BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS.
METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons (\"q\"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms.
RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one (\"candidate\") and IgG index, OCB, and leukocytes in another (\"routine\"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms.
CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

Periodontitis (PD) is characterized by bacterial infection and inflammation of tooth-supporting structures and can lead to tooth loss. PD affects ∼47% of the US population over age 30 years and has a heritability of about 50%. Although the host immunoinflammatory response and genetic background play a role, little is known of the underlying genetic factors. We examined natural genetic variation in lipopolysaccharide (LPS)-induced PD across a panel of inbred mouse strains, the hybrid mouse diversity panel (HMDP). We observed a strain-dependent sixfold difference in LPS-induced bone loss across the HMDP with a heritability of 53%. We performed a genomewide association study (GWAS) using FAST-LMM, which corrects for population structure, and identified loci significantly associated with PD. We examined candidate genes at a locus on chromosome 5, which suggested a relationship between LPS-induced bone loss and, together with expression data, identified Cxcl family members as associated with PD. We observed an increase in Cxcl10 protein, as well as immune cells and pro-inflammatory cytokines in C57BL/6J (high bone loss strain) but not in A/J (low bone loss strain) after LPS injections. Genetic deletion of CXCR3 (Cxcl9 and10 receptor) demonstrated a ∼50% reduction in bone loss and reduced osteoclasts after LPS injections. Furthermore, WT mice treated with AMG-487 (a CXCR3 antagonist) showed a ∼45% reduction in bone loss and decreased osteoclasts after LPS injections. We conclude that CXCR3 is a strong candidate for modulating the host response in individuals susceptible to PD. © 2018 American Society for Bone and Mineral Research.

OBJECTIVE: To explore the diagnostic value of serum C-X-C chemokine ligand 16 (CXCL16) in subjects with diabetic coronary artery disease (T2DM-CAD).
METHODS: One hundred twenty Chinese subjects, including patients with coronary artery disease (CAD group), diabetic coronary artery disease (T2DM-CAD group), type 2 diabetes mellitus (T2DM group), and healthy controls of similar age and gender (control group), were enrolled in this study. Serum CXCL16 was detected by a sandwich-type enzyme linked immunosorbent assay (ELISA). Simultaneously, other clinical biochemical parameters such as high-sensitivity C-reactive protein (hs-CRP), uric acid (UA), and glucose (Glu) were tested based on standard methods.
RESULTS: Compared to the levels in the CAD group (3.912±1.061 mg/L) and the T2DM group (4.115±0.876 mg/L), the levels of serum CXCL16 in the T2DM-CAD group were significantly increased (5.707±1.404 mg/L, P<0.01). In the T2DM-CAD group, serum CXCL16 concentrations correlated positively with hs-CRP (r=0.772, P<0.001) and uric acid levels (r=0.476, P<0.01). Multiple linear regression analysis indicated that hs-CRP might be the only influencing factor for serum CXCL16 levels (β=0.772, P<0.001). Furthermore, in the T2DM-CAD group/T2DM group, the area under the curve of CXCL16 was 0.824, and the area under the curve of hs-CRP was 0.842; no significant difference was found (z=0.245, P>0.05).
CONCLUSIONS: Serum CXCL16 may be a novel biomarker for the diagnosis of patients with T2DM-CAD.

Chemokine modulation in response to pathogens still needs to be fully characterised in fish, in view of the recently described novel chemokines present. This paper reports the first comparative study of CXC chemokine genes transcription in salmonids (brown trout), with a particular focus on the fish specific CXC chemokines (CXCL_F). Adopting new primer sets, optimised to specifically target mRNA, a RT-qPCR gene screening was carried out. Constitutive gene expression was assessed first in six tissues from SPF brown trout. Transcription modulation was next investigated in kidney and spleen during septicaemic infection induced by a RNA virus (Viral Haemorrhagic Septicaemia virus, genotype Ia) or by a Gram negative bacterium (Yersinia ruckeri, ser. O1/biot. 2). From each target organ specific pathogen burden, measured detecting VHSV-glycoprotein or Y. ruckeri 16S rRNA, and IFN-γ gene expression were analysed for their correlation to chemokine transcription. Both pathogens modulated CXC chemokine gene transcript levels, with marked up-regulation seen in some cases, and with both temporal and tissue specific effects apparent. For example, Y. ruckeri strongly induced chemokine transcription in spleen within 24h, whilst VHS generally induced the largest increases at 3d.p.i. in both tissues. This study gives clues to the role of the novel CXC chemokines, in comparison to the other known CXC chemokines in salmonids.

OBJECTIVE: CXCL16 is an interferon-γ-regulated chemokine and scavenger receptor for oxidized low-density lipoprotein that is expressed in atherosclerotic lesions. High soluble CXCL16 levels during acute cardiovascular events may indicate impaired long-term prognosis, but it is not known if CXCL16 is associated with the risk of developing cardiovascular disease in healthy individuals. We aimed to assess whether soluble CXCL16 is associated with risk of myocardial infarction (MI) in a nested case-control study within a large population-based cohort.
METHODS: We conducted a case-control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women free of known cardiovascular disease were followed for a first myocardial infarction (MI), and during 11.3 years of follow-up, 1587 incident MIs were registered. These cases were compared to 3959 age- and sex-matched controls.
RESULTS: Among MI cases, the median CXCL16 concentration was 9.9 ng/ml (interquartile range 7.2-12.6) compared to 9.6 ng/ml (interquartile range 6.9-12.3) among controls (p < 0.001). Although the difference in median value between cases and controls was small, MI risk was twice as high (OR, 2.08; 95% CI: 1.74-2.50) among participants in the highest quartile compared to participants in the lowest quartile of CXCL16 after adjustment for age and sex. Additional adjustment for serum lipids, body mass index, smoking habits, diabetes mellitus, serum creatinine, and high-sensitivity C-reactive protein attenuated the excess risk by about half, yielding an odds ratio of 1.46 (95% CI: 1.19-1.79).
CONCLUSIONS: Soluble CXCL16 may provide novel information in clinical cardiovascular risk assessment, but its importance needs to be verified in other prospective population studies.

OBJECTIVE: Traffic-related particulate matter (PM) is one of the major sources of air pollution in metropolitan areas. This study is to observe the interactive effects of gene and fine particles (particles smaller than 2.5 μm - PM2.5) on the respiratory system and explore the mechanisms linking PM2.5 and pulmonary injury.
METHODS: The participants include 110 traffic policemen and 101 common populations in Shanghai, China. Continuous 24 h individual-level PM2.5 is detected and the pulmonary function, high-sensitivity C-reactive protein (hs-CRP), Clara cell protein 16 (CC16) and the polymorphism in CXCL3, NME7 and C5 genes are determined. The multiple linear regression method is used to analyze the association between PM2.5 and health effects. Meanwhile, the interactive effects of gene and PM2.5 on lung function are analyzed.
RESULTS: The individual PM2.5 exposure for traffic policemen was higher than that in the common population whereas the forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FEV1/FVC) and lymphocytes are lower. In contrast, the hs-CRP level is higher. In the adjusted analysis, PM2.5 exposure was associated with the decrease in lymphocytes and the increase in hs-CRP. The allele frequencies for NME7 and C5 have significant differences between FEV1/FVC ≤ 70% and FEV1/FVC > 70% participants. The results didn\'t find the interaction effects of gene and PM2.5 on FEV1/FVC in all the 3 genes.
CONCLUSIONS: The results indicated that traffic exposure to high levels of PM2.5 was associated with systemic inflammatory response and respiratory injury. Traffic policemen represent a high risk group suffering from the respiratory injury.

BACKGROUND: Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study.
METHODS: Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa.
RESULTS: Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC.
CONCLUSIONS: In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression.
BACKGROUND: ANZCTR.org.au ACTRN12610000509066.

There is no reliable way to identify the high-risk patients with intermediate coronary artery lesions (diameter stenosis 20%-70%) in early stage. Soluble CXC chemokine ligand 16 (CXCL16) is a newly discovered chemokine that can mediate inflammatory responses. It is released by proteolytic cleavage of its membrane-bound form, named scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) that can promote the uptake of oxidized low-density lipoprotein cholesterol by macrophages. We have hypothesized that CXCL16 is an indicator of the prognosis of intermediate coronary artery lesions, and thus assessed the association between plasma CXCL16 concentrations and the 2-year prognosis in 616 patients with intermediate coronary artery lesions. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, revascularization and angina pectoris requiring re-hospitalization. During the median follow-up time of 24 months, 69 events occurred. The plasma concentrations of CXCL16 (median 7712.88 pg/ml vs. 6792.43 pg/ml, P = 0.014) and high-sensitivity C-reactive protein (hs-CRP) (median 2.82 mg/L vs. 1.68 mg/L, P < 0.001) were higher in patients with events than patients without events. Cox hazard proportion analysis showed patients in upper CXCL16 quartile were more likely to suffer from adverse outcome than patients in lower quartile (RR = 1.271, P = 0.029, 95% CI: 1.025-1.577) after adjusting for sex, age, smoking, hypertension, diabetes, fat, dyslipidemia, hs-CRP, and medication use. In conclusion, plasma level of CXCL16 is an independent predictor of the prognosis of the patients with intermediate coronary lesions. Elevated plasma CXCL16 is associated with higher risk for these patients.

BACKGROUND: Endotoxins are ubiquitously present in the environment and constitute a significant component of ambient air. These substances have been shown to modulate the allergic response, however a consensus has yet to be reached whether they attenuate or exacerbate asthmatic responses. The current investigation examined whether reducing the concentration of lipopolysaccharide (LPS) in a house dust extract (HDE) containing high concentrations of both cockroach allergens 1 and LPS would attenuate asthma-like pulmonary inflammation.
METHODS: Mice were sensitized with CRA and challenged with the intact HDE, containing 182 ng of LPS, or an LPS-reduced HDE containing 3 ng LPS, but an equivalent amount of CRA. Multiple parameters of asthma-like pulmonary inflammation were measured.
RESULTS: Compared to HDE challenged mice, the LPS-reduced HDE challenged mice had significantly reduced TNFα levels in the bronchoalveolar lavage fluid. Plasma levels of IgE and IgG1 were significantly reduced, however no change in CRA-specific IgE was detected. In HDE mice, plasma IgG2a levels were similar to naïve mice, while LPS-reduced HDE mice had significantly greater concentrations. Reduced levels of LPS in the HDE did not decrease eosinophil or neutrophil recruitment into the alveolar space. Equivalent inflammatory cell recruitment occurred despite having generally higher pulmonary concentrations of eotaxins and CXC chemokines in the LPS-reduced HDE group. LPS-reduced HDE challenge induced significantly higher concentrations of IFNγ, and IL-5 and IL-13 in the BAL fluid, but did not decrease airways hyperresponsiveness or airway resistance to methacholine challenge.
CONCLUSIONS: These data show that reduction of LPS levels in the HDE does not significantly protect against the severity of asthma-like pulmonary inflammation.

BACKGROUND: We have previously shown a different local and systemic angiogenic profile of CXC chemokines in Idiopathic Pulmonary Fibrosis (IPF) patients compared to sarcoidosis. In particular, sarcoidosis showed an angiostatic microenvironment, as compared with the angiogenic cytokine milieu seen in IPF. Purpose of the Study. Our aim was to further investigate the aforementioned finding by measuring the expression of different chemokines in granulomatous and fibrotic diseases. We estimated the levels of vascular endothelial growth factor (VEGF) and its high-affinity receptor, Flt-1 (fms-like tyrosine kinase 1), in bronchoalveolar lavage fluid (BALF) of patients with IPF and pulmonary sarcoidosis. We have also investigated the mRNA expression of angiogenetic chemokines\' receptors such as CXCR2 and CXCR3 and the biological axis of stromal derived factor-1 alpha (SDF-1 alpha or CXCL12 alpha/CXCL12 beta) and receptor, CXCR4.
METHODS: We studied prospectively three groups of patients: (i) one group of 18 patients with IPF, (ii) one group of 16 patients with sarcoidosis, and (iii) 10 normal subjects.
RESULTS: A statistically significant increase has been detected in VEGF mRNA expression in IPF in comparison with pulmonary sarcoidosis (P = .03). In addition, a significant increase has been measured in CXCL12 alpha in sarcoidosis in comparison to IPF (P = .02). Moreover, a statistically significant decrease has been found in Flt-1 protein levels in pulmonary sarcoidosis in comparison with IPF (P = .03). A significant increase in VEGF (P = .03) and CXCR4 (P = .03) mRNA levels has been also detected in sarcoidosis\' patients when compared with healthy controls.
CONCLUSIONS: Our data suggest that increased expression of Flt-1 and downregulation of CXCL12 alpha in IPF may further support the hypothesis of a different angiogenetic profile between fibrotic and granulomatous diseases. However, further studies are needed in order to better investigate these enigmatic diseases.