Investigation of the acute pathogenesis of spondyloarthritis/HLA-B27-associated anterior uveitis based on genome-wide association analysis and single-cell transcriptomics.

BACKGROUND: Patients with spondyloarthritis (SpA)/HLA-B27-associated acute anterior uveitis (AAU) experience recurring acute flares, which pose significant visual and financial challenges. Despite established links between SpA and HLA-B27-associated AAU, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. METHODS: To investigate the acute pathogenesis of SpA/HLA-B27-associated AAU, Mendelian randomization (MR) and single-cell transcriptomic analyses were employed. The MR incorporated publicly available protein quantitative trait locus data from previous studies, along with genome-wide association study data from public databases. Causal relationships between plasma proteins and anterior uveitis were assessed using two-sample MR. Additionally, colocalization analysis was performed using Bayesian colocalization. Single-cell transcriptome analysis utilized the anterior uveitis dataset from the Gene Expression Omnibus (GEO) database. Dimensionality reduction, clustering, transcription factor analysis, pseudotime analysis, and cell communication analysis were subsequently conducted to explore the underlying mechanisms involved. RESULTS: Mendelian randomization analysis revealed that circulating levels of AIF1 and VARS were significantly associated with a reduced risk of developing SpA/HLA-B27-associated AAU, with AIF1 showing a robust correlation with anterior uveitis onset. Colocalization analysis supported these findings. Single-cell transcriptome analysis showed predominant AIF1 expression in myeloid cells, which was notably lower in the HLA-B27-positive group. Pseudotime analysis revealed dendritic cell terminal positions in differentiation branches, accompanied by gradual decreases in AIF1 expression. Based on cell communication analysis, CD141+CLEC9A+ classic dendritic cells (cDCs) and the APP pathway play crucial roles in cellular communication in the Spa/HLA-B27 group. CONCLUSIONS: AIF1 is essential for the pathogenesis of SpA/HLA-B27-associated AAU. Myeloid cell differentiation into DCs and decreased AIF1 levels are also pivotal in this process.

A large meta-analysis identifies genes associated with anterior uveitis.

Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.

Association of TBX21 gene polymorphisms and acute anterior uveitis risk in a Chinese population: A case-control study.

Copy number variations (CNVs) in TBX21 gene have been reported to be significantly and positively correlated with acute anterior uveitis (AAU). Our study was performed to further determine whether single nucleotide polymorphisms (SNPs) in TBX21 gene confer susceptibility to AAU in a Chinese population. In our case-control study, 420 AAU patients and 918 healthy controls were included. SNP genotyping was conducted via the MassARRAY™ iPLEX Gold platform. Association and haplotype analyses were performed via SPSS 23.0 and SHEsis software. No significant association was observed between two candidate SNPs of TBX21 gene (rs4794067, rs11657479) and susceptibility to AAU (Pc > 0.05). In stratification analysis, the result also showed no significant difference between the HLA-B27 positive AAU patients and non-typed healthy controls. Additionally, no association was detected between TBX21 haplotypes and AAU risk. In conclusion, the polymorphisms rs4794067 and rs11657479 in TBX21 gene did not confer disease susceptibility to AAU in a Chinese population.

Progress in the genetics of uveitis.

Uveitis is the most common form of intraocular inflammatory disease and is a significant cause of visual impairment worldwide. Aetiologically, uveitis can also be classified into infectious uveitis and non-infectious uveitis. The common non-infectious forms of uveitis include acute anterior uveitis (AAU), Behçet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, birdshot chorioretinopathy (BSCR), sarcoid uveitis. In addition, a few monogenic autoinflammatory disorders can also cause uveitis, such as Blau Syndrome and haploinsufficiency of A20 (HA20). Although the exact pathogenesis of non-infectious uveitis is still unclear, it is well-recognised that it involves both genetic and environmental risk factors. A hallmark of uveitis is its strong associations with human leucocyte antigens (HLA). For examples, AAU, BD and BSCR are strongly associated with HLA-B27, HLA-B51, and HLA-A29, respectively. In uveitis studies, multiple GWAS have successfully been conducted and led to identification of novel susceptibility loci, for example, IL23R has been identified in BD, VKH and AAU. In this review, we summarize the latest progress on the genetic associations of both HLA and non-HLA genes with major forms of uveitis, including AAU, BD, VKH, BSCR, sarcoid uveitis, Blau Syndrome and HA20, and potential future research directions.

Association of Killer Cell Immunoglobulin-like Receptor and Human Leukocyte antigen-C Genotype with HLA-B27 Associated Acute Anterior Uveitis and Idiopathic Acute Anterior Uveitis in a Chinese Han Population.

PURPOSE: whether killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens C (HLA-C) are associated with HLA-B27 associated acute anterior uveitis (B27AAU) and idiopathic AAU (IAAU) remains unclear. METHODS: PCR with sequence-specific primers was used to analyze KIR genes and HLA-C alleles in a Chinese Han population of 196AAU patients and 210 control subjects. RESULTS: The higher frequencies of HLA-C2 and KIR2DL1/HLA-C2 (p = .009 and p = .044, respectively) and the lower frequencies of HLA-C1C1 and HLA-C1 (p = .034 and p = .009, respectively) were observed in B27AAU than control group. The higher frequencies of KIR2DL2 and KIR2DL2/HLA-C1 (p = .009 and p = .044, respectively) and the lower frequencies of KIR2DL3 and KIR2DL3/HLA-C1 (p = .000 and p = .001, respectively) were observed in IAAU than control group. CONCLUSIONS: HLA-C2 and KIR2DL1/HLA-C2, KIR2DL2, and KIR2DL2/HLA-C1 might be susceptible for B27AAU and IAAU, respectively. HLA-C1C1 and HLA-C1, KIR2DL3 and KIR2DL3/HLA-C1 might protect from B27AAU and IAAU, respectively.

Mesalazine Suppresses Proinflammatory Cytokines in Patients with Acute Anterior Uveitis Independently of HLA-B27.

PURPOSE: The aim is to unravel the mechanism of mesalazine (5-ASA) on proinflammatory cytokines in PBMCs of patients with HLA-B27 +and HLA-B27 -acute anterior uveitis (AAU), and whether this may explain the different effects of 5-ASA in both disoders. METHODS: PBMCs from 12 HLA-B27+ and 4 HLA-B27- AAU patients were preincubated with 5-ASA and stimulated with LPS. As mesalazine (5-ASA) could be involved in ER stress, proinflammatory and ER stress-associated cytokines and markers were measured. RESULTS: Mesalazine (5-ASA) suppressed IL-6 mRNA in healthy donors and in HLA-B27+ and HLA-B27- patients but did not lead to induction and secretion of IL-1ß. In HLA-B27 + or - patients the ER stress-associated markers CHOP (DDIT3) and ATF6 were suppressed. CONCLUSIONS: Here we show that mesalazine (5-ASA) inhibits the transcription of proinflammatory and (ER) stress associated cytokines and markers, independently of the HLA-B27 status. Results show the similarities of both AAU types but do not decipher the mechanism why the HLA-B27 status determines the therapeutic response to mesalazine in AAU.

Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals.

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor-ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor-ligand interactions.

Genomewide Association Study of Acute Anterior Uveitis Identifies New Susceptibility Loci.

Purpose: Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. Methods: We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. Results: We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10-8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10-7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10-7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10-6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10-7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10-6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10-7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. Conclusions: We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

Recent Developments in HLA B27 Anterior Uveitis.

There has been steady progress in understanding the pathogenesis, clinical features, and effective treatment of acute anterior uveitis (AU) over the past 5 years. Large gene wide association studies have confirmed that AU is a polygenic disease, with overlaps with the seronegative arthropathies and inflammatory bowel diseases, associations that have been repeatedly confirmed in clinical studies. The role of the microbiome in AU has received increased research attention, with recent evidence indicating that human leukocyte antigen B27 (HLA B27) may influence the composition of the gut microbiome in experimental animals. Extensive clinical investigations have confirmed the typical features of acute AU (AAU) and its response to topical, regional and systemic immunosuppressive treatment. Increased understanding of the role of cytokines has resulted in studies confirming the value of anti-cytokine therapy [anti-tumor necrosis factor (anti-TNF) and interleukin 6 (IL-6) therapy] in severe and recurrent cases of AAU, particularly in subjects with an associated spondyloarthopathy (SpA) and in juvenile idiopathic arthritis (JIA)-associated AAU.

The LMP2 CfoI polymorphism is associated with ankylosing spondylitis (AS) risk but not with acute anterior uveitis (AAU): A meta-analysis.

BACKGROUND: Ankylosing spondylitis (AS) is one of the most common chronic inflammatory disorders affecting the sacroiliac joints, spine, and peripheral joints. Apart from HLA-B27, the LMP2 gene has been shown to play a role in the pathogenesis of AS as well as AAU in AS. However, genetic associations between LMP2 CfoI polymorphism and AS and AAU were inconclusive. We aimed to investigate the correlation of LMP2 CfoI polymorphism and AS and AAU using meta-analysis. METHODS: An exhaustive search was conducted using the PubMed, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure (CNKI) electronic databases. The strength association was assessed by crude ORs with 95% CI. RESULTS: Eight eligible records with 449 AS patients and 317 healthy controls were included in the present study. The allelic model of the LMP2 CfoI polymorphism is associated with AS risk (OR = 0.60, 95%CI = [0.32, 1.11], P = .003). A stratified analysis based on ethnicity has shown that the allelic model of LMP2 CfoI was associated with AS in the Caucasian population (OR = 0.72, 95%CI = [0.55, 0.93], P = .01) but not in the Asian population (P > .05). Furthermore, no association was detected between LMP2 CfoI polymorphism and AS complication (AAU). CONCLUSION: Our combined results revealed that the allelic model of LMP2 CfoI might be a protective factor for AS in the Caucasian population. Nevertheless, future studies on different ethnicities with larger sample sizes are needed to obtain a more convincing result.

Association of TLR2 Gene Polymorphisms with Presumed Viral-Induced Anterior Uveitis in male Han Chinese.

The purpose of this study was to investigate whether single nucleotide polymorphisms (SNPs) of TLR2, TLR3, TLR4 and TLR9 genes are associated with susceptibility to presumed viral-induced anterior uveitis (PVIAU) and Posner-Schlossman syndrome (PSS). A case-control study was performed in 205 PVIAU patients and 1007 healthy controls. A total of 15 SNPs were genotyped by MassARRAY platform and iPLEX Gold Assay. Data were analyzed using a Chi-square (χ2) test and Fisher's exact calibration test. Two hundred and three PSS patients served as an extra control to investigate whether there were similar genetic factors between PVIAU and PSS in the context of these tested SNPs in TLR genes. The results showed that the frequency of TLR2/rs7656411 GG genotype and G allele were significantly higher in PVIAU patients as compared with healthy controls (P = 1.10 × 10-4, corrected P value [Pc] = 4.93 × 10-3, odds ratio [OR] = 1.848; P = 3.57 × 10-4, Pc = 1.07 × 10-2, OR = 1.478, respectively). Gender stratification analysis showed a significantly increased frequency of the G allele in male patients (P = 7.46 × 10-5, Pc = 2.24 × 10-3, OR = 1.894). A weak correlation was found between two SNPs (rs3804100 and rs5743705) of the TLR2 gene with PSS. However, after Bonferroni correction, statistical significance was lost. This study shows that the polymorphisms of TLR2/rs7656411 are positively associated with PVIAU in male Chinese patients. PVIAU and PSS have a different genetic background in the context of the tested SNPs.

Is a positive family history of spondyloarthritis relevant for diagnosing axial spondyloarthritis once HLA-B27 status is known?

OBJECTIVES: A positive family history (PFH) of spondyloarthritis, in particular a PFH of AS or acute anterior uveitis, is associated with HLA-B27 carriership in chronic back pain patients. As it is unknown, the study aimed to investigate if a PFH contributes to diagnosing axial spondyloarthritis (axSpA) once HLA-B27 status is known. METHODS: In axSpA-suspected patients from the Assessment of SpondyloArthritis international Society (ASAS), DEvenir des Spondyloarthropathies Indifférenciéés Récentes (DESIR) and SPondyloArthritis Caught Early (SPACE) cohorts, logistic regression analyses were performed with HLA-B27 status and PFH according to the ASAS definition (ASAS-PFH) as determinants and clinical axSpA diagnosis as outcome at baseline. Analyses were repeated with a PFH of AS or acute anterior uveitis. RESULTS: In total, 1818 patients suspected of axSpA were analysed (ASAS n = 594, DESIR n = 647, and SPACE n = 577). In patients from the ASAS, DESIR and SPACE cohorts, respectively 23%, 39% and 38% had an ASAS-PFH, 52%, 58% and 43% were HLA-B27 positive, and 62%, 47% and 54% were diagnosed with axSpA. HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS-PFH was not [ASAS cohort: HLA-B27 odds ratio (OR): 6.9 (95% CI: 4.7, 10.2), ASAS-PFH OR: 0.9 (95% CI: 0.6, 1.4); DESIR: HLA-B27 OR: 2.1 (95% CI: 1.5, 2.9), ASAS-PFH OR: 1.0 (95% CI 0.7, 1.3); SPACE: HLA-B27 OR: 10.4 (95% CI: 6.9, 15.7), ASAS-PFH OR: 1.0 (95% CI: 0.7, 1.5)]. Similar negative results were found for PFH of AS and acute anterior uveitis. CONCLUSION: In three independent cohorts with different ethnical backgrounds, ASAS, DESIR and SPACE, a PFH was not associated independently of HLA-B27 with a diagnosis of axSpA. This indicates that in the vast majority of patients presenting with back pain, a PFH does not contribute to the likelihood of an axSpA diagnosis if HLA-B27 status is known.

Growth hormone-releasing hormone receptor mediates cytokine production in ciliary and iris epithelial cells during LPS-induced ocular inflammation.

The receptor for growth hormone-releasing hormone (GHRH-R) has been shown to upregulate specifically in the ciliary and iris epithelial cells and infiltrating cells in the aqueous humor in a rat model of acute anterior uveitis. Treatment with GHRHR-R antagonist alleviates significantly these inflammatory responses. Herein we investigated whether the ciliary and iris epithelial cells can respond directly to lipopolysaccharide (LPS) without the influences of circulating leukocytes to produce inflammatory mediators through a GHRH-R mediated mechanism. In explant cultures of rat ciliary body and iris, LPS caused a substantial increase of GHRH-R in 24 h. Immunohistochemistry showed a localization of TLR4, the receptor for LPS, and an elevated expression of IL-6 and IL-1ß in ciliary and iris epithelial cells after LPS treatment. LPS also elevated the level of IL-1ß, IL-6, and iNOS and increased secretion of IL-1ß and IL-6 from the explants. The GHRH-R antagonist, MIA-602, suppressed the elevated expression of IL-1ß and IL-6, and reduced the release of IL-6. Such effects were not seen for the GHRHR agonist, MR-409. When co-cultured with leukocytes, expression of GHRH-R in the ocular explants was further enhanced during LPS treatment. Our results demonstrate a direct action of LPS on ciliary and iris epithelial cells to produce pro-inflammatory factors through a GHRH-R mediated mechanism, and suggest a role of these epithelial cells, in addition to the resident antigen presenting cells, in immune surveillance of the eye. Infiltrating leukocytes may enhance these inflammatory responses by regulating GHRH-R in ciliary and iris epithelial cells, in addition to their functions of synthesizing proinflammatory cytokines.

Novel gene targets for miRNA146a and miRNA155 in anterior uveitis.

BACKGROUND/AIMS: Anterior uveitis (AU) is the most common form of intraocular inflammation. MicroRNAs (miRNA) are small, non-coding RNAs functioning as post-transcriptional repressors of gene expression. Knowledge of miRNAs can implicate specific genes and pathogenic signalling pathways in disease. This study examines miRNA expression, function and target genes in AU pathogenesis. METHODS: AU and healthy control (HC) peripheral blood mononuclear cells (PBMC) were initially screened for expression of five miRNAs by real-time PCR. Regulation of the aberrantly expressed miRNAs by TLR1/2, TLR3, TLR4, IL1ß and TNFα was quantified by real-time PCR and paired cytokine outputs measured by ELISA. Functional effects of miRNA overexpression using transfected THP1 cells examined IL6, IL8, IL10 and IL1ß cytokine outputs by ELISA. Target genes were identified using TargetScan online computational algorithm and relevant targets verified by cloning of the 3'UTR and luciferase reporter gene assays. RESULTS: Increased expression of miRNA146a (p<0.01), miRNA155 (p<0.05) and miRNA125a5p (p<0.01) was demonstrated in AU PBMC compared with HC. miRNA155 was increased following TLR1/2 (p<0.05) and TLR4 (p<0.05) stimulation and miRNA146a increased in response to IL1ß (p<0.05). In a proinflammatory environment, miRNA155 overexpression in THP1 cells yielded increased cytokine output whereas miRNA146a overexpression showed decreased cytokine output. CD80, PRKCE and VASN were confirmed as novel targets for miRNA146a and SMAD2, TYRP1 and FBXO22 for miRNA155. CONCLUSION: This study identifies overexpression of proinflammatory miRNA155, regulatory miRNA146a and miRNA125a-5p in AU. CD80, PRKCE and VASN are novel miRNA146a targets and SMAD2, TYRP1 and FBXO22 are novel targets for miRNA155.

PD-1 Polymorphisms Are Associated with Susceptibility of Acute Anterior Uveitis in Chinese Population.

Acute anterior uveitis (AAU) is an ordinary type of uveitis, which is an autoimmune disease produced by T cells. Programmed apoptosis protein 1 (PD-1) is a vital negative regulatory protein of immune tolerance. We detect the single nucleotide polymorphisms (SNPs) rs41386349, rs10204525, and rs2227982 of PD-1 to investigate the correlation between PD-1 polymorphisms and AAU. A total of 166 AAU patients and 263 controls were recruited in this case-control study. Compared with controls, the frequencies of the GG genotypes were higher in rs10204525 in AAU patients (p = 0.012). There were obvious increases in frequencies of the TT genotypes in rs2227982 and the GG genotypes in rs10204525 in human leukocyte antigen (HLA)-B27-negative AAU patients compared with controls (p = 0.03; p = 0.015, respectively). There were also increases in frequencies of TT genotypes in rs2227982 and the GG genotypes in rs10204525 in the patients without ankylosing spondylitis (AS) when compared with controls (p = 0.021; p = 0.003, respectively). Furthermore, the frequencies of TT genotypes in rs2227982 were higher in female patients diagnosed with AAU than with control group (p = 0.033). Our results showed that SNPs rs2227982 and rs10204525 were interrelated to AAU; the influence on AAU could be related with gender, HLA-B27, and AS status.

A study of the key genes and inflammatory signaling pathways involved in HLA-B27-associated acute anterior uveitis families.

The present study was conducted to investigate the key genes and the inflammatory signaling pathways involved in HLA-B27-associated acute anterior uveitis (AAU) families. Four families with HLA-B27­positive aau patients and their HLA-B27-positive blood relatives were included in the study. peripheral blood monocytes were isolated from the subjects and stimulated by lipopolysaccharides (LPS). Gene expression microarrays were used to identify the differentially expressed genes (DEGs), and the DEGs were analyzed by a range of bioinformatics-based techniques, including Gene Ontology (GO), Pathway analysis, Signal-Net analysis and Gene Relation Network (Gene-Rel-Net). Finally, ELISA was used to quantify cytokines in the supernatant. The gene expression microarrays identified 801 DEGs, including 349 upregulated and 452 downregulated genes. The GO analysis revealed several important functions, including metabolic, immune and inflammatory responses. The pathway analysis highlighted the enhanced activity of Staphylococcus aureus infection, chemokine and metabolic signaling pathways, as well as cytokine-to­cytokine receptor interactions. A total of 18 DEGs that were found to play critical roles by Signal-Net and Gene-Rel-Net and verified by quantitative polymerase chain reaction analysis were identified as key genes. In conclusion, monocytes from the AUU patients were more sensitive and exhibited a more prominent inflammatory response to stimulation by LPS compared with monocytes from healthy HLA-B27-positive blood relatives. These characterized DEGs may provide new evidence for the pathogenesis of AAU and help identify new therapeutic targets.

Elevated Interleukin 37 Expression Associated With Disease Activity in HLA-B27 Associated Anterior Uveitis and Idiopathic Anterior Uveitis.

BACKGROUND & OBJECTIVE: Interleukin 37 (IL-37) is an important regulator of the anti-inflammatory T-cell response. In this study, we investigated its expression and function in peripheral blood mononuclear cells (PBMCs) of patients with HLA-B27 associated acute anterior uveitis (AAU) and idiopathic AAU. METHODS: 15 patients with HLA-B27-associated AAU, 10 patients with idiopathic AAU and 22 controls were recruited to this study from August 2013 to December 2016. Complete ophthalmological examinations were performed and clinical features were clearly documented. Blood samples were collected and peripheral blood mononuclear cells were extracted. IL-37 messenger RNA (mRNA) and protein expression in peripheral blood mononuclear cells (PBMCs) were examined by performing RT-PCRs and western blot, respectively. Cytokines in the supernatants of stimulated dendritic cells (DCs) with IL-37 were assayed by multiplex immunoassay. RESULTS: An increased level of IL-37 mRNA and protein expression by PBMCs was found in the patient group with clinically active AAU compared to controls. There was no significant difference in IL-37 mRNA and protein expression levels between HLA-B27 associated AAU and idiopathic AAU. IL-37 significantly inhibited the production of IL-1ß, IL-6, IL-10, IL-21, IL-23, TNF-α and IFN-γ. IL-37 levels of mRNA and protein expression showed a significant positive correlation with disease activity. CONCLUSIONS: Elevated IL-37 expression is associated with disease activity in HLA-B27 associated AAU and idiopathic AAU. IL-37 can inhibit proinflammatory cytokine productions in AAU. Manipulation of IL-37 may offer a new therapeutic target for these entities.

Association of IL33 and IL1RAP Polymorphisms With Acute Anterior Uveitis.

BACKGROUND: AAU (acute anterior uveitis) is the most common entity of uveitis characterized by acute vision loss and violent sore eyes. IL-33 and IL-1RacP have been found to play crucial roles in the innate immune system. OBJECTIVE: In the present study, we investigated the association of IL33 and IL1RAP genes with AAU. METHOD: A total of 549 AAU patients and 1080 unrelated healthy controls were recruited for this study. Ten single nucleotide polymorphisms (SNPs) were genotyped using Sequenom Mass ARRAY technology. RESULTS: Our findings demonstrated that IL1RAP-rs3773978 significantly associated with AAU and could serve as a genetic risk marker in Chinese AAU patients. A significantly increased frequency of the A allele and AA homozygosity of IL1RAP-rs3773978 was observed in AAU patients compared with that in controls (p=0.001, pc=0.01, OR=1.282, 95% CI 1.106 to 1.487; p=0.0003, pc=0.003, OR=1.647, 95% CI 1.255 to 2.163, respectively). Further stratification analyses showed that the genetic correlation may differ depending on HLA-B27 status, AS (ankylosing spondylitis) status, attack times and laterality status. CONCLUSION: Our findings provide new insights that enhance the current knowledge of uveitis genetics by demonstrating the specific functional roles of IL1RAP and other IL-1 family genes in uveitis.

Genotype-Phenotype Association Study Reveals CFI-Rs13104777 to be a Protective Genetic Marker Against Acute Anterior Uveitis.

PURPOSE: To investigate the roles of CFI, genotype-phenotype associations were identified in AAU. METHODS: A case-control study was conducted in a total of 575 subjects consisting of 279 AAU patients and 296 healthy controls. Genotypic analyses were performed using Sequenom MassARRAY technology. Analyses were stratified to a series of clinical ophthalmic confounding factors. RESULTS: A lower frequency of the CFI-rs13104777 C allele was found in the AAU cohort compared with the controls, and, thus, was significantly associated with AAU pathogenesis (p = 0.041, OR = 0.712, 95% CI: 0.513-0.987). Stratified analysis also demonstrated the associations may differ depending on the HLA-B27 status and laterality status. CONCLUSIONS: This study has revealed a significant genetic role for CFI-rs13104777 in AAU. This influence may be dependent on human leukocyte antigen (HLA)-B27 and disease laterality. Overall, the results provide evidence for a pathogenic role for CFI in AAU and expand our knowledge on the genetic basis of AAU.