Serum Concentrations Of S100A12 Research Articles

Usefulness of Proguanylin, Pentraxin 3 and S100A12 Serum Concentrations in Diagnosis and Monitoring the Disease Activity in Crohn's Disease.

The aim of our case-control study was to identify novel biomarkers of Crohn's disease (CD) that hold the potential to be employed in both disease diagnosis and monitoring activity. In the context of the contribution of intestinal barrier integrity and immune response to the pathogenesis of CD, we assessed the serum concentrations of proguanylin (pro-GN), pentraxin 3 (PTX3) and S100A12 in 20 patients before and after anti-inflammatory treatment, as well as in 20 healthy individuals. Statistical analyses revealed a significant difference in the levels of pro-GN (5.5 vs. 11.35, p < 0.001), PTX3 (2117.9 vs. 1608.37, p < 0.05) and S100A12 (79.4 vs. 19.74, p < 0.001) between pretreatment patients with CD and healthy individuals. Moreover, we noted a significant relationship between the serum profile of PTX3 and disease activity, expressed as CDAI, both before (p < 0.005, r = 0.63) and after (p < 0.05, r = 0.60) treatment. A similar correlation was noted in the case of S100A12 (p < 0.005, r = 0.81), albeit exclusively within the post-treatment group of patients. Anti-inflammatory treatment resulted in an elevation of pro-GN concentration (5.5 vs. 8.04, p < 0.001) and a reduction in PTX3 level (2117.9 vs. 1609.5, p < 0.05) in the serum of patients with CD. In comparison to our previous research conducted on a group of patients with ulcerative colitis (UC), those with CD exhibited reduced levels of PTX3 (2117.9 vs. 3197.05, p < 0.005) and elevated concentrations of S100A12 (79.4 vs. 39.36, p < 0.05). The results obtained from this investigation suggest that measurements of pro-GN, PTX3 and S100A12 could prove beneficial in the diagnosis of Crohn's disease. Assessment of changes in the serum profile of PTX3 appears to be a good marker of response to treatment but also, along with analysis of S100A12 protein serum levels, a useful marker in differentiating CD from UC.

Definition and validation of serum biomarkers for optimal differentiation of hyperferritinaemic cytokine storm conditions in children: a retrospective cohort study.

Cytokine storm syndromes are life-threatening complications that can occur in children with rheumatic conditions (macrophage activation syndrome [MAS]), inherited cytotoxicity defects (ie, primary haemophagocytic lymphohistiocytosis [HLH]), or as a result of infection or malignancies (ie, secondary HLH). To adequately steer treatment, an early and clear discrimination of these entities is essential. We aimed to define and validate serum biomarker profiles that can differentiate between primary HLH, secondary HLH (predominantly infection-associated), and MAS associated with systemic juvenile idiopathic arthritis (systemic JIA-MAS). In this multicentre, retrospective, cohort study, serum samples from patients (0-18 years) with a clinical diagnosis of primary HLH, secondary HLH, or systemic JIA-MAS were analysed by immunoassays for 55 cytokines and chemokines. Serum samples were collected from patients treated at seven clinical centres in Europe and North America. 15 serum biomarkers were validated using an independent commercial assay, and the diagnostic accuracy of the best performing biomarkers was tested in an independent validation cohort. Serum samples were collected between Dec 7, 2010, and Jan 26, 2018. In the discovery cohort of 43 patients (24 girls and 19 boys) multi-marker analyses revealed distinct serum biomarker profiles associated with primary or secondary HLH versus systemic JIA-MAS. Ten biomarkers were identified that were differentially elevated in either HLH or systemic JIA-MAS and distinguished between these clinical entities, six of which were tested in an independent validation cohort of 79 patients (34 girls and 45 boys). Serum concentrations of S100A12 and interleukin-18, as well as ratios of both S100A12 and IL-18 with chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10 were identified as the most promising candidates for differential diagnostics. At initial presentation, when it is unclear whether a patient with excessive hyperferritinaemic inflammation has primary HLH, infection-associated secondary HLH, or MAS, high serum concentrations of S100A12 indicate an initial differential diagnosis of systemic JIA-MAS, thus helping to guide subsequent treatment decisions. We therefore suggest the inclusion of serum S100A12 and IL-18 in the diagnostic investigations for hyperferritinaemic syndromes; however, the definition and introduction of universially applicable cutoff values are still required. German Research Foundation, the Center for Interdisciplinary Clinical Research at University Hospital Muenster, the EU's Horizon 2020 research and innovation programme, and the Deutsche Kinderkrebsstiftung.

S100A12 Serum Levels and PMN Counts Are Elevated in Childhood Systemic Vasculitides Especially Involving Proteinase 3 Specific Anti-neutrophil Cytoplasmic Antibodies.

Objectives: Chronic primary systemic vasculitidies (CPV) are a collection of rare diseases involving inflammation in blood vessels, often in multiple organs. CPV can affect adults and children and may be life- or organ-threatening. Treatments for adult CPV, although effective, have known severe potential toxicities; safety and efficacy of these drugs in pediatric patients is not fully understood. There is an unmet need for biologic measures to assess the level of disease activity and, in turn, inform treatment choices for stopping, starting, or modifying therapy. This observational study determines if S100 calcium-binding protein A12 (S100A12) and common inflammatory indicators are sensitive markers of disease activity in children and adolescents with CPV that could be used to inform a minimal effective dose of therapy.Methods: Clinical data and sera were collected from 56 participants with CPV at study visits from diagnosis to remission. Serum concentrations of S100A12, C-reactive protein (CRP) and hemoglobin (Hb) as well as whole blood cell counts and erythrocyte sedimentation rate (ESR) were measured. Disease activity was inferred by physician's global assessment (PGA) and the pediatric vasculitis activity score (PVAS).Results: Serum concentrations of standard markers of inflammation (ESR, CRP, Hb, absolute blood neutrophil count), and S100A12 track with clinically assessed disease activity. These measures—particularly neutrophil counts and sera concentrations of S100A12–had the most significant correlation with clinical scores of disease activity in those children with vasculitis that is associated with anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3.Conclusions: S100A12 and neutrophil counts should be considered in the assessment of disease activity in children with CPV particularly the most common forms of the disease that involve proteinase 3 ANCA.Key messages:- In children with chronic primary systemic vasculitis (CPV), classical measures of inflammation are not formally considered in scoring of disease activity.- Inflammatory markers—specifically S100A12 and neutrophil count—track preferentially with the most common forms of childhood CPV which affect small to medium sized vessels and involve anti neutrophil cytoplasmic antibodies (ANCA) against proteinase-3.

Three Innate Cytokine Biomarkers Predict Presence of Acute Otitis Media and Relevant Otopathogens

1.1Diagnosis of Acute Otitis Media (AOM) is challenging, resulting in frequent over diagnosis and improper prescription of antibiotics. A serum biomarker of AOM would significantly improve pediatric care for this common illness. 1.2Serum samples were studied from 197 children 6-36 months old during health, during viral Upper Respiratory Infection (URI) without middle ear involvement, and at the onset of AOM (confirmed by tympanocentesis). Serum concentrations of S100A12, IL-10, and ICAM-1 were measured by ELISA. Otopathogens were identified by culture of middle ear fluid. A predictive model for infection and causative otopathogen was developed based on density distributions of the measured cytokines. 1.3A biomarker score derived from subject age and serum concentrations of S100A12, IL-10, and ICAM-1 was significantly able to distinguish both between health and disease and between upper respiratory infections with and without middle ear involvement (AOM vs URI), and further predicted the specific causative bacterial pathogen. This biomarker could also identify recurrent OM-prone children. 1.4For the first time we show that a biomarker risk score derived from serum cytokine levels can predict the presence of bacterial AOM, the likely Otopathogen, and the recurrent OM-prone child. 1.5(1) AOM is a widespread pediatric infection with a substantial economic burden. (2) Three serum cytokines can discriminate between URI and AOM, reducing over diagnosis. (3) Prediction of responsible pathogen enables targeted antibiotic prescription.

Serum S100A12 as a prognostic biomarker of severe traumatic brain injury

BackgroundS100A12 is related to acute brain injury and inflammation. We investigated the clinical prognostic value of serum S100A12 in patients with severe traumatic brain injury (sTBI). MethodsSerum S100A12, S100B, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) concentrations were measured in 102 healthy controls and 102 sTBI patients. We recorded 30-day mortality and in-hospital major adverse events (IMAEs) including acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. Trauma severity was assessed by admission Glasgow Coma Scale scores. ResultsWhen compared to the controls, serum S100A12, S100B, CRP, IL-6 and TNF-α concentrations were significantly increased in the patients. Serum concentrations of S100A12 significantly correlated with admission Glasgow Coma Scale scores and serum concentrations of S100B, CRP, IL-6 and TNF-α. Patients with any IMAEs or non-survivors within 30 days had obviously higher serum concentrations of S100A12, S100B, CRP, IL-6 and TNF-α than other remaining ones. Serum S100A2 was independently associated with IMAEs and 30-day mortality and overall survival. Receiver operating characteristic curve analysis showed that S100A12 concentrations had significant discriminatory ability for patients at risk of any IMAEs and death within 30 days. ConclusionS100A12 might be associated with brain inflammation and evaluation of serum concentrations of S100A12 could be helpful in the early prognostic prediction in sTBI patients.

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF. Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF. In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease. The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.

S100A12 expression in patients with primary biliary cirrhosis

Objectives: S100 calcium binding protein A12 (S100A12) has been supposed to be a pro-inflammatory factor associated with non-infectious inflammatory diseases. However, whether S100A12 is involved in the inflammatory process of primary biliary cirrhosis (PBC) has not been shown.Methods: The levels of S100A12 mRNA transcripts in peripheral mononuclear blood cells (PBMCs) of 66 Chinese patients with primary biliary cirrhosis (PBC), 62 healthy controls (HC) and 55 chronic hepatitis B (CHB) were measured by qRT-PCR. S100A12 serum concentrations in 34 PBC patients were measured by ELISA.Results: The levels of S100A12 mRNA transcripts in PBMCs of patients with PBC were significantly higher than healthy controls (p < 0.01) and that of patients with CHB (p < 0.01). Importantly, the levels of S100A12 mRNA in PBMCs and S100A12 protein levels in serum were positively correlated with biochemical indicators of bile duct and hepatocyte damage.Conclusion: S100A12 might participate in the damage of biliary epithelial cells and hepatocytes in PBC, and analysis of S100A12 expression could be useful as a surrogate marker for the evaluation of PBC activity.

Validation of Relapse Risk Biomarkers for Routine Use in Patients With Juvenile Idiopathic Arthritis

The myeloid-related proteins 8 and 14 (MRP-8/MRP-14) and neutrophil-derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme-linked immunosorbent assays (ELISAs) in order to validate systems available for routine use. MRP-8/MRP-14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed. For MRP-8/MRP-14, the PhiCal Calprotectin and Buhlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN-RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs. For the prediction of JIA relapse after stopping medication, the biomarkers MRP-8/MRP-14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP-8/MRP-14 and S100A12 ELISAs showed a performance comparable to well-established experimental ELISA protocols when assay-specific cutoffs for the indication of relapse prediction are thoroughly applied.

Effect of diet type on serum and faecal concentration of S100/calgranulins in the captive cheetah

Gastrointestinal disease is omnipresent in captive cheetahs ( Acinonyx jubatus ), in contrast to its free-ranging populations. The current study aimed to evaluate the effect of diet type (meat-only whole prey) on gastrointestinal health in captive cheetahs by measuring faecal and serum concentrations of S100/calgranulins. This paper reports faecal S100A12 and calprotectin concentrations in 12 captive cheetahs fed supplemented beef versus whole rabbit for one month in a cross-over design. Also, serum S100A12 and calprotectin concentrations were determined in four cheetahs fed whole rabbit and six cheetahs fed supplemented beef, and these were compared to the faecal concentrations of the respective marker proteins. Both the immunoassay for canine calprotectin and canine S100A12 were precise and reproducible for use with serum samples and faecal extracts. Whereas the assay for S100A12 was linear and accurate, an inconsistent linearity of the canine calprotectin assay was observed and could be indicative of an insufficient cross-reactivity of the specific antibody used for this assay. Serum concentrations of S100A12 and calprotectin were not altered by diet type, and were not correlated with the respective concentrations in faeces. Numerically (P=0.241) greater calprotectin concentrations and greater (P=0.041) faecal S100A12 concentrations were detected in cheetahs fed supplemented beef compared with whole rabbit. These findings demonstrate that whole prey feeding may decrease intestinal inflammation in the captive cheetah. Consequently, the relation between diet type and intestinal inflammatory conditions in the captive cheetah warrants further investigation.

Highly Expressed S100A12 in Aortic Wall of Patients with DeBakey Type I Aortic Dissection Could be a Promising Marker to Predict Perioperative Complications

Thoracic aortic dissection (TAD) is a catastrophic acute disease with a high postoperative mortality and few biochemical factors are known to predict outcomes. This study evaluated whether S100A12 could be a promising marker for TAD. A total of 72 patients with DeBakey Type I TAD and 18 heart donors as control group were studied. Immunohistochemistry of TAD tissue for S100A12 and hematoxylin-eosin staining, and alizarin red staining were examined. The expression of S100A12, proinflammatory protein specific for early recruited phagocytes, was studied by Western blotting of biopsies. In addition, S100A12 was further detected in serum samples from the same groups. S100A12 was markedly expressed in the tissue of patients with TAD in comparison with healthy control subjects (48; 66.7% vs. 0%). Serum concentrations of S100A12 in patients with TAD were significantly higher than in healthy controls (27.5 ± 2.2 vs. 16.0 ± 1.9 μg/L; P < 0.001). The upward trend of serum was consistent with that of tissue. The length of hospitalization differed significantly among S100A12 immunohistochemical groups (P < 0.001). Increased S100A12 serum levels correlated significantly with postoperative stay in hospital (r = 0.457; P < 0.001). Our findings suggest that an elevated S100A12 level could play a crucial role in systemic inflammation and may be a promising biomarker for predicting cardiovascular events and perioperative complications in patients with TAD.

S100A12 Gene Expression Is Increased in Peripheral Leukocytes in Chronic Kidney Disease Stage 4-5 Patients with Cardiovascular Disease

Background/Aims: S100A12 induces vascular inflammation contributing to the development of atherosclerosis. Serum S100A12 concentration is shown to be elevated in patients with chronic kidney disease (CKD), however the reason remains unclear. Methods: Transcriptional levels of S100A12 and RAGE (receptor for advanced glycation end products) were measured in peripheral leukocytes by quantitative real-time RT-PCR. Subjects were 40 patients with CKD stage 4-5, 20 of whom were affected with cardiovascular disease (CVD), and 20 healthy subjects. Serum concentrations of S100A12 and soluble RAGE were measured using enzyme-linked immunosorbent assay. Results: The serum concentration of S100A12 was significantly higher in CKD patients than in healthy subjects (78.5 ± 70.5 vs. 23.7 ± 19.2 ng/ml, p = 0.0035), but that of soluble RAGE was not. The relative quantity of S100A12 mRNA was significantly greater in leukocytes from CKD patients than in those from healthy subjects [mean (95% confidence interval of the mean): 3.1 (2.2-3.9) vs. 1.2 (0.8-1.7), p = 0.0001], however that of RAGE mRNA was not. The serum concentration of S100A12 was significantly correlated with the relative quantity of S100A12 mRNA among uremic CKD patients (r² = 0.656, p < 0.0001). Both the serum concentration and gene expression of S100A12 were significantly higher in patients who had CVD than in those who did not. Conclusion: Excessive expression of the S100A12 gene in uremic leukocytes is relevant to its increased serum concentration, particularly in those affected with CVD.

Serum S100A12 and Temporomandibular Joint Magnetic Resonance Imaging in Juvenile Idiopathic Arthritis Egyptian Patients: A case Control Study

This study aimed to measure serum levels of the proinflammatory protein S100A12, investigate clinical as well as contrast enhanced magnetic resonance imaging findings of temporomandibular joint inflammation among juvenile idiopathic arthritis patients and to find out the correlation between each of them, moreover with different disease parameters as temporomandibular joint inflammation may occur without clinical manifestations; it is in need for thorough evaluation and S100A12 may be a future anti-inflammatory treatment in JIA. Twenty patients with Juvenile Idiopathic Arthritis (JIA) and 10 healthy control subjects underwent measurement of S100A12 serum concentrations by sandwich ELISA. Temporomandibular Joints (TMJs); clinical and post contrast Magnetic Resonance Imaging (MRI) examinations were performed. MRI findings were scored. Results showed that TMJ arthritis was detected in 80% of JIA patients using MRI. Serum S100A12 levels were significantly increased in patients compared to controls. Serum concentrations of S100A12 and total MRI scores were significantly higher in JIA patients with active disease compared to those without activity. Systemic and polyarticular JIA patients showed significant increase in S100A12 levels and total MRI scores compared to those with oligoarticular JIA. The MRI TMJ abnormalities revealed significant association with clinical signs of TMJ inflammation but not with symptoms. A significant correlation was found between serum S100A12 concentrations and MRI score as well as between each of them and different clinical, laboratory disease parameters. Serum S100A12 levels showed significant positive correlation with synovial enhancement score. To conclude TMJ arthritis could be detected in most cases of JIA patients using contrast enhanced MRI. Increased S100A12 levels may point to synovial inflammation. Clinical signs of TMJ arthritis may be used as filter for MRI examination. Further studies on larger scale of JIA patients are needed for monitoring TMJ inflammation and S100A12 may be a potential target of future anti-inflammatory therapy.

Neutrophil-derived S100A12 as novel biomarker of inflammation in familial Mediterranean fever

ObjectiveFamilial Mediterranean fever (FMF) is characterised by recurrent periodic febrile attacks and persistent subclinical inflammation. The damage-associated molecular pattern (DAMP) protein S100A12 has proven to be a sensitive marker for...

Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis.

Vascular inflammation in giant cell arteritis is generally described as a process involving dendritic cells, T-lymphocytes, and effector tissue macrophages. Less is known about the contribution of phagocytes that are recruited early, such as monocytes and neutrophils. These cells express and secrete pro-inflammatory S100 proteins which directly activate endothelial cells. In this study the expression of S100A8/S100A9 and S100A12, pro-inflammatory proteins specific for early recruited phagocytes, was studied in biopsies from 36 patients with giant cell arteritis. In addition, serum concentrations of these proteins were analysed in serum samples from 42 patients and 35 healthy controls. The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries. Besides neutrophils, cells expressing these proteins belonged to a pro-inflammatory subtype of CD68-positive monocytes. In contrast, S100A12 expression was restricted to neutrophils that were found around the vasa vasorum within the adventitial layer. Both S100A8/S100A9 and S100A12 serum concentrations were significantly higher in patients with giant cell arteritis than in healthy controls. In conclusion, recently recruited phagocytes expressing pro-inflammatory S100 proteins take part in the vascular inflammation of giant cell arteritis. They may play important roles at the vasa vasorum of affected vessels, which represent sites of entry for recruited inflammatory cells. These data indicate that phagocytes within the adventitia and media contribute to the process of inflammation via release of the pro-inflammatory S100 proteins S100A8, S100A9, and S100A12.

Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations.

Phagocytes are extensively involved in the synovial inflammation associated with chronic arthritis. The aim of our study was to determine neutrophil activation in juvenile rheumatoid arthritis (JRA) by analyzing S100A12 (EN-RAGE; calgranulin C), a proinflammatory protein secreted by human neutrophils. S100A12 serum concentrations were determined in 124 patients with chronic active polyarticular-, oligoarticular-, or systemic-onset JRA. S100A12 was also analyzed in synovial fluid obtained from 22 patients. Changes in S100A12 levels in response to anti-tumor necrosis factor alpha (anti-TNF alpha) therapy, intraarticular injections of corticosteroids, and methotrexate (MTX) treatment were analyzed. Forty-five patients were followed up after successful antiinflammatory treatment, for a mean period of 2.8 years. The mean serum level of S100A12 was 395 ng/ml in patients with active polyarticular JRA and 325 ng/ml in patients with active oligoarticular JRA (normal <120 ng/ml). The level of S100A12 was approximately 10-fold higher in synovial fluid than in serum, indicating release at sites of local inflammation. In patients with systemic-onset JRA, the mean level of S100A12 was 3,700 ng/ml. Moreover, serum levels decreased in response to different antiinflammatory therapies (i.e., intraarticular injections of corticosteroids, MTX, or etanercept). S100A12 levels were elevated in 20 patients who experienced disease flares after the initial induction of remission, even weeks before the relapses became clinically apparent. S100A12 serum concentrations indicate neutrophil activation in JRA and correlate with disease activity. S100A12 may indicate synovial inflammation even when other signs of arthritis are absent. Its function as a proinflammatory factor secreted by activated neutrophils makes this protein a potential target for future therapies.

S100A12 (EN-RAGE) in monitoring Kawasaki disease

The calcium-binding protein S100A12 causes inflammation through interaction with the multiligand receptor for advanced glycation end products (RAGE). Blocking of S100A12 showed promising therapeutic effects in mice. We investigated 31 individuals with Kawasaki disease, and recorded an association between expression of S100A12 and activity of Kawasaki disease. Serum concentrations of S100A12 decreased quickly in 28 patients who responded to treatment with gammaglobulin (from 463 microg/L [SD 316] to 184 microg/L [147] within 24 h, p<0.0001). Since the interaction of S100A12 with multiligand receptors has a key role in inflammatory responses, this protein could serve as a novel target for future therapeutic interventions in inflammatory disorders.