HLA-B27.

Effects of fumonisin B1 on HLA class I antigen presentation and processing pathway in GES-1 cells in vitro

Similarities and differences between axial spondyloarthritis and axial psoriatic arthritis.

Background Endoplasmic reticulum aminopeptidase 1 (ERAP1) is known to participate in the pathogenesis of ankylosing spondylitis (AS). This study aimed to evaluate the relationship between promoter methylation and mRNA levels of ERAP1 and AS susceptibility. Methods DNA methylation levels of 100 AS patients and 100 healthy controls (HCs) were tested using a targeted bisulfite sequencing assay. To verify the results of DNA methylation, mRNA levels of ERAP1 were measured in 20 AS patients and HCs used quantitative real-time reverse transcription-polymerase chain reaction. Results The DNA methylation levels of two CpG islands containing 31 loci in ERAP1 promoter were measured. ERAP1_1 (P< .001) and ERAP1_2 (P< .001) islands were significantly hypermethylated in AS patients compared with HCs. In the verification study, the mRNA levels of ERAP1 were significantly decreased in AS patients. The ROC curve analysis showed that the sensitivity, specificity and area under curve were 0.717, 0.737, and 0.779 of differential methylated CpG loci of ERAP1 for AS diagnosis. In AS patients, the methylation levels of EARP1 were associated with family history, non-steroidal anti-inflammatory drugs use, X-ray classification, and clinical manifestations. Conclusions Our study demonstrated that the ERAP1 gene is significantly hypermethylated, and mRNA levels of EARP1 decreased, in AS patients. Our findings suggested that the aberrant methylation of ERAP1 promoter may be involved in the pathogenesis of AS and could be considered as a diagnostic tool and therapeutic target of AS. Abbreviations AS: Ankylosing Spondylitis; AUC: Area Under Curve; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; CI: Confidence Interval; CpG: Cytosine-guanine Dinucleotide; CRP: C-reactive Protein; ERAP1: Endoplasmic Reticulum Aminopeptidase 1; ESR: Erythrocyte Sedimentation Rate; EWAS: Epigenome-Wide Association Study; HLA: Human Leukocyte Antigen; OR: Odds Ratio; PCR: Polymerase Chain Reaction; ROC: Receiver Operating Characteristic; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs.

BackgroundPsoriatic arthritis (PsA) and ankylosing spondylitis (AS) represent the prototypical spondyloarthritides. PsA patients may also suffer from axial disease (axPsA). Despite overlapping symptoms, axPsA and AS may be distinct disorders...

Background lncRNAs have been recognized as powerful regulators of numerous genes and pathways in the pathogenesis of inflammatory and autoimmune diseases, including SLE, RA, T1DM, MS, autoimmnue thyroid disease, Sjogren’s syndrome psoriasis, and Crohn’s disease[1]. The role of lncRNAs in the pathogenesis of Ankylosing Spondylitis (AS) is just beginning to be investigated Objectives To determine whether the altered expression of lncRNA NR_003542 and NR_026756 in peripheral blood of AS patients could provide insights into the pathogenesis of AS. Methods Peripheral blood mononuclear cells (PBMCs) lncRNA NR_003542 and NR_026756 expression were measured in 30 active AS (AAS)group, 30 inactive AS (IAS) group and 30 healthy control (HC) subjects. Clinical characteristics of the subjects are summarized in Table1. Results 1. Clinical and laboratory characteristics of the three groups (Table 1) BASDAI: bath ankylosing spondylitis disease activity index, BASFI: bath ankylosing spondylitis functional index,HLA-B27:Human leukocyte antigen B27.ESR:erythrocyte sedimentation,WBC:leukocyte, GLOB: globulin, a: the P value of the non-parametric Mann-Whitney test. 2. Comparison of the two lncRNAs expression among the three groups (Figure 1) 3. Correlations between levels of two lncRNAs expression s and clinical data in AS patients (Figure 2) Conclusion Altered expression of lncRNA-NR_003542 and NR_026756 in peripheral blood of AS patients might be involved in the pathogenesis of AS, higher expression of lncRNA-NR_003542 and lower expression of NR_026756 might be as the biomarkers for the disease activity of AS, further study would be needed to expound on the exact role of the two lncRNAs in AS.

Ankylosing spondylitis (AS) is an inflammatory disease, and choroidal thickness (CT) has been proposed and evaluated as a potential marker of systemic inflammation associated with AS and other inflammatory diseases. This study compared CT measurements taken from patients with severe AS disease activity without eye inflammation with those taken from healthy subjects. This cross-sectional, multicenter study compared CT in 44 patients with high AS disease activity, and no history of eye inflammation with CT in 44 matched healthy subjects aged between 18 and 65 years. In the AS group, the correlation between CT and C-reactive protein, human leukocyte antigen (HLA) B27 positivity, disease duration, and disease activity was calculated. Mean CT values of patients with AS were significantly higher in the right eye, the left eye, and the thickest choroid eye. The right eye mean CT was 338.3 ± 82.8 μm among patients with AS and 290.5 ± 71.2 μm among healthy subjects (p = 0.005). The left eye mean CT was 339.5 ± 84.7 μm for patients with AS and 298.4 ± 68.9 μm for healthy subjects (P = 0.015). The thickest choroid eye CT was 358.4 ± 82.1 μm among patients with AS and 314.1 ± 65.2 μm among healthy subjects (P = 0.006). We did not find a significant correlation between CT and disease activity, C-reactive protein, human leukocyte antigen B27 positivity, or disease duration. Patients with active AS but without a history of eye inflammation had a thicker choroid than healthy subjects. This finding suggests that CT is a marker of systemic inflammation in patients with inflammatory disease, regardless of known eye symptoms.

This study designed to assess the relationship between tumor necrosis factor (TNF)-α promoter polymorphisms and disease susceptibility to human leukocyte antigen (HLA)-B27-positive ankylosing spondylitis (AS). One hundred and nineteen HLA-B27(+) AS patients, 95 HLA-B27(+) healthy controls, and 135 random healthy controls were enrolled in this study. Six single nucleotide polymorphisms (SNPs) of the TNF-α promoter at positions -1031T/C, -863C/A, -857C/T, -646G/A, -308G/A, and -238G/A were analyzed. Differences between groups were evaluated using the chi-square test or Fisher's exact test. Haplotypes from each SNP were constructed, and differences in haplotypic frequencies between groups were evaluated. There were significant differences in the allelic and genotypic frequencies of 1031T/C, -863C/A, and -857C/T TNF-α promoters polymorphisms between HLA-B27(+) AS patients and random controls, but not between patients with AS and HLA-B27(+) healthy individuals. TNF-α polymorphisms did not influence the extra-spinal clinical features in patients with AS. The haplotypic sequence -1031T/-863C/-857C/-308G increased the risk of susceptibility to AS compared to random controls (P (corr) < 0.001, OR = 2.756, 95% CI = 1.894-4.010), whereas the sequence -1031C/-863A/-857C/-308G appeared to be associated with decreased susceptibility to AS compared to random controls (P (corr) = 0.006, OR = 0.396, 95% CI = 0.231-0.679). This study indicates that TNF-α promoter polymorphism between controls and AS patients with HLA-B27(+) genetic background is not associated with susceptibility to AS. However, TNF-α polymorphism, irrespective of HLA-B27, increases risk of susceptibility to AS in general population.

Repeated exposure to HIV does not necessarily result in infection and HIV infection does not inevitably lead to the development of the AIDS. Multiple immunological and genetic features can confer resistance to HIV acquisition and progression at different steps in viral infection; a full understanding of these mechanisms could result in the development of novel therapeutic and vaccine approaches for HIV infection. In this review, we focus on the genetic mechanisms associated with resistance to HIV infection and to the progression to AIDS.

Inhibition of ERAP1 represses HLA-B27 free heavy chains expression on polarized macrophages and interrupts NK cells activation and function from ankylosing spondylitis

PurposeAcute 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

The publication of a case report by Sang et al. in which immune-mediated sensorineural hearing loss was observed in a patient with ankylosing spondylitis (AS) prompted us to report this case [1]. We wish to describe a patient with AS, sensorineural hearing loss, and minimal aortic insufficiency whose mother and brother are also human leukocyte antigen (HLA)-B27-positive AS patients. The 22-year-old male was first referred to our department in March 2003 with lower back pain, prolonged morning stiffness, pain in the right hip, synovitis in the left knee, and bilateral hearing loss. He had had lower back pain and stiffness for 4 years. On physical and neurological examination, the patient showed pain and limitation of lumbar spine movement and loss of lumbar lordosis. He had had right hip pain for 3 weeks and synovitis in the left knee for 2 weeks. Sacroiliac stress tests were positive bilaterally. On testing, the chest wall expansion was 3.5 cm. Modified Schober’s test was 4 cm in range, finger-to-ground distance was 10 cm, and occiput-to-wall distance was 0 cm. Results of the laboratory investigations showed haemoglobin 13.0 g/dl, white cell count 17.1·103/ll, predominantly neutrophils (83.4%), increased erythrocyte sedimentation rate of 58 mm/h (Westergren), normal serum chemistry, and normal urine analysis. Immunology screening showed a positive result for Creactive protein of 15.3 mg/dl (normal 0.00–0.800) and negative tests for rheumatoid factor, antinuclear antibodies, and antibodies against double-stranded DNA. Human leukocyte antigen typing was positive for B27. The immunoglobulin G level was increased to 1740 mg/dl (normal 751–1560). Immunoglobulin A and M levels were 231 mg/dl (normal 82–453) and 146 mg/ dl (normal 46–304), respectively. Synovial fluid analysis of the left knee was normal. Pulmonary function tests and arterial blood gas analysis were also found to be normal. Anterior radiography of the pelvis and computed tomography of the sacroiliac joints showed bilateral sacroiliitis. Magnetic resonance imaging of the lumbar vertebrae was normal. The diagnosis of AS was made according to New York criteria [2], and the patient was given sulphasalazine at a dosage of 2 g/day. The patient had additionally suffered from hearing loss for about 6 months. He did not indicate any other previous disease that could affect hearing. In clinical evaluation, the outer ear, tympanic membrane, and middle ear were found to be normal. Pure tone audiometry results revealed bilateral sensorineural hearing loss in the speech frequencies measuring 80 dB in the left ear and 100 dB in the right ear. Magnetic resonance imaging of the temporal bone was normal. Sensorineural hearing loss is a rare complication of ankylosing spondylitis and described in only three reports as an accompanying symptom of AS. This situation prompted us to report this interesting case. Conductive hearing loss in association with AS has been discussed previously. In that report, Magaro suggested the possible occurrence of conductive hearing loss due to arthritic involvement of the ossicular joints in patients with AS [3]. In contrast to this finding, De Miguel suggested in a letter that middle ear involvement did not occur in patients with AS, and he pointed out that loss of sensorineural hearing was found more frequently in patients than in a control population, Rheumatol Int (2004) 24: 252–253 DOI 10.1007/s00296-003-0425-x

ABSTRACTPurpose: To evaluate corneal parameters of patients with ankylosing spondylitis (AS) by Scheimpflug imaging and also to clarify the associations between disease severity and clinical status of AS and corneal parameters. Methods: Fifty-seven patients with AS and 57 healthy subjects were included in this cross-sectional study. All participants underwent a detailed ophthalmological evaluation. Corneal parameters were measured by Pentacam. In addition, Schirmer test, tear break-up time (TBUT), corneal fluorescein staining, and Ocular Surface Disease Index (OSDI) scores were evaluated. Duration of disease and scores of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Quality of Life scale (ASQoL) of the patients were recorded. The laboratory evaluation consisted of human leukocyte antigen (HLA)-B27, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Results: Corneal parameters were significantly different between patients with AS and healthy controls. The mean central corneal thickness (538 ± 26 µm versus 569 ± 27 µm, p < 0.001) and the mean corneal volume (59.8 ± 3.33 mm3 versus 62.3 ± 3.40 mm3, p < 0.001) were reduced significantly in AS patients compared to those in healthy controls. The values of TBUT and Schirmer test scores were significantly lower in AS patients than in controls. Also, corneal fluorescein staining and OSDI scores were higher in AS patients than in controls. Factors related to the corneal parameters were dry eye tests (TBUT, Schirmer test, corneal fluorescein staining), OSDI score, and CRP (p < 0.05 for all). Conclusion: The AS patients have thinner corneas compared to control subjects, which may be affected by tear disfunction and inflammatory processes.

ObjectivesTo determine the association of Human leukocyte antigen B (HLA‑B) alleles with ankylosing spondylitis and the allelic association of HLA‐B27 with endoplasmic reticulum aminopeptidase 1 (ERAP1) single‐nucleotide polymorphism (SNP) rs30187 in patients with ankylosing spondylitis (AS).MethodsWe studied 48 consecutively enrolled well‐defined AS patients and 48 healthy controls recruited from the outpatient clinic of the rheumatology department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. To genotype HLA‐B alleles from peripheral blood DNA, we designed sequence‐specific primers for polymerase chain reaction. Sanger's sequencing method was used to detect the ERAP1 rs30187 SNP. The HLA‐B allele distributions were compared between cases and controls. To infer an allelic association between HLA‐B27 and ERAP1, allele distributions from both loci were compared using cross‐tabulations. Chi‐squared test or Fisher's exact test was used to quantify the association, and their strength of association was tested by odds ratio (OR) with 95% confidence interval (CI).ResultsThe frequency of HLA‐B27 was found to be higher in AS patients (60.4%) than in healthy controls (8.3%). HLA‐B27 allele had an OR of 16.8 (95% CI = 5.2–54.4) for the development of AS. Overall, 4% of AS patients had both HLA‐B27 and HLA‐B40. No significant association was found between ERAP1 rs30187 SNP and HLA‐B27 in patients with AS (OR = 1.7, 95% CI = 0.5–5.6).ConclusionsHLA‐B27 was significantly associated with AS in patients in Bangladesh. However, no association between ERAP1 rs30187 SNP and HLA‐B27 was observed.

SummaryPrevious studies show that endoplasmic reticulum‐associated aminopeptidase (ERAP1/ERAP2) and runt‐related transcription factor 3 (RUNX3) gene polymorphisms are associated with AS (ankylosing spondylitis) in European Caucasians. However, contradictory results were reported in different Asian populations. The purpose of this study was to determine whether eleven candidate single nucleotide polymorphisms (SNPs) in ERAP1/ERAP2 and six in RUNX3 genes confer susceptibility to AS with or without acute anterior uveitis (AAU) [AS+AAU+ or AS+AAU–] in Chinese Han. Therefore, a case–control association study was performed in 882 AS+AAU–, 884 AS+AAU+ and 1727 healthy controls. Genotyping was performed using the iPLEXGold genotyping assay. A meta‐analysis was performed to assess the association of polymorphisms of ERAP1 with AS susceptibility in Asian populations. No association was found between SNPs of ERAP1/ERAP2/RUNX3 and susceptibility of AS with or without AAU. A case–control study between patients with human leucocyte antigen HLA‐B27‐positive and healthy controls also failed to demonstrate an association of the tested SNP with AS with or without AAU. Moreover, a meta‐analysis showed that there was no association of rs30187, rs27037, rs27980, rs27434 and rs27582 in ERAP1 with AS in Chinese Han. Taken together, 17 SNPs in ERAP1/ERAP2 and RUNX3 genes did not confer disease susceptibility to AS in Chinese Han.

Membrane immunoglobulin (mIg) M and D heavy chains possess minimal (KVK) cytoplasmic tails and associate with the Ig alpha/Ig beta (CD79) dimer to achieve surface expression and antigen presentation function. In contrast, the cytoplasmic tail of mIgG is extended by 25 residues (gamma ct). We have tested the possibility that mIgG can perform antigen capture and presentation functions independently of the Ig(alpha)/beta dimer. We show that CD4/(gamma)ct chimeras are efficiently endocytosed partially dependent on a tyrosine residue in (gamma)ct. In addition, human mIgG was expressed on the surface of Ig(alpha)/Ig(beta)-negative non-lymphoid cells and mediated antigen capture and endocytosis. Antigen-specific human mIgG targeted antigen to MIIC-type vesicles in the Ig(alpha)/beta negative melanoma Mel JuSo and augmented antigen presentation 1000-fold, identical to the augmentation seen in Ig(alpha)/beta-positive B-cells expressing the same transfected mIgG. Thus, unlike mIgM, mIgG has autonomous antigen capture and presentation capacity, which may have evolved to reduce or eliminate the BCR's dependence on additional accessory molecules.