Serum CXCL10 Research Articles

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan.

339: Maternal and fetal umbilical cord levels of chemokines in normal and PreE pregnancies - A prospective trial

Preeclampsia (PreE) is the de novo development of hypertension and proteinuria after 20 weeks of gestation affecting 3-8% of pregnancies, and has a link to alterations of feto-placental stress that pass to the offspring causing detrimental effects. We aimed at comparing the clinical outcomes and chemokines from the maternal and cord blood between patients with and without PreE. We recruited 20 normal pregnant (NP) and PreE patients in an IRB approved prospective cohort at our institution. We evaluated maternal age, body mass index (BMI), blood pressure (BP), and gestational age (GA) at delivery along with measured serum levels of six chemokines in maternal-fetal paired samples using ELISA test. The markers are; Human CCL4/MIP-1beta, Human CXCL10/IP-10, Eotaxin/CCL11, RANTES (CCL5), Human MCP1, Human M-CSF. Maternal: The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in PreE (SBP 162 ± 17; DBP 97 ± 12) compared to NP (SBP 121 ± 3; DBP 75 ± 9; p <0.05). GA at delivery in weeks was lower in PreE (35.1 ± 3.8) compared to NP (39.2 ± 0.3; p <0.05), as well as birth weight in PrE (2556 ± 977) compared to NP (3385 ± 328; p <0.011) indicating a link to intrauterine growth restriction (IUGR). We did not find a difference in maternal BMI between the two groups. Biomarkers: For all six chemokines CCL4, CXCL10, CCL11, CCL5, MCP1, and M-CSF, maternal and fetal cord serum chemokines levels differ between subjects with and without PreE (p < 0.001). There is also a difference between the maternal and fetal levels for the six chemokines (<0.01). The fetal levels were compared to associated maternal levels for each of the six chemokines using t test and Mann-Whitney U test. Women with PreE had higher BP, preterm deliveries, and fetal IUGR. However, in this cohort the women were of similar age, size, and parity prior to the onset of pregnancy. The six chemokines in the samples from maternal and fetal circulation are greater in the PreE group, and each of the six chemokines samples from the fetuses had values greater than maternal samples which could implicate placental cells as the source. PreE alters the intrauterine environment and activates the detrimental signaling that is transferred to the fetus resulting in the aforementioned complications.

Time-Dependent Changes in Local and Serum Levels of Inflammatory Cytokines as Markers for Incised Wound Aging of Skeletal Muscles.

Wound age estimation is an important research field in forensic pathology. The expression levels of cytokines in the incised skeletal muscle were analyzed using a mouse model to explore the applicability for wound aging. A 5-mm long incisional wound was made at the biceps femoris muscle, and the muscle and serum were sampled at 6, 12, 24 and 48 hours after injury. Using a multiplex bead-based immunoassay, we measured the tissue levels of nine cytokines (IL-1β, IL-6, IL-7, CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10), which are all involved in the pathways of inflammatory response and tissue injury. Immunoassay of post-injury muscle samples revealed significant increases in the levels of six cytokines, except for CCL3, CCL4 and IL-7, at 6 hours after injury. The elevated tissue levels of these six cytokines were maintained during 48 hours after injury, although the levels of IL-6 and CXCL1 were significantly decreased at 12 hours. In case of CCL3, its tissue levels were increased only at 12 hours. By contrast, CCL4 and IL-7 levels were increased only at 48 hours. Moreover, serum levels of most cytokines, except for CXCL1, remained unchanged during 24 hours after injury, followed by significant increases at 48 hours. Serum CXCL1 levels were increased at 6 hours and then decreased to the basal levels. Thus, the significant increase in the muscle levels of CXCL1 and IL-7 was observed at 6 and 48 hours after injury, respectively. Measuring muscle CXCL1 and IL-7 levels is helpful for estimating incised wound aging.

CXCR3 blockade combined with cyclosporine A alleviates acute graft-versus-host disease by inhibiting alloreactive donor T cell responses in a murine model

Chemotaxis of T cells to acute graft-versus-host disease (aGvHD) target tissues directed by chemokines and their receptors plays a key role in the pathogenesis of aGvHD. Blockade of lymphocyte migration by targeting chemokine receptors may be a viable strategy for the prevention and treatment of aGvHD, which is quite distinguishable from typical efforts to use immunosuppressive medications that have been associated with some side effects. CXCR3 and its ligands have been reported to be correlated with aGvHD pathogenesis. Using the small-molecule CXCR3 antagonist AMG487, we demonstrated that AMG487 combined with cyclosporine A (CsA) effectively alleviated aGvHD with a prolonged mean survival time and significantly inhibited the infiltration of inflammatory cells in aGvHD target tissues in a murine aGvHD model. In addition, AMG487 combined with CsA inhibited the activation, proliferation and differentiation of donor-derived T cells in the spleens. Further results showed that the concentrations of Th1 cells associated with pro-inflammatory cytokines such as IFN-γ and TNFα in serum were decreased. In addition, AMG487 treatment did not alter CXCR3 and CCR5 expression in donor-derived T cells but elevated the serum CXCL9 and CXCL10 levels. This novel and effective approach has the potential to develop a new clinical method to prevent and treat aGvHD.

Immune senescence and biomarkers profile of Bambuí aged population-based cohort

During immunosenescence many proinflammatory markers such as cytokines and chemokines are increased. This process called by Franceschi and colleagues as inflammaging is associated with chronic inflammation and the ethiology and pathophysiolgy of many ageing diseases as Alzheimer's and atherosclerosis. The knowledge of immune profile during ageing may provide some interventions that would improve the immune function in elderly and quality of life for old people. However, the identification of a group of potential biomarkers to monitor the ageing process is very difficult. In addition, most of the evidence evaluating immune biomarkers profile is based on data from older Caucasian adults. To our knowledge, no previous Latin American old population-based cohort has evaluated immunological parameters along the ageing process. The present work evaluated CXCL8, CXCL9, CXCL10, CCL2, CCL5, IL-1, IL-6, IL-12, TNF and IL-10 serum levels in 1494 older adults aged 60 to 95 from a population based ageing cohort in Brazil. Our data suggest that there is an increased positive predicted probability of participants to be a high producer of IL-6, CXCL8 and CXCL9. Moreover, results did not differ between men and women, except for CXCL10 that increased only in men. Results were not different in the adjusted model by many potential confounders, including African genomic ancestry. Together, these findings add novel insights about the immunologic aspects of ageing supported by a large population-based cohort study that provides evidences that corroborate with the inflammaging proposal and subsidize the establishment of biomarkers for monitoring the health status of aged population.

CXCL‐10 and Interleukin‐6 are reliable serum markers for vitiligo activity: A multicenter cross‐sectional study

This cross-sectional multicenter study aimed to evaluate serum CXCL-10, as an activity marker for vitiligo, and compare it with other putative serum and tissue markers. Serum CXCL-10 was compared to interferon gamma (IFN-γ), interleukin 6 (IL-6), and IL-17 using ELISA in 55 non-segmental vitiligo patients (30 active and 25 stable) and 30 healthy controls. Marginal skin biopsy was taken for immunohistochemical evaluation of CD8+T cells and CXCL-10+ve cells. Serum levels of CXCL-10, IL-17, and IL-6 were elevated in all vitiligo patients compared to controls (p<.05). All investigated serum markers were higher in active versus stable vitiligo. Tissue expression of CXCL-10+ve cells and CD8+ve T cells was stronger in vitiligo patients compared to controls, and tissue CXCL-10+ve cell expression was stronger in active versus stable cases. Positive correlations were noted between the different serum and tissue markers. CXCL-10 was the most specific, whereas IL-6 was the most sensitive serum marker to distinguish active from stable disease.

The correlational research among serum CXCL13 levels, circulating plasmablasts and memory B cells in patients with systemic lupus erythematosus: A STROBE-compliant article.

We investigated whether serum CXC ligand 13 protein (CXCL13) levels correlate with the circulating plasmablasts and memory B-cells alteration in systemic lupus erythematosus (SLE) patients. The diagnostic use of CXCL13 concentrations in active lupus was also analyzed.A total of 36 SLE patients and 18 healthy controls were included. Serum CXCL13 levels were examined by enzyme-linked immunosorbent assay. The frequency and absolute count of circulating plasmablasts and memory B cells were analyzed by flow cytometry. Receiver operating characteristic curves (ROC curves) were generated to analyze the utility of serum CXCL13 level and plasmablasts frequency as tools for the recognition of active SLE.Elevation of serum CXCL13 levels, higher plasmablasts frequency, and reduction of memory B-cells count were observed in SLE patients, compared with healthy controls. Interestingly, correlational analyses showed not only significantly positive association between CXCL13 levels and SLE Disease Activity Index (SLEDAI) or plasmablasts frequency, but an inverse correlation between CXCL13 concentration and memory B-cell count. ROC curves showed that serum CXCL13 level and plasmablasts frequency were practical in identifying active disease from overall SLE patients, with considerable accuracy.Serum CXCL13 levels correlate with the alteration of plasmablasts and memory B cells in SLE. CXCL13 may be used as a practical tool in judgment of active SLE.

Up-regulation of chemokine CXCL13 in systemic candidiasis

Candida albicans is the leading cause of healthcare associated bloodstream infections. Chemokine CXCL13 is well-known involved in inflammation, but its role in candidemia has not been assessed. Our study firstly demonstrated that serum CXCL13 levels were significantly elevated in candidemic patients compared with bacteremic patients and control subjects by ELISA, and CXCL13 concentrations were positively and significantly correlated with clinical Sequential Organ Failure Assessment (SOFA) scores and several laboratory parameters in patients. Moreover, ROC curve analysis showed the diagnostic efficiency of CXCL13 was superior to CRP and PCT. To further study the role of CXCL13, a mouse model was established. Importantly, the data showed the dramatically elevated levels of CXCL13 in mice serum and infected kidney, were significantly correlated with renal fungal burden and pathology scores. In conclusion, our results indicated that CXCL13 had strong potential as a novel biomarker of diagnosis and prognosis for candidemia.

Increased serum production of soluble CD163 and CXCL5 in patients with moyamoya disease: Involvement of intrinsic immune reaction in its pathogenesis

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is still unknown, intrinsic immune reactions such as autoimmune response has been implicated in the pathogenesis of MMD. Recently, the RING finger protein 213 (RNF213) was found to be an important risk gene for MMD, and is predominantly expressed in blood cells and the spleen. Thus, we hypothesized that patients with MMD represent an intrinsic autoimmune status mediated by M2-polarized macrophages, which play an important role in tissue remodeling and angiogenesis. We compared the serum level of soluble (s)CD163, an activating marker for CD163+ M2-polarized macrophages that has been implicated in a variety of autoimmune disorders, between MMD patients and healthy controls. We also analyzed serum levels of CXCL5, an augmented cytokines that has been correlated with the severity of autoimmune diseases. As a result, the serum sCD163 levels of MMD patients (281,465 pg/ml) were significantly higher than those of healthy controls (174,842 pg/ml) (p = .004). The serum CXCL5 levels of MMD patients (679.02 pg/ml) were significantly higher than those of healthy controls (401.79 pg/ml) (p = .046). There were no differences in the serum sCD163 and CXCL5 levels between each genotype of the RNF213 polymorphism (wild-type or variant) among MMD patients. Although this is a pilot study and further validation with larger number of samples is necessary, our results indicate that patients with MMD may have increased autoimmune activity, and our results shed light on the pathogenesis of MMD via CD163+ M2-polarized macrophages.

CXCL10/CXCR3 axis is associated with disease activity and the development of mucocutaneous lesions in patients with Beh\xe7et\u2019s disease

The objective of this study was to investigate CXC chemokines and its receptor in patients with Behcet’s disease (BD) and their associations with disease activity. Blood samples were collected from 109 BD patients and 36 age- and sex-matched healthy controls (HCs). Twenty-two follow-up blood samples were collected in BD patients. Serum CXC chemokines (CXCL1, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13 and CXCL16) and cell surface marker expression (CD3, CD4 and CXCR3) in peripheral blood mononuclear cells (PBMCs) were assayed. Clinical features including disease activity were evaluated at the time of blood collection. CXCR3 expression in skin and intestinal lesions from BD patients and HCs was assessed via immunohistochemistry. Serum CXCL10 levels were correlated with disease activity in terms of Behçet’s Disease Current Activity Form (BDCAF) (p < 0.001). In follow-up BD patients, changes in serum CXCL10 levels tended to be correlated with those of BDCAF. The percentage of CXCR3 expression in CD3-positive cells in PBMCs was inversely correlated with serum CXCL10 levels in BD patients (p = 0.022). By immunohistochemistry, the number of CXCR3-positive mononuclear cells was higher in skin and intestinal lesions of BD patients than in those of HCs. These results suggest that the CXCL10/CXCR3 axis may contribute to the pathogenesis of BD.

Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis.

Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status. Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria. In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05). The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.

Inhibition of MEK-ERK1/2-MAP kinase signalling pathway reduces rabies virus induced pathologies in mouse model

The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis of many viral infections, but its role during rabies virus (RV) infection in vivo is not clear. In the present study, we investigated the potential role of MEK-ERK1/2 signalling pathway in the pathogenesis of rabies in mouse model and its regulatory effects on pro-inflammatory cytokines and other mediators of immunity, and kinetics of immune cells. Mice were infected with 25 LD50 of challenge virus standard (CVS) strain of RV by intracerebral (i.c.) inoculation and were treated i.c. with U0126 (specific inhibitor of MEK1/2) at 10 μM/mouse at 0, 2, 4 and 6 days post-infection. Treatment with U0126 resulted in delayed disease development and clinical signs, increased survival time with lesser mortality than untreated mice. The better survival of inhibitor-treated and RV infected mice was positively correlated with reduced viral load and reduced viral spread in the brain as quantified by real-time PCR, direct fluorescent antibody test and immunohistochemistry. CVS-infected/mock-treated mice developed severe histopathological lesions with increased Fluoro-Jade B positive degenerating neurons in brain, which were associated with higher levels of serum nitric oxide, iNOS, TNF-α, and CXCL10 mRNA. Also CVS-infected/U0126-treated mice revealed significant decrease in caspase 3 but increase in Bcl-2 mRNA levels and less TUNEL positive apoptotic cells. CVS-infected/U0126-treated group also showed significant increase in CD4+, CD8+ T lymphocytes and NK cells in blood and spleen possibly due to less apoptosis of these cells. In conclusion, these data suggest that MEK-ERK1/2 signalling pathway play critical role in the pathogenesis of RV infection in vivo and opens up new avenues of therapeutics.

131 Neonatal Treatment with Endogenous Repair Agents Reverses Abnormal Thermal Sensation in a Preclinical Model of Cerebral Palsy

Abstract INTRODUCTION Patients with cerebral palsy are prone to chronic pain. Discovery of effective interventions for this population necessitates understanding mechanisms of pain, and their potential reversibility. Pain circuits undergo perinatal maturation, and are thus vulnerable to early CNS insults. We hypothesized that neonatal treatment could mitigate abnormal pain circuit maturation. METHODS Using an established preclinical model of cerebral palsy, chorioamnionitis was induced on embryonic day 18. Rat pups were born at term (E22, ∼30 weeks human gestation). On postnatal day 1 (P1) rats were randomized to treatment (erythropoietin 2000 U/kg/dayx5d plus melatonin 20 mg/kg/dayx5d) or vehicle. Adult rats of both sexes were tested for mechanical and thermal sensation. Lumbar spinal cord assays were performed with immunoblotting, and serum with multiplex electrochemiluminscence. Groups were compared with two-way ANOVA and post-hoc correction, with P &lt; 0.05 significant. RESULTS &gt;Rats exposed to prenatal injury (injury-vehicle) showed hindpaw allodynia with mechanical non-nociceptive testing using von Frey at P30 compared to shams (P &lt; 0.01), that was less pronounced at P60 (P = 0.07), perhaps due to delayed A-fiber maturation after injury. Treatment did not alter responses. By contrast, injury-vehicle rats exhibited c-fiber hypersensitivity to thermal tail immersion with maturation, compared to shams (P &lt; 0.01). The thermal deficit was fully repaired by neonatal treatment (injury-vehicle versus injury-treatment, P &lt; 0.01). CXCL1 is implicated in calpain-mediated degradation of KCC2 in neuropathic pain. Injury-vehicle rats had elevated serum CXCL1 and lumbar cord KCC2 degradation products compared to shams (both P &lt; 0.01). Neonatal treatment normalized serum CXCL1 on P7 (P &lt; 0.01). CONCLUSION Using a prenatal CNS injury that mimics gait abnormalities of cerebral palsy, our initial results show for the first time that prenatal injury also produces complex abnormalities in maturation of lumbar spinal cord sensation. Moreover, hypersensitivity to thermal stimuli appears to be normalized after neonatal treatment with endogenous neuroreparative agents that are currently in clinical trials for preterm infants.

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

BackgroundHuman African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease.Methodology/Principal findingsThe expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness.Conclusions/SignificanceThe results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.

Interferon-alpha treatment rapidly clears Hepatitis E virus infection in humanized mice

Antiviral treatment options for chronic Hepatitis E Virus (HEV) infections are limited and immunological determinants of viral persistence remain largely unexplored. We studied the antiviral potency of pegylated interferon-α (pegIFNα) against HEV infections in humanized mice and modelled intrahepatic interferon stimulated gene (ISG) responses. Human gene expression levels in humanized mouse livers were analyzed by qPCR and Nanostring. Human CXCL10 was measured in mouse serum. HEV genotype 3 (gt3) infections were cleared from liver and feces within 8 pegIFNα doses in all mice and relapsed after a single pegIFNα injection in only half of treated animals. Rapid viral clearance by pegIFNα was confirmed in HEV gt1, but not in Hepatitis B Virus infected animals. No ISG induction was observed in untreated HEV gt3 and gt1 infected humanized livers compared to control chimeric mice, irrespective of the human hepatocyte donor, viral isolate or HEV infection duration. Human specific ISG transcript levels in mouse liver increased significantly after pegIFNα treatment and induced high circulating human CXCL10 in mouse serum. In conclusion, HEV gt1 and gt3 infections do not elicit innate intrahepatic immune responses and remain highly sensitive to pegIFNα in immunocompromised humanized mice.

Immune dysregulation in patients with carpal tunnel syndrome

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

Rapid changes in peripheral lymphocyte concentrations during interferon-free treatment of chronic hepatitis C virus infection.

Treatment of chronic hepatitis C virus (HCV) infection with direct‐acting antivirals results in a rapid decline in viral load and markers of hepatic inflammation, including serum chemokine (C‐X‐C motif) ligand 10 (CXCL10) concentration, which is followed in most cases by a sustained virologic response. Whether parallel changes of significance occur in the cellular composition of peripheral blood is relatively unknown. We hypothesized that longitudinal characterization of peripheral blood during treatment would provide insight into cellular migration and immune activation, which would have implications for understanding host immunity both before and after HCV treatment and may relate to HCV clearance. We analyzed longitudinal peripheral innate and adaptive immune cell populations by flow cytometry from 95 subjects enrolled in two direct‐acting antiviral clinical trials and examined chemokine receptor expression on T lymphocytes in 43 patients. Within 1‐2 weeks of initiating treatment, significant increases were observed in the concentration of peripheral cluster of differentiation 4–positive (CD4+) and CD8+ T lymphocytes but not monocyte or natural killer cells. In tandem with these changes, the percent of both CD4+ and CD8+ T lymphocytes with an activated phenotype (human leukocyte antigen [HLA] DR+ and CD38+) decreased, and T‐lymphocyte surface expression of chemokine (C‐X‐C motif) receptor 3, the chemokine receptor for CXCL10, increased. Conclusion: Rapid changes in peripheral cellular populations occur during direct‐acting antiviral treatment of HCV infection, which could potentially relate to hepatic efflux of tissue lymphocytes due to altered inflammation and chemokine receptor signaling, providing critical insight into the relationship between host immunity and viral clearance during HCV infection. (Hepatology Communications 2017;1:586–594)

RNA-seq Reveals Transcriptomic Differences in Inflamed and Noninflamed Intestinal Mucosa of Crohn's Disease Patients Compared with Normal Mucosa of Healthy Controls.

Aberrant gene expression in the gut mucosa might contribute to the initiation and progression of Crohn's disease (CD). RNA sequencing (RNA-seq) provides precise measurements of expression levels of transcripts and their isoforms. The aim of this study was to use RNA-seq to investigate transcriptomic differences and identify significantly differentially expressed transcripts in inflamed and noninflamed intestinal mucosa of CD patients. RNA-seq was performed on 13 pairs of inflamed and noninflamed intestinal mucosa from 13 CD patients and on sex-matched normal mucosa of 13 healthy controls. Significantly differentially expressed transcripts were validated by immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and enzyme-linked immunosorbent assay. RNA-seq revealed genome-wide transcriptomic differences between normal mucosa, noninflamed, and inflamed CD mucosa. Among 950 differentially expressed genes, 19 were up- or downregulated (upregulation: ANGPT2, CHN1, CPXM1, CPZ, CXCL1, FCN3, GJC1, HSD11B1, LZTS1, MEOX1, MMP12, PLA1A, SERPINE1, SGIP1, and TRPC4; downregulation: FAM189A1, PDE6A, SLC38A4, and HMGCS2) with statistical significance (p < 0.01 and q < 0.05). Among them, CXCL1 exhibited the highest fold change between groups. Immunohistochemistry for CXCL1 revealed no expression in normal mucosa, slightly increased expression in noninflamed CD mucosa, and highly increased expression in inflamed CD mucosa. Quantitative reverse transcriptase polymerase chain reaction showed that CXCL1 expression was significantly associated with epithelial damage, increased infiltration of polymorphonuclear leukocytes, and submucosal fibrosis. Serum CXCL1 concentration measured by enzyme-linked immunosorbent assay was better correlated with CD activity index (r = 0.660) than with C-reactive protein (r = 0.204). RNA-seq revealed transcriptomic differences between normal mucosa, noninflamed CD mucosa, and inflamed CD mucosa. Intestinal and serum CXCL1 was substantially increased with CD activity and can be used as a potential biomarker of CD.

CXCL10 and CXCL13 chemokines in patients with relapsing remitting and primary progressive multiple sclerosis

ObjectivesMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system characterized by a variable clinical course. Different pathogenic mechanisms responsible for relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS) are modulated by immunological process with important role of chemokine network. CXCL10 and CXCL13 chemokines act as chemoattractants and modulators of proinflammatory reactions promoting process of demyelination. In the present study, we investigated the concentrations of CXCL10 and CXCL13 in serum and cerebrospinal fluid (CSF) of patients with RRMS and PPMS. Materials and methodsThe study groups comprised 25 RRMS patients (39,5±12years), 24 PPMS patients (49,9±10,5years), 31 healthy individuals (36±10,4years) with tension headache without symptoms of inflammatory diseases. A quantitive test kit based on ELISA has been used for chemokines measurement. Correlations analysis between the levels of CXCL10, CXCL13 and patient age, duration of MS, EDSS and IgG index were done. ResultsThe mean concentration of CXCL10 in the CSF was statistically significantly higher in RRMS in comparison with the control group. The mean concentration of CXCL13 in the CSF was significantly higher in RRMS and PPMS than in the control group. The results have shown that in the stable phase of MS without relapse, mean concentration of CXCL10 and CXCL13 in CSF did not differ significantly between RRMS and PPMS. In PPMS a positive correlation between IgG index and CSF CXCL10 level or CSF CXCL13 level was observed. In RRMS a positive correlation between IgG index and CSF CXCL13 level was observed. ConclusionsThese data indicate involvement of CXCL10 and CXCL13 chemokines in immunopathogenetic mechanisms in MS. There was no significant difference between mean CXCL10 or CXCL13 concentrations in the CSF in both RRMS and PPMS patients. No significant correlations were found between patient age and chemokines levels in theCSF in all groups. It suggest that these chemokines play similar role in inflammatory process despite more pronounced neurodegenerative process in PPMS.

Psoriasis, Psoriatic Arthritis, and Thyroid Autoimmunity.

Psoriasis (PsO) is a chronic relapsing/remitting autoimmune skin disease, associated with an increased risk of other autoimmune disorders. Psoriatic arthritis (PsA) is a chronic inflammatory arthritis occurring approximately in 30% of PsO patients. Sporadic cases of association between PsO and autoimmune thyroid disorders (AITDs) have been reported. However, two different recent studies did not find any association between them. In patients with PsO and PsA, an association with AITD has been shown by most of the studies in adults, but not in the juvenile form. In PsA women and men, thyroid autoimmunity [positive antithyroid peroxidase (AbTPO) antibodies, hypoechoic thyroid pattern] and subclinical hypothyroidism were more prevalent than in the general population. An association has been shown also in patients with PsO, arthritis, and inflammatory bowel disease, who have more frequently AITD. A Th1 immune predominance has been shown in early PsO, and PsA, with high serum CXCL10 (Th1 prototype chemokine), overall in the presence of autoimmune thyroiditis. This Th1 immune predominance might be the immunopathogenetic base of the association of these disorders. A raised incidence of new cases of hypothyroidism, thyroid dysfunction, positive AbTPO, and appearance of a hypoechoic thyroid pattern in PsA patients, especially in women, has been shown recently, suggesting to evaluate AbTPO levels, thyroid function, and thyroid ultrasound, especially in PsA women. Thyroid function follow-up and suitable treatments should be performed regularly in PsA female patients at high risk (thyroid-stimulating hormone within the normal range but at the higher limit, positive AbTPO, hypoechoic, and small thyroid).