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.

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.

A Novel Mutation in Helical Domain 2 of NOD2 in Sporadic Blau Syndrome.

We report a 12-year-old girl who presented with bilateral granulomatous anterior uveitis accompanied by boggy arthritis of knee and ankle joints, intermittent fever, and nodular skin rash. She was diagnosed with sporadic Blau syndrome (early-onset sarcoidosis) based on above clinical signs and presence of non-necrotising granuloma on iris biopsy. DNA sequencing revealed a previously unreported heterozygous mutation consisting of a G>A transition in exon 4 of the NOD2 gene. This resulted in a glutamic acid to lysine substitution in helical domain 2 of the nucleotide binding and oligomerization (NACHT) region, possibly reducing efficiency of auto-inhibition in NOD2 signaling. Interestingly, the ocular inflammation resolved completely following therapeutic vitrectomy in both eyes whereas the systemic symptoms of fever and arthritis continued to wax and wane while on treatment with oral methotrexate and corticosteroids.

[Uveitis in spondyloarthritis]. / Uveitis bei Spondyloarthritiden.

Acute anterior uveitis (AAU) is the most frequent uveitis subtype. It is often associated with HLA-B27 and with inflammatory rheumatic diseases, in particular with spondyloarthritis (SpA), which itself is strongly associated with HLA-B27. About 40-60% of patients with AAU have an associated spondyloarthritis, and 20-40% of patients with spondyloarthritis also have uveitis. The incidence of AAU in patients with SpA clearly correlates with disease duration. The AAU has an acute onset, usually affects only one eye at a time, and shows a tendency for recurrence. Early therapy of AAU with topical steroids is relevant for good visual outcomes. Minimum duration of therapy of flares of AAU is 6-8 weeks in order to prevent early recurrency. The rate of local complications correlates with the rate of AAU flares and the visual outcome is often good. Refractory uveitis and frequent recurrencies of AAU may be treated with conventional disease-modifying antirheumatic drugs (DMARDs, such as sulfasalazine and methotrexate) and biologicals (e.g. TNF-alpha inhibitors). Any first episode of AAU diagnosed by an ophthalmologist should prompt referral to rheumatology for suspected SpA, particularly if rheumatic symptoms are present.

Ankylosing Spondylitis: HLA-B*27-Positive Versus HLA-B*27-Negative Disease.

PURPOSE OF REVIEW: We review our current knowledge about the clinical features of patients with ankylosing spondylitis (AS) who possess HLA-B*27 versus those who lack this gene. RECENT FINDINGS: ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. A genetic study supports the existence of an HLA-B27-independent common link between gut inflammation and AS. It is unusual to observe familial occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, psoriasis, or IBD. Although there are many similarities among AS patients possessing HLA-B*27 versus those lacking this gene, the former group has a younger age of onset, a shorter delay in diagnosis, a better clinical response to tumor necrosis factor inhibitors, a greater familial occurrence, a greater risk for occurrence of acute anterior uveitis, and a lower risk for occurrence of psoriasis and IBD. ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. It is unusual to observe occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, IBD, or psoriasis. A recent genetic study supports the existence of an HLA-B*27-independent common link between gut inflammation and AS.

LRBA deficiency with autoimmunity and early onset chronic erosive polyarthritis.

LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency associates immune deficiency, lymphoproliferation, and various organ-specific autoimmunity. To date, prevalent symptoms are autoimmune cytopenias and enteropathy, and lymphocytic interstitial lung disease. In 2 siblings from a consanguineous family presenting with early onset polyautoimmunity, we presumed autosomal recessive inheritance and performed whole exome sequencing. We herein report the first case of early-onset, severe, chronic polyarthritis associated with LRBA deficiency. A novel 1bp insertion in the LRBA gene, abolishing protein expression, was identified in this family. Among the 2 brothers homozygous for LRBA mutation, one developed Evans syndrome and deceased at age 8.5 from complications of severe autoimmune thrombocytopenia. His brother, who carried the same homozygous LRBA mutation, early-onset erosive polyarthritis associated with chronic, bilateral, anterior uveitis and early onset type 1 diabetes mellitus. This report widens the clinical spectrum of LRBA deficiency and, in lights of the variable phenotypes described so far, prompts us to screen for this disease in patients with multiple autoimmune symptoms in the family, including severe, erosive, polyarticular juvenile arthritis.

Association of Genetic Variations in TNFSF15 With Acute Anterior Uveitis in Chinese Han.

PURPOSE: T cells play an important role in the pathogenesis of uveitis. Recent studies have indicated that the TNFSF15 gene that encodes the TL1A protein can regulate the differentiation and activation of T cells. TNFSF15 gene polymorphisms have been found to be associated with several autoimmune disorders. A possible association of TNFSF15 with acute anterior uveitis (AAU) has not yet been reported and was therefore the purpose of our study. METHODS: Eight single nucleotide polymorphisms (SNPs) were examined using TaqMan SNP Genotyping Assay or PCR-restriction fragment length polymorphism in 983 AAU patients and 1128 healthy controls. Genotype distributions and allele frequencies were compared using χ2 analysis between AAU patients and healthy controls. Stratified analysis was also performed according to ankylosing spondylitis (AS) status. The TNFSF15 mRNA expression was quantified by real-time PCR. RESULTS: A significantly decreased frequency of the TT genotype in TNFSF15-rs3810936 was found in AAU patients (P = 6.36 × 10(-6), corrected P[Pc] = 1.52 × 10(-4), OR = 0.6, 95% CI = 0.5-0.8). Stratification according to AS status did not reveal a difference concerning the association with TNFSF15-rs3810936. None of the other TNFSF15 SNPs tested were associated with AAU. CONCLUSIONS: This study shows an association between TNFSF15-rs3810936 and AAU and suggests that the TL1A/DR3 pathway may be implicated in the pathogenesis of this disease.

A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool).

BACKGROUND: To date, there are no formal guidelines or referral pathways for acute anterior uveitis (AAU) patients developed or endorsed by any international or national societies. The objective of our study was to develop and validate an assessment algorithm for referral from ophthalmologists of appropriate AAU patients to rheumatology that will aid the early diagnosis of the spondyloarthropathy (SpA). METHODS: All consecutive patients attending the emergency department of local ophthalmology hospital with AAU, but who did not have a known diagnosis of SpA, were eligible to participate in this study. Patients with any other known cause of AAU were excluded. Two independent cohorts were enrolled. Test algorithm and Dublin Uveitis Evaluation Tool (DUET) algorithm (revised form of test algorithm) were used in these cohorts to identify patients as SpA suspects and non-SpA controls, respectively. RESULTS: STUDY PHASE-1. ALGORITHM DEVELOPMENT COHORT (n=101): After rheumatologic evaluation of the entire cohort, 41.6% (n=42) had undiagnosed SpA. Our test algorithm was noted to have: sensitivity 100% and specificity 53.5%. Further regression analysis resulted in the development of the DUET algorithm which made the following improvements: sensitivity 95%, specificity 98%, positive likelihood ratio (LR) 56.19, and negative LR 0.04. STUDY PHASE-2. DUET ALGORITHM VALIDATION COHORT (n=72): After rheumatologic evaluation of the cohort, 40% (n=29) were diagnosed with SpA, with the following performance of DUET algorithm-sensitivity 96%, specificity 97%, positive LR 41.5 and negative LR 0.03. CONCLUSIONS: Approximately 40% of patients presenting with idiopathic AAU have undiagnosed SpA. A simple to apply algorithm is described with excellent sensitivity and specificity.

FoxO1 gene confers genetic predisposition to acute anterior uveitis with ankylosing spondylitis.

PURPOSE: Recent studies have shown that a decrease of regulatory T (Treg) cells may contribute to the activity of acute anterior uveitis (AAU) and ankylosing spondylitis (AS). A number of immunogenetic factors including IL2RA, miR-27a, miR-182, and FoxO1 are associated with Treg cell function. In this study, we investigated the association between polymorphisms of these genes and AAU with or without AS in a Chinese Han population. METHODS: Using PCR-restricted fragment length polymorphism (RFLP) assay, a two-stage association study was performed in 680 AAU patients with or without AS and 1280 controls. Gene expression was quantified by real-time PCR. RESULTS: In the first stage study, an association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls. The results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU patients with AS (AA genotype: P = 6.23 × 10(-5), odds ratio [OR] = 1.86; A allele: P = 2.17 × 10(-4), OR = 1.53). No significant association of the other 9 SNPs with AAU with or without AS was observed. In the second stage study, an association analysis of FoxO1/rs2297626 was performed in 210 AAU patients with AS and 630 controls. The second stage and combined studies confirmed the association of FoxO1/rs2297626 with AAU with AS (AA genotype: P = 3.45 × 10(-8), OR = 1.85; A allele: P = 1.55 × 10(-7), OR = 1.55). CONCLUSION: This study suggests that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS.

Description of a new family with cryopyrin-associated periodic syndrome: risk of visual loss in patients bearing the R260W mutation.

OBJECTIVE: The aim of this study was to describe a family with cryopyrin-associated periodic syndrome (CAPS) in which the disease was unveiled after the ophthalmologic evaluation. METHODS: Family and personal histories from each of the patients were recorded. Each underwent a full ophthalmological examination along with the physical examination. The mutational analysis of the NLRP3 gene was performed by means of direct sequencing. RESULTS: The proband was admitted during an episode of unilateral anterior uveitis. She had a history of recurrent red eye and had been suffering episodes of skin rash and arthralgia induced by cold since childhood. At examination, she showed a reticulated corneal mid-stroma. Her mother and her younger sister also suffered from relapsing episodes of skin rash and fever triggered by cold as well as flares of red eye. They had developed premature hearing loss. In both cases, opacities in the corneal mid-stroma were evidenced with a slit lamp. The genetic analysis detected the heterozygous germline p.R260W mutation in the NLRP3 gene in the three women, confirming the diagnosis of CAPS. Treatment with anakinra resulted in complete remission of flares. CONCLUSION: In this family, a structural NLRP3 mutation was associated with classic MuckleWells features of different degrees of severity. Interstitial keratitis with corneal opacification, usually ascribed to neonatal-onset multisystem inflammatory disease, was found. We underscore that ocular involvement in MuckleWells syndrome should be carefully assessed, since it can lead to visual impairment.

Copy number variations of complement component C4 are associated with Behçet's disease but not with ankylosing spondylitis associated with acute anterior uveitis.

OBJECTIVE: Complement component C4 copy number variations are associated with various inflammatory diseases. This study was undertaken to investigate whether copy number variations of C4 are also involved in the pathogenesis of Behçet's disease (BD). METHODS: Gene expression was examined by enzyme-linked immunosorbent assay (ELISA) or real-time polymerase chain reaction (PCR). Copy number variations of C4 isotypes (C4A and C4B) were detected by real-time PCR in 905 patients with BD, 205 patients with ankylosing spondylitis (AS) and acute anterior uveitis, and 1,238 controls. The activation of CD4+ T cells was analyzed by flow cytometry, and cytokine production was detected by ELISA. RESULTS: Protein expression of total C4 in serum was significantly increased in patients with active BD compared with those with inactive BD or controls (Bonferroni corrected P [Pcorr ] = 1.64 × 10(-4) and Pcorr = 0.037, respectively), but not in patients with AS and acute anterior uveitis. Copy number variation analysis identified a significantly increased frequency of more than 2 copies of C4A in BD patients (P = 1.65 × 10(-7) , odds ratio [OR] 2.84). HLA-B51, which is located on the same chromosome as C4, showed a strong association with BD in the Han Chinese population (P = 8.90 × 10(-65) , OR 5.05), but logistic regression showed that C4A copy number variation was an independent risk factor for BD. A significantly increased expression of C4A was observed in the high copy number groups (>2 copies or 2 copies) versus the low copy number group (Pcorr = 0.019 and Pcorr = 0.044, respectively). Increased production of interleukin-6 (IL-6) was also observed in the high C4A copy number group (Pcorr = 0.037). No effect of C4 copy number variation on the expression of T cell activation markers was detected. CONCLUSION: Our findings indicate that a high copy number of C4A confers risk for BD by modulating the expression of C4A and enhancing IL-6 production.

SNPs in the TNF-α gene promoter associated with Behcet's disease in Moroccan patients.

OBJECTIVE: Behçet's disease (BD) is a multisystemic inflammatory disease, mainly characterized by recurrent oral and genital ulcers (GUs), skin lesions and uveitis. Several genetic factors such as the TNF-α gene have been evaluated as contributors to the pathogenesis of BD. We aimed to evaluate the association between six TNF-α SNPs and susceptibility to BD, or the major clinical manifestations, in Moroccan patients. The six SNPs studied were: c.-1211C>T (rs1799964), c.-1043C>A (rs1800630), c.-1037C>T (rs1799724), c.-556G>A (rs1800750), c.-488G>A (rs1800629) and c.-418G>A (rs361525), known as -1031T>C, -863C>A, -857C>T, -376G>A, 308G>A and -238G>A, respectively. METHODS: SNPs were genotyped by direct sequencing in 120 unrelated Moroccan BD and 112 ethnically matched healthy controls. Allele and genotype distributions were compared between groups using chi-square or Fisher's exact tests. RESULTS: The frequency of the -1211C allele was higher in (i) BD patients than in controls [P = 0.02, odds ratio (OR) = 1.68, 95% CI 1.10, 2.56] and in (ii) patients with GUs than in those without (P = 0.002, OR = 3.84, 95% CI 1.55, 9.49). The -418A frequency was lower in patients with uveitis (P = 0.0003, OR = 0.19, 95% CI 0.07, 0.5). CONCLUSION: We report the first association between BD and TNF-α SNPs in Moroccan patients. We mainly observed that -1211C constitutes a susceptibility allele for both BD and GU, as previously reported for other populations. The -418A allele could be considered as a good prognostic factor for anterior uveitis, in Moroccan BD patients.

Lack of association of miR-146a and Ets-1 gene polymorphisms with Fuchs uveitis syndrome in Chinese Han patients.

PURPOSE: The aim of this study was to investigate the potential association of microRNA-146a (miR-146a) and V-Ets oncogene homolog 1 (Ets-1) gene polymorphisms with Fuchs Uveitis syndrome (FUS). METHODS: Three single-nucleotide polymorphisms (SNPs), miR-146a/rs2910164, ets-1/rs1128334, and ets-1/rs10893872 were genotyped in 219 Han Chinese patients with FUS and 612 healthy controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotype counts were analyzed by the χ² test. RESULTS: No significant difference concerning the genotypic and allelic frequencies of rs2910164, rs1128334, and rs10893872 polymorphisms could be found between patients with FUS and the normal controls. Analysis according to gender did not show any influence of sex on the association of miR-146a and Ets-1 with FUS. CONCLUSIONS: Our results suggest that the investigated three SNPs, miR-146a/rs2910164, ets-1/rs1128334, and ets-1/rs10893872, are not associated with FUS in the Han Chinese population.

HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN). METHODS: Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18). RESULTS: The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p<0.0001; RR 14.3 (6.9-29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8-9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant). CONCLUSION: The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Expressions of lymphotactin and its receptor, XCR, in Lewis rats with experimental autoimmune anterior uveitis.

BACKGROUND: To demonstrate the expression of lymphotactin and its receptor (XCR) in the iris/ciliary body and popliteal lymph node, and to clarify their roles in experimental autoimmune anterior uveitis (EAAU). METHODS: Uveitis was induced in Lewis rats by injection of melanin-associated antigen into the peritoneum and footpad. At defined time points, mRNA expression levels of lymphotactin and XCR in the iris/ciliary body and popliteal lymph node were measured by semiquantitative polymerase chain reaction. Lymphotactin levels in aqueous humor and serum after immunization were determined by enzyme-linked immunosorbent assay. In a separate experiment, an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC; 200 mg/kg/day), was injected daily into the intraperitoneum after immunization. Cellular sources of lymphotactin were determined by immunhistochemical staining and flow cytometry. RESULTS: Lymphotactin mRNA was upregulated in the iris/ciliary body with a peak level at day 14, which is in line with the disease course. XCR mRNA was expressed maximally and then declined gradually from days 5 to 21. With an expression pattern similar to that of mRNA expression, lymphotactin in aqueous humor had attracted corresponding numbers of leukocytes. PDTC markedly inhibited the expression of lymphotactin in aqueous humor and serum. Immunohistochemical staining and flow cytometry analysis revealed that the expression of lymphotactin was detected in infiltrated inflammatory cells, dominantly CD8+ T cells, and increased along with inflammation. CONCLUSIONS: The lymphotactin and XCR interaction might direct distinct lymphocytes subsets to inflammatory sites. Lymphotactin could regulate the inflammatory process. Lymphotactin expression may be modulated, at least in part, through the NF-κB signaling pathway.

Familial case of Blau syndrome associated with a CARD15/NOD2 mutation.

PURPOSE: Blau syndrome is a rare autosomal dominant disorder characterized by early onset granulomatous arthritis, uveitis, skin rash and camptodactyly. We report a familial case of Blau syndrome associated with a CARD15/NOD2 mutation. METHODS: PCR amplification and automated DNA sequencing of the complete CARD15/NOD2 coding sequence was performed. RESULTS: Molecular analysis in affected subjects disclosed a heterozygous c.1147G>C point mutation in CARD15/NOD2 exon 4, that predicts a p.E383K change at the protein level. CONCLUSIONS: Blau syndrome should be considered in the differential diagnosis of childhood uveitis and the genetic analysis of the CARD15/NOD2 gene is helpful in the diagnosis.

Interstitial pneumonitis in Blau syndrome with documented mutation in CARD15.

This is the first report of a CARD15 mutation-positive patient with Blau syndrome who exhibited interstitial lung disease, a feature historically considered absent from Blau syndrome, while typical of the adult form of sarcoidosis. This case illustrates the continued evolution of the phenotype of a disease initially conceived as a familial inflammatory granulomatous disease limited to the triad of synovitis, dermatitis, and uveitis.

Cytokine gene polymorphisms involved in chronicity and complications of anterior uveitis.

The aim of this study was to identify key cytokine polymorphisms associated with disease susceptibility, clinical phenotype, and outcome in patients with chronic anterior uveitis (CAU) as compared to those with recurrent self-limiting anterior uveitis (RAU). One hundred fifty seven British Caucasian patients with anterior uveitis were identified and divided into those where the inflammatory process lasted less than 3 months (RAU=118) and those where the inflammation persisted longer than 3 months (CAU=39). Patients with CAU were further sub-divided into idiopathic CAU, CAU associated with systemic disease, CAU with and without complications (posterior synechiae, posterior subcapsular lens opacity, raised intraocular pressure, cystoid macular oedema, and poor response to treatment). Sixty-six healthy controls were ethnically matched. TaqMan PCR amplification was used to genotype five single nucleotide polymorphisms in cytokine genes; IL-1RN+2018, IL-6-174, IL-10-1082, TNF-238, TNF-308 and these were correlated with clinical phenotype.

Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with HLA-B27-associated uveitis: association with susceptibility and clinical manifestations.

PURPOSE: The existence of genetic variations in a number of cytokines has been considered to influence susceptibility or relate to disease severity in various autoimmune diseases. Among these, single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF-alpha) promoter at nucleotides -308 and -238 are considered to be protective against inflammation in HLA-B27-positive individuals, whereas the SNP at position -857 has been associated with disease development in anterior uveitis. We investigate a hypothesized association between the TNF-alpha -857 C-to-T, -308 G-to-A, and the TNF-alpha -238 G-to-A SNPs and the presence of HLA-B27-associated uveitis. DESIGN: Retrospective case-control study. PARTICIPANTS: One hundred fourteen Caucasian patients with HLA-B27-associated uveitis were studied. Mean age of patients was 44.9+/-14 years (range, 16-81), and mean duration of HLA-B27-associated uveitis was 115.6+/-104 months (range, 6 months-51 years). Eighty-six patients (75.4%) suffered from an additional systemic manifestation of the disease. Sixty-three unrelated healthy HLA-B27-positive blood donors and 88 unrelated healthy HLA-B27-negative individuals served as controls. METHODS: Genotypes were determined by polymerase chain reaction. MAIN OUTCOME PARAMETERS: Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development. RESULTS: Frequencies of the TNF-alpha -308GA and TNF-alpha -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative control group, 23% at -308 (P = 0.003), and 7.9% at -238 (P = 0.0003). When compared with healthy HLA-B27-positive controls, a significantly lower frequency of the TNF-alpha -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-alpha -308GA genotype was also found to be lower in patients than among HLA-B27-positive control subjects, without, however, reaching statistical significance (6.1%, P = 0.07). No difference in frequencies was seen among the different groups for the SNPs at position -857. CONCLUSION: Our data suggest that HLA-B27-positive individuals show a higher susceptibility towards development of an intraocular inflammation in the presence of an A allele at nucleotide -238 and, to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.