajalingam R, Reed EF, Park MS, Rao NA, Holland GN: HLA-DRB1 and -DQB1 alleles in Mestizo patients with Vogt-Koyanagi-Harada's disease in Southern California. Hum Immunol 2004, 65: 1477–1482. doi:10.1016/j.humimm.2004.07.236

    Article  CAS  PubMed  Google Scholar 

  33. Pivetti-Pezzi P, Accorinti M, Colabelli-Gisoldi RA, Pirraglia MP: Vogt-Koyanagi-Harada disease and HLA type in Italian patients. Am J Ophthalmol 1996, 122: 889–891.

    Article  CAS  PubMed  Google Scholar 

  34. Goldberg AC, Yamamoto JH, Chiarella JM, Marin ML, Sibinelli M, Neufeld R, Hirata CE, Olivalves E, Kalil J: HLA-DRB1*0405 is the predominant allele in Brazilian patients with Vogt-Koyanagi-Harada disease. Hum Immunol 1998, 59: 183–188.

    Article  CAS  PubMed  Google Scholar 

  35. Kim MH, Seong MC, Kwak NH, Yoo JS, Huh W, Kim TG, Han H: Association of HLA with Vogt-Koyanagi-Harada syndrome in Koreans. Am J Ophthalmol 2000, 129: 173–177.

    Article  CAS  PubMed  Google Scholar 

  36. Iqniebi A, Gaafar A, Sheereen A, Al-Suliman A, Mohamed G, Al-Hussein K, Tabbara KF: HLA-DRB1 among patients with Vogt-Koyanagi-Harada disease in Saudi Arabia. Mol Vis 2009, 15: 1876–1880.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Islam SM, Numaga J, Matsuki K, Fujino Y, Maeda H, Masuda K: Influence of HLA-DRB1 gene variation on the clinical course of Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 1994, 35: 752–756.

    CAS  PubMed  Google Scholar 

  38. Damico FM, Cunha-Neto E, Goldberg AC, Iwai LK, Marin ML, Hammer J, Kalil J, Yamamoto JH: T-cell recognition and cytokine profile induced by melanocyte epitopes in patients with HLA-DRB1*0405-positive and -negative Vogt-Koyanagi-Harada uveitis. Invest Ophthalmol Vis Sci 2005, 46: 2465–2471. doi:10.1167/iovs.04–1273

    Article  PubMed  Google Scholar 

  39. Nomura S, Matsuzaki T, Ozaki Y, Yamaoka M, Yoshimura C, Katsura K, Xie GL, Kagawa H, Ishida T, Fukuhara S: Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura. Blood 1998, 91: 3616–3622.

    CAS  PubMed  Google Scholar 

  40. Alaez C, Flores AH, Concha del Rio LE, Munguia A, Rodriguez A, Garcia D, Arellanes L, Gorodezky C: Major histocompatibility complex and strong human leukocyte antigen-DRB1 and gender association with Vogt-Koyanagi-Harada syndrome in Mexican Mestizos. Hum Immunol 2011, 72: 1198–1203. doi:10.1016/j.humimm.2011.09.002

    Article  CAS  PubMed  Google Scholar 

  41. Tiercy JM, Rathinam SR, Gex-Fabry M, Baglivo E: A shared HLA-DRB1 epitope in the DR beta first domain is associated with Vogt-Koyanagi-Harada syndrome in Indian patients. Mol Vis 2010, 16: 353–358.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Jaini R, Kaur G, Mehra NK: Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the North Indian population. Hum Immunol 2002, 63: 24–29.

    Article  CAS  PubMed  Google Scholar 

  43. Gupta A, Kamal S, Gupta V, Bambery P, Kaura B: HLA typing in Vogt-Koyanagi-Harada syndrome in North Indian patients. Ocul Immunol Inflamm 2007, 15: 89–97. doi:10.1080/09273940601186727

    Article  CAS  PubMed  Google Scholar 

  44. Perkins D, Wang Z, Donovan C, He H, Mark D, Guan G, Wang Y, Walunas T, Bluestone J, Listman J, Finn PW: Regulation of CTLA-4 expression during T cell activation. J Immunol 1996, 156: 4154–4159.

    CAS  PubMed  Google Scholar 

  45. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, et al.: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003, 423: 506–511. doi:10.1038/nature01621

    Article  CAS  PubMed  Google Scholar 

  46. Harbo HF, Celius EG, Vartdal F, Spurkland A: CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis. Tissue Antigens 1999, 53: 106–110.

    Article  CAS  PubMed  Google Scholar 

  47. Hudson LL, Rocca K, Song YW, Pandey JP: CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region. Hum Genet 2002, 111: 452–455. doi:10.1007/s00439–002–0807–2

    Article  CAS  PubMed  Google Scholar 

  48. Gonzalez-Escribano MF, Rodriguez R, Valenzuela A, Garcia A, Garcia-Lozano JR, Nunez-Roldan A: CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis. Tissue Antigens 1999, 53: 296–300.

    Article  CAS  PubMed  Google Scholar 

  49. Lei C, Dongqing Z, Yeqing S, Oaks MK, Lishan C, Jianzhong J, Jie Q, Fang D, Ningli L, Xinghai H, Daming R: Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population. Eur J Hum Genet 2005, 13: 823–828. doi:10.1038/sj.ejhg.5201423

    Article  PubMed  CAS  Google Scholar 

  50. Deng L, Zhou H, Yang J, Xiao J, Wang B, Wang L, Ou X, Feng Y: CTLA-4 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease. Int J Clin Exp Pathol 2013, 6: 2548–2553.

    PubMed Central  PubMed  Google Scholar 

  51. Knight AK, Serrano D, Tomer Y, Cunningham-Rundles C: CTLA-4 gene exon-1 +49 A/G polymorphism: lack of association with autoimmune disease in patients with common variable immune deficiency. J Clin Immunol 2007, 27: 95–100. doi:10.1007/s10875–006–9049–8

    Article  CAS  PubMed  Google Scholar 

  52. Yanagawa T, Maruyama T, Gomi K, Taniyama M, Kasuga A, Ozawa Y, Terauchi M, Hirose H, Maruyama H, Saruta T: Lack of association between CTLA-4 gene polymorphism and IDDM in Japanese subjects. Autoimmunity 1999, 29: 53–56.

    Article  CAS  PubMed  Google Scholar 

  53. Du L, Yang P, Hou S, Lin X, Zhou H, Huang X, Wang L, Kijlstra A: Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome. Clin Immunol 2008, 127: 43–48. doi:10.1016/j.clim.2008.01.004

    Article  CAS  PubMed  Google Scholar 

  54. Jha P, Sohn JH, Xu Q, Nishihori H, Wang Y, Nishihori S, Manickam B, Kaplan HJ, Bora PS, Bora NS: The complement system plays a critical role in the development of experimental autoimmune anterior uveitis. Invest Ophthalmol Vis Sci 2006, 47: 1030–1038.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Manickam B, Jha P, Matta B, Liu J, Bora PS, Bora NS: Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses. J Biol Chem 2011, 286: 8472–8480.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Yang MM, Lai TY, Tam PO, Chiang SW, Chan CK, Luk FO, Ng TK, Pang CP: CFH 184G as a genetic risk marker for anterior uveitis in Chinese females. Mol Vis 2011, 17: 2655–2664.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Yang MM, Lai TY, Tam PO, Chiang SW, Chan CK, Luk FO, Ng TK, Pang CP: Complement factor H and interleukin gene polymorphisms in patients with non-infectious intermediate and posterior uveitis. Mol Vis 2012, 18: 1865–1872.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Arocker-Mettinger E, Asenbauer T, Ulbrich S, Grabner G: Serum interleukin 2-receptor levels in uveitis. Curr Eye Res 1990, 9: 25–29.

    Article  PubMed  Google Scholar 

  59. Lacomba MS, Martin CM, Chamond RR, Galera JM, Omar M, Estevez EC: Aqueous and serum interferon gamma, interleukin (IL) 2, IL-4, and IL-10 in patients with uveitis. Arch Ophthalmol 2000, 118: 768–772.

    Article  CAS  PubMed  Google Scholar 

  60. Liu L, Xu Y, Wang J, Li H: Upregulated IL-21 and IL-21 receptor expression is involved in experimental autoimmune uveitis (EAU). Mol Vis 2009, 15: 2938–2944.

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Hamzaoui K, Hamza M, Ayed K: Production of TNF-alpha and IL-1 in active Behcet's disease. J Rheumatol 1990, 17: 1428–1429.

    CAS  PubMed  Google Scholar 

  62. Charteris DG, Lightman SL: Comparison of the expression of interferon gamma, IL2, IL4, and lymphotoxin mRNA in experimental autoimmune uveoretinitis. Br J Ophthalmol 1994,78(10):786–790.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Cordeiro CA, Moreira PR, Costa GC, Dutra WO, Campos WR, Orefice F, Teixeira AL: Interleukin-1 gene polymorphisms and toxoplasmic retinochoroiditis. Mol Vis 2008, 14: 1845–1849.

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Trinchieri G: Interleukin-12 and its role in the generation of TH1 cells. Immunol Today 1993, 14: 335–338.

    Article  CAS  PubMed  Google Scholar 

  65. Frassanito MA, Dammacco R, Cafforio P, Dammacco F: Th1 polarization of the immune response in Behcet's disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum 1999, 42: 1967–1974.

    Article  CAS  PubMed  Google Scholar 

  66. Yanagihori H, Oyama N, Nakamura K, Mizuki N, Oguma K, Kaneko F: 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: 1534–1540.

    Article  CAS  PubMed  Google Scholar 

  67. Li X, Bai L, Fang J, Hou S, Zhou Q, Yu H, Kijlstra A, Yang P: Genetic variations of IL-12B, IL-12Rbeta1, IL-12Rbeta2 in Behcet's disease and VKH syndrome. PLoS One 2014, 9: 98373. doi:10.1371/journal.pone.0098373

    Article  CAS  Google Scholar 

  68. Chi W, Yang P, Li B, Wu C, Jin H, Zhu X, Chen L, Zhou H, Huang X, Kijlstra A: IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol 2007, 119: 1218–1224. doi:10.1016/j.jaci.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  69. Shu Q, Yang P, Hou S, Li F, Chen Y, Du L, Jiang Z: 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: 988–991. doi:10.1016/j.humimm.2010.06.020

    Article  CAS  PubMed  Google Scholar 

  70. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421: 744–748. doi:10.1038/nature01355

    Article  CAS  PubMed  Google Scholar 

  71. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ: Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003, 198: 1951–1957. doi:10.1084/jem.20030896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005, 201: 233–240. doi:10.1084/jem.20041257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Jiang Z, Yang P, Hou S, Li F, Zhou H: Polymorphisms of IL23R and Vogt-Koyanagi-Harada syndrome in a Chinese Han population. Hum Immunol 2010, 71: 414–417. doi:10.1016/j.humimm.2010.01.026

    Article  CAS  PubMed  Google Scholar 

  74. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS, Egwuagu CE: TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007, 13: 711–718.

    Article  CAS  PubMed  Google Scholar 

  75. Cua DJ, Kastelein RA: TGF-beta, a 'double agent' in the immune pathology war. Nat Immunol 2006, 7: 557–559. doi:10.1038/ni0606–557

    Article  CAS  PubMed  Google Scholar 

  76. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM: Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006, 24: 677–688.

    Article  CAS  PubMed  Google Scholar 

  77. Parham P: Immunogenetics of killer cell immunoglobulin-like receptors. Mol Immunol 2005, 42: 459–462. doi:10.1016/j.molimm.2004.07.027

    Article  CAS  PubMed  Google Scholar 

  78. Boyton RJ, Altmann DM: Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. Clin Exp Immunol 2007, 149: 1–8. doi:10.1111/j.1365–2249.2007.03424.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Sheereen A, Gaafar A, Iqneibi A, Eldali A, Tabbara KF, Adra C, Al-Hussein K: A study of KIR genes and HLA-C in Vogt-Koyanagi-Harada disease in Saudi Arabia. Mol Vis 2011, 17: 3523–3528.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Levinson RD, Okada AA, Ashouri E, Keino H, Rajalingam R: Killer cell immunoglobulin-like receptor gene-cluster 3DS1–2DL5–2DS1–2DS5 predisposes susceptibility to Vogt-Koyanagi-Harada syndrome in Japanese individuals. Hum Immunol 2010, 71: 192–194. doi:10.1016/j.humimm.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  81. Ishida Y, Agata Y, Shibahara K, Honjo T: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992, 11: 3887–3895.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Rui Y, Honjo T, Chikuma S: Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc Natl Acad Sci USA 2013, 110: 16073–16078. doi:10.1073/pnas.1315828110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Newby PR, Roberts-Davies EL, Brand OJ, Heward JM, Franklyn JA, Gough SC, Simmonds MJ: Tag SNP screening of the PDCD1 gene for association with Graves' disease. Clin Endocrinol (Oxf) 2007, 67: 125–128. doi:10.1111/j.1365–2265.2007.02848.x

    Article  CAS  Google Scholar 

  84. Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST: Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 2003, 62: 492–497.

    Article  CAS  PubMed  Google Scholar 

  85. Lee SH, Lee YA, Woo DH, Song R, Park EK, Ryu MH, Kim YH, Kim KS, Hong SJ, Yoo MC, Yang HI: Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther 2006, 8: R163. doi:10.1186/ar2071

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  86. Kong EK, Prokunina-Olsson L, Wong WH, Lau CS, Chan TM, Alarcon-Riquelme M, Lau YL: A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum 2005, 52: 1058–1062. doi:10.1002/art.20966

    Article  CAS  PubMed  Google Scholar 

  87. Liu C, Jiang J, Gao L, Hu X, Wang F, Shen Y, Yu G, Zhao Z, Zhang X: A promoter region polymorphism in PDCD-1 gene is associated with risk of rheumatoid arthritis in the Han Chinese population of southeastern China. Int J Genomics 2014, 2014: 247637. doi:10.1155/2014/247637

    PubMed Central  PubMed  Google Scholar 

  88. Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME: A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002, 32: 666–669. doi:10.1038/ng1020

    Article  CAS  PubMed  Google Scholar 

  89. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, Carracedo A, Carreira P, Gonzalez-Escribano F, Liz M, Martin J, Ordi J, Vicario JL, Gonzalez A: Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. Arthritis Rheum 2004, 50: 2590–2597. doi:10.1002/art.20436

    Article  CAS  PubMed  Google Scholar 

  90. Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, Carreno-Manjarrez R, Solis-Vallejo E, Lopez-Lara ND, Ruiz-Lopez IK, Rodriguez-Lozano AL, Estrada-Gil JK, Jimenez-Sanchez G, Baca V: Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus. Eur J Hum Genet 2007, 15: 336–341. doi:10.1038/sj.ejhg.5201767

    Article  CAS  PubMed  Google Scholar 

  91. Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, Alarcon-Riquelme ME, Criswell LA: Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun 2007, 8: 279–287. doi:10.1038/sj.gene.6364383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Maurer M, Wiendl H: A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 2005, 58: 50–57. doi:10.1002/ana.20514

    Article  CAS  PubMed  Google Scholar 

  93. Abelson AK, Johansson CM, Kozyrev SV, Kristjansdottir H, Gunnarsson I, Svenungsson E, Jonsen A, Lima G, Scherbarth HR, Gamron S, Allievi A, Palatnik SA, Alvarellos A, Paira S, Graf C, Guilleron C, Catoggio LJ, Prigione C, Battagliotti CG, Berbotto GA, Garcia MA, Perandones CE, Truedsson L, Steinsson K, Sturfelt G, Pons-Estel B, Alarcon-Riquelme ME: No evidence of association between genetic variants of the PDCD1 ligands and SLE. Genes Immun 2007, 8: 69–74. doi:10.1038/sj.gene.6364360

    Article  CAS  PubMed  Google Scholar 

  94. Lin SC, Yen JH, Tsai JJ, Tsai WC, Ou TT, Liu HW, Chen CJ: Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum 2004, 50: 770–775. doi:10.1002/art.20040

    Article  CAS  PubMed  Google Scholar 

  95. Iwamoto T, Ikari K, Inoue E, Toyama Y, Hara M, Yamanaka H, Tomatsu T, Momohara S, Kamatani N: Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population. J Hum Genet 2007, 52: 557–560. doi:10.1007/s10038–007–0145–2

    Article  CAS  PubMed  Google Scholar 

  96. Asad S, Nikamo P, Torn C, Landin-Olsson M, Lernmark A, Alarcon-Riquelme M, Kockum I: No evidence of association of the PDCD1 gene with type 1 diabetes. Diabet Med 2007, 24: 1473–1477. doi:10.1111/j.1464–5491.2007.02297.x

    Article  CAS  PubMed  Google Scholar 

  97. Jiao Q, Liu C, Yang Z, Ding Q, Wang M, Li M, Zhu T, Qian H, Li W, Tu N, Fang F, Ye L, Zhao Z, Qian Q: Upregulated PD-1 expression is associated with the development of systemic lupus erythematosus, but not the PD-1.1 allele of the PDCD1 gene. Int J Genomics 2014, 2014: 950903.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Meng Q, Liu X, Yang P, Hou S, Du L, Zhou H, Kijlstra A: PDCD1 genes may protect against extraocular manifestations in Chinese Han patients with Vogt-Koyanagi-Harada syndrome. Mol Vis 2009, 15: 386–392.

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Bottini N, Peterson EJ: Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol 2014, 32: 83–119. doi:10.1146/annurev-immunol-032713–120249

    Article  CAS  PubMed  Google Scholar 

  100. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004, 36: 337–338. doi:10.1038/ng1323

    Article  CAS  PubMed  Google Scholar 

  101. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK: Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005, 76: 561–571. doi:10.1086/429096

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK: A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004, 75: 330–337. doi:10.1086/422827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Michou L, Lasbleiz S, Rat AC, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Pierlot C, Glikmans E, Garnier S, Dausset J, Vaz C, Fernandes M, Petit-Teixeira E, Lemaire I, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Dieude P, Cornelis F: Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene. Proc Natl Acad Sci USA 2007, 104: 1649–1654. doi:10.1073/pnas.0610250104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Ichimura M, Kaku H, Fukutani T, Koga H, Mukai T, Miyake I, Yamada K, Koda Y, Hiromatsu Y: Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population. Thyroid 2008, 18: 625–630. doi:10.1089/thy.2007.0353

    Article  CAS  PubMed  Google Scholar 

  105. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW: Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004, 75: 504–507. doi:10.1086/423790

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Horie Y, Kitaichi N, Katsuyama Y, Yoshida K, Miura T, Ota M, Asukata Y, Inoko H, Mizuki N, Ishida S, Ohno S: Evaluation of PTPN22 polymorphisms and Vogt-Koyanagi-Harada disease in Japanese patients. Mol Vis 2009, 15: 1115–1119.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Zhang Q, Qi J, Hou S, Du L, Yu H, Cao Q, Zhou Y, Liao D, Kijlstra A, Yang P: A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis. PLoS One 2014, 9: e96943. doi:10.1371/journal.pone.0096943

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  108. Heilmann K, Hoffmann U, Witte E, Loddenkemper C, Sina C, Schreiber S, Hayford C, Holzlohner P, Wolk K, Tchatchou E, Moos V, Zeitz M, Sabat R, Gunthert U, Wittig BM: Osteopontin as two-sided mediator of intestinal inflammation. J Cell Mol Med 2009, 13: 1162–1174. doi:10.1111/j.1582–4934.2008.00428.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Lund SA, Giachelli CM, Scatena M: The role of osteopontin in inflammatory processes. J Cell Commun Signal 2009, 3: 311–322. doi:10.1007/s12079–009–0068–0

    Article  PubMed Central  PubMed  Google Scholar 

  110. Chu M, Yang P, Hu R, Hou S, Li F, Chen Y, Kijlstra A: Elevated serum osteopontin levels and genetic polymorphisms of osteopontin are associated with Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 2011, 52: 7084–7089. doi:10.1167/iovs.11–7539

    Article  CAS  PubMed  Google Scholar 

  111. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000, 289: 2350–2354.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Liu YC, Penninger J, Karin M: Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol 2005, 5: 941–952. doi:10.1038/nri1731

    Article  CAS  PubMed  Google Scholar 

  113. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Neale BM, Izmailova E, Roubenoff R, Parker AN, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al.: Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007, 39: 1477–1482. doi:10.1038/ng.2007.27

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons D, Hider S, Bruce IN, Wilson AG, Marinou I, Morgan A, Emery P, Carter A, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Strachan D, Worthington J: Rheumatoid arthritis association at 6q23. Nat Genet 2007, 39: 1431–1433. doi:10.1038/ng.2007.32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR: Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009, 41: 199–204. doi:10.1038/ng.311

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, Burtt NP, Guiducci C, Parkin M, Gates C, Plenge RM, Behrens TW, Wither JE, Rioux JD, Fortin PR, Graham DC, Wong AK, Vyse TJ, Daly MJ, Altshuler D, Moser KL, Gaffney PM: Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008, 40: 1059–1061. doi:10.1038/ng.200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ, Bates JS, Hu Y, Kelly JA, Kaufman KM, Guthridge JM, Alarcon-Riquelme ME, Anaya JM, Bae SC, Bang SY, Boackle SA, Brown EE, Petri MA, Gallant C, Ramsey-Goldman R, Reveille JD, Vila LM, Criswell LA, Edberg JC, Freedman BI, Gregersen PK, Gilkeson GS, Jacob CO, James JA, Kamen DL, et al.: Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet 2011, 43: 253–258. doi:10.1038/ng.766

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Li H, Liu Q, Hou S, Du L, Zhou Q, Zhou Y, Kijlstra A, Yang P: TNFAIP3 gene polymorphisms in a Chinese Han population with Vogt-Koyanagi-Harada syndrome. PLoS One 2013, 8: e59515. doi:10.1371/journal.pone.0059515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Baugh JA, Bucala R: Macrophage migration inhibitory factor. Crit Care Med 2002, 30: S27–35.

    Article  CAS  Google Scholar 

  120. Donn RP, Plant D, Jury F, Richards HL, Worthington J, Ray DW, Griffiths CE: Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J Invest Dermatol 2004, 123: 484–487. doi:10.1111/j.0022–202X.2004.23314.x

    Article  CAS  PubMed  Google Scholar 

  121. Sanchez E, Gomez LM, Lopez-Nevot MA, Gonzalez-Gay MA, Sabio JM, Ortego-Centeno N, de Ramon E, Anaya JM, Gonzalez-Escribano MF, Koeleman BP, Martin J: Evidence of association of macrophage migration inhibitory factor gene polymorphisms with systemic lupus erythematosus. Genes Immun 2006, 7: 433–436. doi:10.1038/sj.gene.6364310

    Article  CAS  PubMed  Google Scholar 

  122. Nohara H, Okayama N, Inoue N, Koike Y, Fujimura K, Suehiro Y, Hamanaka Y, Higaki S, Yanai H, Yoshida T, Hibi T, Okita K, Hinoda Y: Association of the -173G/C polymorphism of the macrophage migration inhibitory factor gene with ulcerative colitis. J Gastroenterol 2004, 39: 242–246. doi:10.1007/s00535–003–1284–7

    Article  CAS  PubMed  Google Scholar 

  123. Donn R, Alourfi Z, Zeggini E, Lamb R, Jury F, Lunt M, Meazza C, De Benedetti F, Thomson W, Ray D: A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 2004, 50: 1604–1610. doi:10.1002/art.20178

    Article  PubMed  Google Scholar 

  124. Berdeli A, Ozyurek AR, Ulger Z, Gurses D, Levent E, Salar K, Gurpinar AR: Association of macrophage migration inhibitory factor gene -173 G/C polymorphism with prognosis in Turkish children with juvenile rheumatoid arthritis. Rheumatol Int 2006, 26: 726–731. doi:10.1007/s00296–005–0062–7

    Article  CAS  PubMed  Google Scholar 

  125. Akcali A, Pehlivan S, Pehlivan M, Sever T, Neyal M: Association of macrophage migration inhibitory factor gene promoter polymorphisms with multiple sclerosis in Turkish patients. J Int Med Res 2010, 38: 69–77.

    Article  CAS  PubMed  Google Scholar 

  126. Kotake S, Kitaichi N, Ohno S: Macrophage migration inhibitory factor in uveitis. Int Ophthalmol Clin 2002, 42: 99–103.

    Article  PubMed  Google Scholar 

  127. Kitaichi N, Kotake S, Sasamoto Y, Namba K, Matsuda A, Ogasawara K, Onoe K, Matsuda H, Nishihira J: Prominent increase of macrophage migration inhibitory factor in the sera of patients with uveitis. Invest Ophthalmol Vis Sci 1999, 40: 247–250.

    CAS  PubMed  Google Scholar 

  128. Zhang C, Liu S, Hou S, Lei B, Zheng X, Xiao X, Kijlstra A, Yang P: MIF gene polymorphisms confer susceptibility to Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Invest Ophthalmol Vis Sci 2013, 54: 7734–7738. doi:10.1167/iovs.13–12187

    Article  CAS  PubMed  Google Scholar 

  129. Jimenez-Cervantes C, Solano F, Kobayashi T, Urabe K, Hearing VJ, Lozano JA, Garcia-Borron JC: A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP1). J Biol Chem 1994, 269: 17993–18000.

    CAS  PubMed  Google Scholar 

  130. Sturm RA, Teasdale RD, Box NF: Human pigmentation genes: identification, structure and consequences of polymorphic variation. Gene 2001, 277: 49–62.

    Article  CAS  PubMed  Google Scholar 

  131. Oetting WS: The tyrosinase gene and oculocutaneous albinism type 1 (OCA1): a model for understanding the molecular biology of melanin formation. Pigment Cell Res 2000, 13: 320–325.

    Article  CAS  PubMed  Google Scholar 

  132. Sundaresan P, Sil AK, Philp AR, Randolph MA, Natchiar G, Namperumalsamy P: Genetic analysis of oculocutaneous albinism type 1 (OCA1) in Indian families: two novel frameshift mutations in the TYR Gene. Mol Vis 2004, 10: 1005–1010.

    CAS  PubMed  Google Scholar 

  133. Chaki M, Mukhopadhyay A, Chatterjee S, Das M, Samanta S, Ray K: Higher prevalence of OCA1 in an ethnic group of eastern India is due to a founder mutation in the tyrosinase gene. Mol Vis 2005, 11: 531–534.

    CAS  PubMed  Google Scholar 

  134. Horie Y, Takemoto Y, Miyazaki A, Namba K, Kase S, Yoshida K, Ota M, Hasumi Y, Inoko H, Mizuki N, Ohno S: Tyrosinase gene family and Vogt-Koyanagi-Harada disease in Japanese patients. Mol Vis 2006, 12: 1601–1605.

    CAS  PubMed  Google Scholar 

  135. Takase H, Futagami Y, Yoshida T, Kamoi K, Sugita S, Imai Y, Mochizuki M: Cytokine profile in aqueous humor and sera of patients with infectious or noninfectious uveitis. Invest Ophthalmol Vis Sci 2006, 47: 1557–1561. doi:10.1167/iovs.05–0836

    Article  PubMed  Google Scholar 

  136. Ohno S: Immunological aspects of Behcet's and Vogt-Koyanagi-Harada's diseases. Trans Ophthalmol Soc UK 1981,101(Pt 3):335–341.

    PubMed  Google Scholar 

  137. Horie Y, Kitaichi N, Takemoto Y, Namba K, Yoshida K, Hirose S, Hasumi Y, Ota M, Inoko H, Mizuki N, Ohno S: Polymorphism of IFN-gamma gene and Vogt-Koyanagi-Harada disease. Mol Vis 2007, 13: 2334–2338.

    PubMed  Google Scholar 

  138. Gregersen PK: Modern genetics, ancient defenses, and potential therapies. N Engl J Med 2007, 356: 1263–1266. doi:10.1056/NEJMe078017

    Article  PubMed  Google Scholar 

  139. Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA: Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 2003, 16: 208–214.

    Article  PubMed  Google Scholar 

  140. Laberge G, Mailloux CM, Gowan K, Holland P, Bennett DC, Fain PR, Spritz RA: Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res 2005, 18: 300–305.

    Article  PubMed  Google Scholar 

  141. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA: NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007, 356: 1216–1225.

    Article  CAS  PubMed  Google Scholar 

  142. Horie Y, Saito W, Kitaichi N, Miura T, Ishida S, Ohno S: Evaluation of NLRP1 gene polymorphisms in Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 2011, 55: 57–61. doi:10.1007/s10384–010–0887–9

    Article  PubMed  Google Scholar 

  143. Kandimalla ER, Zhu FG, Bhagat L, Yu D, Agrawal S: Toll-like receptor 9: modulation of recognition and cytokine induction by novel synthetic CpG DNAs. Biochem Soc Trans 2003,31(Pt 3):654–658.

    Article  CAS  PubMed  Google Scholar 

  144. Ito R, Ota M, Meguro A, Katsuyama Y, Uemoto R, Nomura E, Nishide T, Kitaichi N, Horie Y, Namba K, Ohno S, Inoko H, Mizuki N: Investigation of association between TLR9 gene polymorphisms and VKH in Japanese patients. Ocul Immunol Inflamm 2011, 19: 202–205. doi:10.3109/09273948.2011.553981

    Article  CAS  PubMed  Google Scholar 

  145. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT: Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006, 441: 231–234.

    Article  CAS  PubMed  Google Scholar 

  146. Manel N, Unutmaz D, Littman DR: The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008, 9: 641–649.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. O'Garra A, Stockinger B, Veldhoen M: Differentiation of human T(H)-17 cells does require TGF-beta! Nat Immunol 2008, 9: 588–590. doi:10.1038/ni0608–588

    Article  PubMed  CAS  Google Scholar 

  148. Chen Y, Yang P, Li F, Hou S, Jiang Z, Shu Q, Kijlstra A: Association analysis of TGFBR3 gene with Vogt-Koyanagi-Harada disease and Behcet's disease in the Chinese Han population. Curr Eye Res 2012, 37: 312–317. doi:10.3109/02713683.2011.635398

    Article  CAS  PubMed  Google Scholar 

  149. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH: Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 2007, 178: 4901–4907.

    Article  CAS  PubMed  Google Scholar 

  150. Hu K, Hou S, Li F, Xiang Q, Kijlstra A, Yang P: 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: 3360–3365. doi:10.1167/iovs.13–11615

    Article  CAS  PubMed  Google Scholar 

  151. Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, Chen HD, Pu XM, Wu RN, Liang CZ, Li JB, Gao TW, Zhang JZ, Wang XL, Wang J, Yang RY, Liang L, Yu JB, Zuo XB, Zhang SQ, Zhang SM, Chen G, Zheng XD, Li P, Zhu J, Li YW, Wei XD, Hong WS, Ye Y, Zhang Y, et al.: Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 2010, 42: 614–618. doi:10.1038/ng.603

    Article  CAS  PubMed  Google Scholar 

  152. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, et al.: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008, 40: 955–962. doi:10.1038/ng.175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, et al.: Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 2009, 136: 523–529.e523.

    Article  PubMed Central  PubMed  Google Scholar 

  154. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, et al.: Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010, 42: 508–514. doi:10.1038/ng.582

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. Kochi Y, Okada Y, Suzuki A, Ikari K, Terao C, Takahashi A, Yamazaki K, Hosono N, Myouzen K, Tsunoda T, Kamatani N, Furuichi T, Ikegawa S, Ohmura K, Mimori T, Matsuda F, Iwamoto T, Momohara S, Yamanaka H, Yamada R, Kubo M, Nakamura Y, Yamamoto K: A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat Genet 2010, 42: 515–519. doi:10.1038/ng.583

    Article  CAS  PubMed  Google Scholar 

  156. Chu X, Pan CM, Zhao SX, Liang J, Gao GQ, Zhang XM, Yuan GY, Li CG, Xue LQ, Shen M, Liu W, Xie F, Yang SY, Wang HF, Shi JY, Sun WW, Du WH, Zuo CL, Shi JX, Liu BL, Guo CC, Zhan M, Gu ZH, Zhang XN, Sun F, Wang ZQ, Song ZY, Zou CY, Sun WH, Guo T, et al.: A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet 2011, 43: 897–901. doi:10.1038/ng.898

    Article  CAS  PubMed  Google Scholar 

  157. Popovici C, Zhang B, Gregoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pebusque MJ: The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood 1999, 93: 1381–1389.

    CAS  PubMed  Google Scholar 

  158. Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pebusque MJ: 8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. Mol Cell Biol 2001, 21: 8129–8142. doi:10.1128/mcb.21.23.8129–8142.2001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Yan X, Habedanck R, Nigg EA: A complex of two centrosomal proteins, CAP350 and FOP, cooperates with EB1 in microtubule anchoring. Mol Biol Cell 2006, 17: 634–644. doi:10.1091/mbc.E05–08–0810

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Yi X, Du L, Hou S, Li F, Chen Y, Kijlstra A, Yang P: FGFR1OP tagSNP but not CCR6 polymorphisms are associated with Vogt-Koyanagi-Harada syndrome in Chinese Han. PLoS One 2013, 8: e69358. doi:10.1371/journal.pone.0069358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature 2001, 411: 199–204. doi:10.1038/35075590

    Article  CAS  PubMed  Google Scholar 

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    Joanne YW Ng, Fiona OJ Luk, Timothy YY Lai & Chi-Pui Pang

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JN carried out the literature review and drafted the manuscript. FL and TL conceived the review, performed the literature review, and revised the draft manuscript critically. CP conceived the review and revised the draft manuscript critically. All authors read and approved the final manuscript.

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Ng, J.Y., Luk, F.O., Lai, T.Y. et al. Influence of molecular genetics in Vogt-Koyanagi-Harada disease. J Ophthal Inflamm Infect 4, 20 (2014). https://doi.org/10.1186/s12348-014-0020-1

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