Hyoun-Ah Kim

Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus.

There is a great deal of interest in the identification of biomarkers that are closely associated with disease activity in systemic lupus erythematosus (SLE), but few biomarkers have been validated. Cytokines play an important role in the pathogenesis of SLE. Therefore, we evaluated the levels of cytokines and their possible association with disease activity. In the present study, we found that the SLE patients had higher IL-6, IL-10, IL-12, and IFN-γ levels, but lower IL-2, than normal controls. Serum IL-6 level was significantly elevated in active SLE patients and correlated with the SLE activity index (SLEDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Serum IL-10 level was also significantly elevated in active SLE patients and revealed positive correlation with SLEDAI and anti-double-stranded DNA (dsDNA) titer and negative correlation with C3, C4, and lymphocyte counts. No significant differences in the levels of cytokines were observed between SLE patients with nephritis and those without nephritis. These data suggest that IL-6 and IL-10 may be a useful biomarker for disease activity in SLE.

C-reactive Protein Is a More Sensitive and Specific Marker for Diagnosing Bacterial Infections in Systemic Lupus Erythematosus Compared to S100A8/A9 and Procalcitonin

Objective. C-reactive protein (CRP), S100A8/A9, and procalcitonin have been suggested as markers of infection in patients with systemic lupus erythematosus (SLE). We investigated the clinical significance of these factors for indication of infection in SLE. Methods. Blood samples were prospectively collected from 34 patients with SLE who had bacterial infections and 39 patients with SLE who had disease flares and no evidence of infection. A second set of serum samples was collected after the infections or flares were resolved. Results. CRP levels of SLE patients with infections were higher than those with flares [5.9 mg/dl (IQR 2.42, 10.53) vs 0.06 mg/dl (IQR 0.03, 0.15), p < 0.001] and decreased after the infection was resolved. S100A8/A9 and procalcitonin levels of SLE patients with infection were also higher [4.69 μg/ml (IQR 2.25, 12.07) vs 1.07 (IQR 0.49, 3.05) (p < 0.001) and 0 ng/ml (IQR 0–0.38) vs 0 (0–0) (p < 0.001), respectively]; these levels were also reduced once the infection disappeared. In the receiver-operating characteristics analysis of CRP, S100A8/A9, and procalcitonin, the area under the curve was 0.966 (95% CI 0.925–1.007), 0.732 (95% CI 0.61–0.854), and 0.667 (95% CI 0.534–0.799), respectively. CRP indicated the presence of an infection with a sensitivity of 100% and a specificity of 90%, with a cutoff value of 1.35 mg/dl. Conclusion. Our data suggest that CRP is the most sensitive and specific marker for diagnosing bacterial infections in SLE.

Prevalence of work-related symptoms and serum-specific antibodies to wheat flour in exposed workers in the bakery industry

BACKGROUND Although bakers asthma (BA) is a common occupational asthma, there have been few reports on this disease in Korean subjects. OBJECTIVES We evaluated the prevalence of serum-specific IgE, IgG1, and IgG4 antibodies in relation to work-related respiratory symptoms in a single industrial bakery. METHODS Three hundred and ninety-two bakery workers were administered and taken a questionnaire regarding respiratory symptoms. For symptomatic workers, the methacholine bronchial challenge test and specific bronchoprovocation tests with wheat extracts were carried out. Skin prick tests were performed and serum-specific IgE, IgG1, and IgG4 antibodies to wheat flour were detected. The IgE- and IgG4-binding components were identified by immunoblotting. RESULTS Sixty-seven workers (17.1%) complained of work-related upper and lower respiratory symptoms. The prevalence of BA based on positive bronchoprovocation test results was 1.5%. The sensitization rate to wheat flour was 5.9% by skin prick test and 6.5% by ELISA, and was closely associated with the presence of atopy and work-related lower respiratory symptoms (P<0.001 for both). IgE immunoblotting revealed six major IgE-binding components (27, 31, 36, 43, 54, and 72 kDa). The presence of wheat-specific IgG1 and IgG4 antibodies was found to be significantly associated with exposure intensity (P<0.05 for both). CONCLUSIONS The overall prevalence of wheat sensitization in a Korean bakery was 5.9%. We confirmed that an IgE-mediated response is the major pathogenic mechanism for the induction of work-related symptoms in wheat-exposed workers. Wheat-specific IgG antibodies may represent current or previous exposure to wheat dust.

Cytokines and their receptors as biomarkers of systemic lupus erythematosus

Systemic lupus erythematosus is the most clinically diverse autoimmune disease. Owing to its heterogeneous presentation, clinical management of systemic lupus erythematosus remains as one of the greatest challenges. Therefore, there is a great need to assess disease activity accurately. Biomarkers can be objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention, and may also predict the risk of the disease, confirm diagnosis, monitor disease activity and provide prognostic information. Cytokines play an important and diverse role in the immune dysregulation in systemic lupus erythematosus. Measuring serum levels of soluble IL-2 receptor, IL-6, IL-10, soluble TNF receptor and IFN-α/IFN-induced genes may be promising biomarkers of disease activity in systemic lupus erythematosus.

Metalloproteinase‐9 is increased after toluene diisocyanate exposure in the induced sputum from patients with toluene diisocyanate‐induced asthma

Background and objective Persistent asthma symptoms are associated with airway inflammation and remodeling, which may be mediated through metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP). The aim of this study was to evaluate MMPs and TIMP involvement in toluene diisocyanate (TDI)‐induced asthma.

Serum S100A8/A9, But Not Follistatin-like Protein 1 and Interleukin 18, May Be a Useful Biomarker of Disease Activity in Adult-onset Still’s Disease

Objective. S100A8/A9, follistatin-like protein 1, and interleukin 18 (IL-18) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still’s disease (AOSD). We investigated the clinical significance of these factors in AOSD. Methods. Blood samples were collected from 36 patients with AOSD, 40 patients with rheumatoid arthritis (RA), and 33 healthy controls. Of the patients with AOSD, followup samples were collected from 16 patients after resolution of disease activity. Results. Serum levels of S100A8/A9 (11.77 ± 8.84 μg/ml) in AOSD patients were higher than those in RA patients (3.53 ± 3.43 μg/ml; p < 0.001) and controls (2.49 ± 1.83 μg/ml; p < 0.001). Follistatin-like protein 1 levels in AOSD were not different from those in RA and controls. IL-18 levels in AOSD (7560.3 ± 7577.6 pg/ml) were higher than those in RA (217.7 ± 292.1 pg/ml; p < 0.001) and controls (139.2 ± 86.2 pg/ml; p < 0.001). The sensitivity and specificity of IL-18 for diagnosing AOSD was highest with a cutoff value of 366.1 pg/ml. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, and systemic disease score; however, IL-18 correlated only with ferritin and systemic disease score. S100A8/A9 was decreased after disease activity was resolved in followup of AOSD patients (9.96 ± 7.35 μg/ml in active AOSD vs 3.6 ± 4.77 μg/ml in resolved cases; p = 0.001). The change of S100A8/A9 was well correlated with that of systemic disease score. Conclusion. The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in patients with AOSD.

Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features, predictive factors, and prognosis in 21 patients.

AbstractHemophagocytic syndrome (HPS) is a potentially life-threatening complication of systemic inflammatory disorders. Adult-onset Still disease (AOSD) is one of the systemic autoimmune diseases associated with reactive hemophagocytic syndrome (RHS). This study aimed to evaluate the characteristic findings, predictive factors, and prognosis of RHS in patients with AOSD.We retrospectively evaluated 109 patients diagnosed with AOSD and reviewed their clinical data and laboratory findings, including the biopsy results of 21 AOSD patients with RHS. Moreover, data from 17 hemophagocytic lymphohistiocytosis (HLH) patients evaluated during the same period were compared with those from the RHS patients.Twenty-one patients (19.3%) developed RHS during the course of AOSD, and only 7 patients (6.4%) were confirmed by bone marrow, liver, or lymph node biopsy. AOSD patients with RHS showed significantly higher frequencies of splenomegaly, hepatomegaly, and lymphadenopathy than did those without RHS. Moreover, patients with RHS showed significantly higher relapse rates than those without RHS (61.9% vs 18.2%, P < 0.001). Possible triggering factors inducing hemophagocytosis were detected in 16 of 21 RHS patients (76.2%): disease flare in 12 patients (75%), infection in 3 patients (18.8%), and drug use in 1 patient (6.3%). AOSD patients with RHS showed higher frequencies of leukopenia, anemia, thrombocytopenia, hypoalbuminemia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia, and elevated lactate dehydrogenase levels than did those without RHS. Multivariate logistic regression with forward selection procedure showed that low platelet count (<121,000/mm3), anemia, and hepatomegaly were independent predictors of RHS. Patients with definite RHS and those with probable RHS showed comparable results. Although RHS is a life-threatening complication of AOSD, long-term prognosis was observed to be similar in patients with and those without RHS. Compared to RHS patients, HLH patients had poor prognosis, such as higher death rates (52.9% vs 9.5%, P = 0.005).RHS can be considered when an AOSD patient shows at least 2 of the following 3 findings: low platelet count, anemia, and hepatomegaly. Diagnostic confirmation by biopsy may not be essential if typical clinical findings of RHS are present. Moreover, prognosis of RHS was better than that of HLH diagnosed by the presence of trilineage cytopenia at admission.

C-Reactive Protein Gene Polymorphisms in Disease Susceptibility and Clinical Manifestations of Korean Systemic Lupus Erythematosus

Objective. C-reactive protein (CRP) is a sensitive marker of inflammation. It is hypothesized that polymorphism of CRP gene contributes to susceptibility to systemic lupus erythematosus (SLE). We tested this hypothesis by identifying CRP gene polymorphisms in Korean patients with SLE. Methods. Approximately 1.5 kb of CRP promoter region was screened for single nucleotide polymorphism (SNP) using direct sequencing and 3 SNP in CRP exons by restriction fragment length polymorphism. The basal levels of CRP were measured by immunoturbidimetry. The effect of −390 C>A or T polymorphism on the promoter activity was analyzed by luciferase reporter assay in Hep3B cells. Results. Allele frequency at polymorphisms within CRP promoter and exon in our Korean patients with SLE differed from that of Caucasians. The A allele was a major allele at position 2043 in Korean SLE patients, whereas G is a major allele in Caucasian SLE. Our SLE patients had minor allele in the −390 polymorphism more frequently versus controls (p = 0.033). CRP 1185 polymorphism was associated with thrombocytopenia (p = 0.043). The basal levels of CRP were significantly higher in individuals who had minor allele in −390 and 2043 polymorphisms (p = 0.03. p = 0.024, respectively). Promoter-reporter construct carrying the −390 A or T allele displayed significantly higher promoter activity than that with the −390 C allele (p < 0.001). Conclusion. CRP gene −390 polymorphism plays a role in disease susceptibility of SLE through regulation of serum CRP level. Our results suggest that elevated basal CRP level may be important in the pathogenesis of SLE, even though CRP responsiveness to noninfectious inflammation of SLE is decreased.

Association of guanosine triphosphate cyclohydrolase 1 gene polymorphisms with fibromyalgia syndrome in a Korean population.

Objective. Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor in nitric oxide (NO) production. Polymorphisms in the GCH1 gene have been implicated in protection against pain sensitivity. The aim of our study was to determine whether single-nucleotide polymorphisms (SNP) in the GCH1 gene affect susceptibility and/or pain sensitivity in fibromyalgia syndrome (FM). Methods. A total of 409 patients with FM and 422 controls were enrolled. The alleles and genotypes at 4 positions [rs3783641(T>A), rs841(C>T), rs752688(C>T), and rs4411417(T>C)] in the GCH1 gene were analyzed. The associations of the GCH1 SNP with susceptibility and clinical measures in patients with FM were assessed. Results. The frequencies of alleles and genotypes of the 4 SNP did not differ between patients with FM and healthy controls. Among 13 constructed haplotypes, we further examined 4 (CCTT, TTCT, TTCA, and CCTA) with > 1% frequency in both FM and controls. No associations of GCH1 polymorphisms with FM-related activity or severity indexes were found, although the number and total score of tender points in patients with FM differed among the 4 haplotypes (p = 0.03 and p = 0.01, respectively). The CCTA haplotype of GCH1 was associated with significantly lower pain sensitivity and occurred less frequently than the CCTT haplotype in patients with FM (p = 0.04, OR 0.45, 95% CI 0.21–0.96). Conclusion. Our study provides evidence that certain GCH1 haplotypes may be protective against susceptibility and pain sensitivity in FM. Our data suggest that NO is responsible for pain sensitivity in the pathogenesis of FM.

Interleukin 6 Gene Polymorphisms Are Associated with Systemic Lupus Erythematosus in Koreans

Objective. Interleukin 6 (IL-6) gene polymorphisms are known to play a role in chronic inflammatory disorders. We searched for polymorphisms in the IL-6 gene and described their pathogenic role in Korean patients with systemic lupus erythematosus (SLE). Methods. Genomic DNA was extracted from 151 patients with SLE and 151 controls, and about 1.4 kb-sized IL-6 genes located between promoter region and exon 2 region were amplified by polymerase chain reaction. The promoter activity was analyzed by luciferase reporter assay in Hep3B cells and HeLa cells. Results. We identified 4 single-nucleotide polymorphisms (SNP; −572 C > G, −278 A > C in the promoter, and 330 T > G, and 334 A > T in exon 2) and a −373 AnTn tract polymorphism in the IL-6 gene. The genotype frequency, −373 A10T11, −278 C, and 334 T allele were significantly associated with SLE (p < 0.001, p = 0.03 and p = 0.005, respectively). Patients with SLE carrying the −572 G allele had anti-dsDNA more frequently (p = 0.007). In addition, thrombocytopenia was significantly more common in patients carrying the −278 C allele (p = 0.006). In the haplotype analysis, patients with SLE had more frequently haplotype HT3 (CA10T11ATA, dominant model, p = 0.012) that was associated with arthritis, leukopenia, anti-dsDNA, and hypocomplementemia. Promoter reporter structures carrying the −278 C allele displayed significantly higher promoter activity than the −278 A allele in Hep3B cells (p < 0.001) and HeLa cells (p < 0.001). Conclusion. These data suggest that IL-6 gene polymorphisms are associated with disease susceptibility and phenotype of SLE. In addition, promoter polymorphisms may be involved in regulation of IL-6 expression.