Plasma Levels Of sCD14 Research Articles

Zidovudine-Based Treatments Inhibit the Glycosylation of ADAM17 and Reduce CD163 Shedding From Monocytes

sCD163, a biomarker of monocyte-macrophage activation, has been identified as a predictor of all-cause mortality in treated HIV-infected individuals. Nevertheless, little is known about whether different antiretroviral drugs differentially regulate sCD163 levels and monocyte activation. A total of 123 patients receiving zidovudine (ZDV)-based (n = 55) or tenofovir disoproxil fumarate (TDF)-based (n = 68) antiretroviral regimens were enrolled, and their viral loads, CD4 counts, as well as plasma sCD163 and sCD14 levels were quantified. Twenty-eight (14 in each group) patients donated additional blood samples for flow cytometry and gene expression analyses using purified monocytes. THP-1 cultures were also used to investigate the effect of ZDV on ADAM17, which is responsible for CD163 shedding. As compared to the TDF-treated group, the ZDV-treated group had lower plasma sCD163 levels and higher CD163 expression on CD14++CD16 monocytes. Five metabolic-inflammatory genes exhibited significantly different expression levels between purified monocytes of the ZDV and TDF groups (IL-6, 2.90-fold lower in ZDV group, P < 0.001; iNOS, 1.81-fold higher; CX3CR1, 1.72-fold lower; MIP-1β, 1.10-fold lower; and PPARγ-1, 1.36-fold higher, P < 0.05). Moreover, we show that ZDV treatment increases the surface expression of CD163 in cultured THP-1 cells, accompanied by the inhibition of glycosylation and surface expression of ADAM17. Compared with TDF treatment, ZDV treatment causes lower plasma sCD163 levels, probably by inhibiting the glycosylation of ADAM17 and CD163 shedding. Our results show that ZDV functions as an ADAM17 inhibitor in vivo and extend our understanding of its immune-modulatory effects and adverse effects.

Persistent high plasma levels of sCD163 and sCD14 in adult patients with measles virus infection.

Background and aimsMeasles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated.MethodssCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls.ResultsAt the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages.ConclusionsThese results indicate that, despite the resolution of symptoms, an important macrophage/monocyte activation persists in measles patients, even after two months from infection.

Soluble CD163 and soluble CD14 plasma levels but not cellular HIV-DNA decrease during successful interferon-free anti-HCV therapy in HIV-1-HCV co-infected patients on effective combined anti-HIV treatment.

Soluble CD163, soluble CD14 and cellular HIV-1-DNA levels reflect two different aspects of HIV infection: immune activation and the reservoir of infected cells. The aim of this study was to describe their relationships in a cohort of HIV-HCV co-infected patients successfully treated for both HCV and HIV infections. Fifty-five patients were recruited and studied prior to the start of direct-acting antivirals (DAAs) (T0), at week 12 of DAA treatment (T1) and 24weeks after T0 (T2). The subjects were classified as having undetectable plasma HIV viraemia (UV) or low-level viraemia (LLV) in the 18months before T2. Plasma levels of sCD163 and of sCD14 were comparable in patients with UV and in subjects with LVL at T0, T1 and T2. The HIV DNA level was positively correlated with LLV but not with sCD163 and sCD14 levels; these two markers of inflammation were positively correlated (p = 0.017). Soluble CD163 and sCD14 decreased over time from T0 to T2 (p = 0.000 and p = 0.034, respectively). In conclusion, the significant decrease in sCD163 and sCD14 levels in patients cured of HCV infection, regardless of the presence of LLV, suggests a main role for HCV in immune activation in HIV-HCV co-infected patients.

Soluble CD14 levels in plasma and breastmilk of Malawian HIV+ women: Lack of association with morbidity and mortality in their exposed infants.

Data on soluble CD14 (sCD14) during pregnancy and lactation are scarce. We assessed the levels of sCD14 in plasma and breastmilk of Malawian HIV-positive women and evaluated the possible association with morbidity and mortality in the HIV-exposed children. One hundred and forty-nine mother/child pairs were studied. Women received antiretroviral therapy from 26weeks of gestation to at least 6months of exclusive breastfeeding. sCD14 concentrations were determined using an enzyme-linked immunosorbent assay. sCD14 levels measured at 26weeks of pregnancy (median: 1418ng/mL, IQR: 1086-1757) were inversely correlated to maternal CD4+ cell count (r=-.283, P=.001) and to neonatal birthweight (r=-.233, P=.008). At 6months, sCD14 plasma levels were significantly higher compared to baseline (1993ng/mL, IQR: 1482-2604, P<.001), and breastmilk sCD14 levels (7668ng/mL, IQR: 5495-10207) were 4-fold higher than in plasma (although the concentrations in the two compartments were not correlated). No association was found between sCD14 levels in plasma or breastmilk and morbidity or mortality in children. Higher sCD14 levels in HIV-positive women were associated with a more compromised maternal immunological status and to a lower neonatal birthweight, but not to poorer clinical outcomes in the HIV-exposed children.

Pre-vaccine plasma levels of soluble inflammatory indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and HIV infection

BackgroundChronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear. MethodsACTG 5232 and CFAR0910 were clinical trials where pre-vaccine levels of plasma IP10, IL-6, sCD163 and sCD14 were measured in viremic HCV- (n = 15) or HIV-infected participants (n = 24) and uninfected controls (n = 10). Accelerated dosing HAV/HBV vaccine and tetanus booster were administered and antibody response was measured at 0, 1, 3, 8, and 24 weeks. ResultsPre-vaccine plasma IP10, IL-6, and sCD14 levels were elevated in both HCV and HIV-infected participants, while sCD163 was also elevated in HCV-infected participants. Pre-immunization tetanus antibody levels were lower in HIV-infected than in uninfected participants, while vaccine induced antibody responses were intact in HCV and HIV-infected participants. After HAV/HBV vaccination, HCV and HIV-infected participants had lower and less durable HAV and HBV antibody responses than uninfected controls.Among HCV-infected participants, pre-vaccine plasma IP10, IL-6, sCD14, and sCD163 levels inversely correlated with HAV, HBV and tetanus antibody responses after vaccine. Low HAV/HBV vaccine responses in HIV-infected participants prohibited assessment of immune correlates. ConclusionsDuring HCV and HIV infection markers of systemic inflammation reflect immune dysfunction as demonstrated by poor response to HAV/HBV neo-antigen vaccine.

Macrophage activation marker sCD163 correlates with accelerated lipolysis following LPS exposure: a human-randomised clinical trial.

BackgroundMacrophage activation determined by levels of soluble sCD163 is associated with obesity, insulin resistance, diabetes mellitus type 2 (DM2) and non-alcoholic fatty liver disease (NAFLD). This suggests that macrophage activation is involved in the pathogenesis of conditions is characterised by adaptions in the lipid metabolism. Since sCD163 is shed to serum by inflammatory signals including lipopolysaccharides (LPS, endotoxin), we investigated sCD163 and correlations with lipid metabolism following LPS exposure.MethodsEight healthy male subjects were investigated on two separate occasions: (i) following an LPS exposure and (ii) following saline exposure. Each study day consisted of a four-hour non-insulin-stimulated period followed by a two-hour hyperinsulinemic euglycemic clamp period. A 3H-palmitate tracer was used to calculate the rate of appearance (Rapalmitate). Blood samples were consecutively obtained throughout each study day. Abdominal subcutaneous adipose tissue was obtained for western blotting.ResultsWe observed a significant two-fold increase in plasma sCD163 levels following LPS exposure (P < 0.001), and sCD163 concentrations correlated positively with the plasma concentration of free fatty acids, Rapalmitate, lipid oxidation rates and phosphorylation of the hormone-sensitive lipase at serine 660 in adipose tissue (P < 0.05, all). Furthermore, sCD163 concentrations correlated positively with plasma concentrations of cortisol, glucagon, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 (P < 0.05, all).ConclusionWe observed a strong correlation between sCD163 and stimulation of lipolysis and fat oxidation following LPS exposure. These findings support preexisting theory that inflammation and macrophage activation play a significant role in lipid metabolic adaptions under conditions such as obesity, DM2 and NAFLD.

Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder.

The human intestinal microbiota exerts beneficial or harmful effects in several disorders. Many factors, including alcohol consumption, may influence its composition and trigger bacterial translocation. Excessive alcohol consumption increases gut permeability and translocation of endotoxin into peripheral circulation. Although plasma endotoxin concentrations have been measured often, quantitative changes following alcohol withdrawal have never been described in subjects with alcohol use disorder (AUD). The aim of this study was to measure microbial translocation (MT) and gut permeability markers in patients with AUD, to compare these markers to healthy controls (HC) and to monitor markers during the first 6weeks of abstinence. Sixty-five patients with AUD and hospitalized for alcohol withdrawal were included. Epidemiological, clinical, biological, and addictological data were gathered. Blood samples were collected at baseline, then 3 and 6weeks after alcohol withdrawal. A hundred healthy volunteers were used as controls. Three markers of MT were monitored in plasma samples: sCD14 and lipopolysaccharide-binding protein (LBP) were quantified using ELISA, and 16S rDNA was quantified using real-time polymerase chain reaction. Zonulin and intestinal fatty acid binding protein (I-FABP) blood levels were also monitored as indirect markers of gut permeability, using ELISA. At baseline, LBP, 16S rDNA, sCD14 and I-FABP markers were significantly higher in patients with AUD than in HC. Six weeks after alcohol withdrawal plasma levels of sCD14 and LBP decreased significantly. Cannabis consumption and body mass index (BMI) before alcohol withdrawal influenced baseline MT levels and the decrease in MT markers after 6weeks. Finally, markers of MT and gut permeability did not correlate with each other before and after alcohol withdrawal. Before alcohol withdrawal, MT markers were higher in patients with AUD than in HC. After 6weeks of abstinence, an improvement in MT markers was observed. Our data suggest that there is a link between MT, its improvement, BMI, and cannabis consumption.

An alternatively activated macrophage marker CD163 in severely obese patients: the influence of very low-calorie diet and bariatric surgery.

CD163 is a marker of macrophages with anti-inflammatory properties and its soluble form (sCD163) is considered a prognostic predictor of several diseases including type 2 diabetes mellitus (T2DM). We explored sCD163 levels at baseline and after very low-calorie diet (VLCD) or bariatric surgery in 32 patients with obesity (20 undergoing VLCD and 12 bariatric surgery), 32 obese patients with T2DM (22 undergoing VLCD and 10 bariatric surgery), and 19 control subjects. We also assessed the changes of CD163 positive cells of monocyte-macrophage lineage in peripheral blood and subcutaneous adipose tissue (SAT) in subset of patients. Plasma sCD163 levels were increased in obese and T2DM subjects relative to control subjects (467.2+/-40.2 and 513.8+/-37.0 vs. 334.4+/-24.8 ng/ml, p=0.001) and decreased after both interventions. Obesity decreased percentage of CD163+CD14+ monocytes in peripheral blood compared to controls (78.9+/-1.48 vs. 86.2+/-1.31 %, p=0.003) and bariatric surgery decreased CD163+CD14+HLA-DR+ macrophages in SAT (19.4+/-2.32 vs. 11.3+/-0.90 %, p=0.004). Our data suggest that increased basal sCD163 levels are related to obesity and its metabolic complications. On the contrary, sCD163 or CD163 positive cell changes do not precisely reflect metabolic improvements after weight loss.

Comparative evaluation of microbial translocation products (LPS, sCD14, IgM Endocab) in HIV-1 infected Indian individuals

BackgroundMicrobial translocation of lipopolysaccharides (LPS), soluble CD14 (sCD14) and IgM Endocab levels have been reported to be associated with disease progression in HIV-1 infection. In this longitudinal study, plasma levels of different microbially translocated products (LPS, sCD14, Endocab) was investigated in HIV-1 infected Indian Individuals stratified as Rapid (R), Viremic slow (VS), Slow progressors (S) and healthy controls. MethodTen healthy and twenty HIV-1 infected individuals were enrolled. Plasma levels of LPS, sCD14, Endocab was examined using commercially available Limulus Amebocyte assay and enzyme-linked immunosorbent assay (ELISA) enzyme linked immunosorbant assay. ResultsElevated levels of sCD14, IgM EndoCab and LPS were observed during HIV-1 infection compared to healthy controls. Rapid progressors had higher levels of sCD14, IgM EndoCab, LPS (median% 1553, 3596, 202.2) compared to viremic slow, slow progressors and healthy controls both at baseline and follow up visits. At baseline, LPS correlated positively with IgM Endocab and negatively with sCD14 levels while at follow-up, significant positive correlation was observed between IgM Endocab and sCD14 (IgM EndoCab r = 0.490, p = 0.05; sCD14 r = 0.051, p = 0.830). Plasma levels of sCD14 correlated positively with viral load in rapid, viremic slow and slow progressors while CD + T cell count correlated positively with sCD14 and IgM EndoCab levels in viremic slow and slow progressors. ConclusionOur findings indicate that elevated levels of sCD14, IgM EndoCab and LPS in HIV-1 infected individuals are strong predictors of disease progression and could be considered as candidate biomarkers for disease monitoring.

Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon.

Background and aimsIncreased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN).MethodssCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls.ResultsAt baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups.Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize.ConclusionsThese results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection.

Active HCV infection is associated with increased circulating levels of interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble CD163 and inflammatory monocytes regardless of liver fibrosis and HIV coinfection

Interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble (s) CD163 and sCD14 play an important role in the pathogenesis of HCV and HIV infection and are involved in inflammation and liver fibrosis. The aim of the present study was to evaluate at a single time point, plasma soluble biomarkers and inflammatory monocytes subsets in different groups of subjects: (i) HIV monoinfected patients on suppressive ART; (ii) HIV/HCV coinfected patients on ART, with undetectable HIV viremia (including either subjects who had active HCV replication or those who cleared HCV); (iii) HCV monoinfected individual with active viral replication. Hundred and twenty-nine plasma samples were analyzed including HCV and HIV monoinfected patients, HIV/HCV coinfected patients, with active HCV infection (AHI) or with HCV viral clearance (VHC) and healthy donors (HD). Levels of IP-10, sCD163 and sCD14 were measured by ELISA. Absolute cell counts of monocyte subpopulations were enumerated in whole blood by using flow cytometric analyses. IP-10 and sCD163 plasma levels were higher in HCV monoinfected and in AHI coinfected pts compared to HIV monoinfected and HD, whereas sCD14 levels were higher only in HIV monoinfected patients. Considering the degree of fibrosis, sCD163 and sCD14 levels positively correlated with kPa values (as assessed by fibroscan) and FIB-4 in HCV monoinfected group. On the other hand, IP-10 did not correlate with the fibrosis stage and it was found increased also in patients with low fibrosis. Moreover, we found an increase of the inflammatory NCM subset, in non-cirrhotic HCV subjects, while no alterations were observed in HIV, AHI and VHC. Our study suggests a scenario in which active HCV infection is associated with a strong pro-inflammatory state, even in the initial stage of liver fibrosis, regardless the presence of HIV coinfection, thus underlying the need of an early anti-HCV treatment.

Soluble plasma proteins ST2 and CD163 as early biomarkers of nephropathy in Swedish patients with diabetes, 15\u201334\xa0years of age: a prospective cohort study

BackgroundThe aim of this study was to investigate plasma levels of sST2 and sCD163 to determine whether they at an early stage could predict development of diabetic nephropathy and/or diabetic retinopathy in patients at clinical onset.MethodsPatients diagnosed with diabetes mellitus at age 15–34 years between 1987 and 1988 (n = 220) were included. Data such as BMI, smoking, HbA1c and islet cell antibodies were collected at time of diagnosis. Within the 10 year follow-up period, 112 patients (51%) developed following diabetes related complications; retinopathy (n = 91), nephropathy (n = 12) or both (n = 9). Plasma concentrations of sST2 and sCD163 were measured at time of diagnosis and levels compared between different complication groups.ResultsPlasma levels of sST2 were significantly higher in patients who later developed nephropathy (n = 21; 1012 [773–1493] pg/ml) compared to those who did not (n = 199; 723 [449–1084] pg/ml; p = 0.006). A tendency for higher plasma levels of sCD163 was observed but not statistically significant (p = 0.058).ConclusionssST2 and sCD163 show promise as potential biomarkers for the development of nephropathy already at clinical onset. sST2 and/or sCD163 could possibly be part of a biomarker panel aimed to find patients at high risk of developing nephropathy. Both markers need to be investigated in a larger prospective study.

Associations between inflammation and senescent/exhaustion markers, CD57, KLRG1, and PD-1 differ in elderly and young

Abstract Background Inflammatory indices such as IL-6 and soluble CD14 are elevated in the elderly, and aging is also associated with immune senescence and exhaustion. Soluble indices of inflammation and immune senescence have independently been associated with mortality and morbidity in the elderly. Whether these pathways are mechanistically linked is not clear. Methods This pilot study examined the relationship of plasma levels of IL-6, IP10, and sCD14 to T cell expression of immune checkpoint markers PD-1, CD57, and KLRG1 inelderly (≥70 years old; n=10) and young (≤40 years old;n=10) participants. Results Elderly participants had elevated plasma levels of IL-6 (p= &amp;lt;0.0001), sCD14 (p=0.0009), and IP10 (p= 0.012) compared to young participants. Surface expression of PD-1 (p= 0.002), CD57 (p= 0.0005), and KLRG1 (p= 0.04) was elevated on memory CD4 T cell in elderly participants. Co-expression of immune checkpoint markers PD-1, CD57, and KLRG1 on CD4 T cells inversely correlated with plasma levels of IL-6 in the elderly; whereas coexpression of checkpoint markers on CD8 T cells positively correlated with plasma levels of IP10 in young participants. Plasma levels of sCD14 positively associated with PD-1 expression on CD4 TEM cells in elderly but inversely correlated with PD-1 expression onCD8 CM and TEM cells in young participants. Conclusion The relationship between soluble indices of inflammation and immune check pointmarker expression varies between elderly and young and between CD4 and CD8 T cells. Further studies are warranted to understand the complex interactions of inflammation and immune senescence and how they contribute tomortality and morbidity in the elderly.

Enhanced susceptibility to alcohol-induced bacterial translocation, immune activation, and persistent inflammation in patients with alcoholic hepatitis: a prospective observational study

Abstract Up to 30% chronic heavy drinkers develop a spectrum of severe alcoholic liver diseases, including alcoholic hepatitis (AH). Alcohol-induced impairment of intestinal integrity and microbial translocation into the portal vein lead to immune activation and play a major role in the pathogenesis of AH. To better understand why AH develops only in some heavy drinkers and the effect of alcohol abstinence on immunity, we conducted a prospective study to compare plasma LPS levels and peripheral blood immunoprofiles between 68 AH patients and 65 heavy drinkers without liver disease (HDC) who were followed up to 12 months. Plasma samples were also obtained from 31 health donors (HD). Plasma LPS was detected in a higher portion of AH patients than HDC (80% vs 49%) at baseline, and in only 8% HD. However, LPS levels were not different between AH an HDC subjects with detectable LPS. Compared with HDC, AH patients had higher baseline plasma levels of sCD14, sCD163, sICAM-1, sVCAM-1, IL-22, TNF-α, IL-8, IP10, IL-4, IL-6, IL-9, IL-10, FGF2, IL-7, IL-15, and TGF-α, but lower levels of the anti-inflammatory chemokine MDC. AH patients also had more activated, yet dysfunctional monocytes, T cells, and B cells as they expressed higher levels of CD38 and CD69, but lower levels of HLA-DR, CD80, and CD86. In spite of having significant bacterial translocation, HDC showed little evidence of immune activation. With alcohol abstinence, levels of many dysregulated immune markers normalized in AH patients. However, TNF-α, IL-8, IL-10, sCD163, and sVCAM-1 levels remained higher. Conclusion AH patients were more susceptible to alcohol-induced bacterial translocation and immune activation. Alcohol abstinence reduced but did not fully reverse immunological abnormalities.

Brief Report: Soluble CD163 in CMV-Infected and CMV-Uninfected Subjects on Virologically Suppressive Antiretroviral Therapy in the ICONA Cohort.

To contribute to the understanding of the role played by cytomegalovirus (CMV) in sustaining monocyte/macrophage-mediated immune activation in antiretroviral therapy treated HIV-infected subjects. We selected 23 CMV-uninfected and 46 CMV-infected HIV+ subjects, matched for age, CD4 nadir, HIV infection duration, and viral hepatitis serostatus. All subjects were on successful antiretroviral therapy since at least 1 year. A group of 16 healthy donors with similar age and sex was also included. Plasma levels of tumor necrosis factor-alpha, interleukin-6, sCD163, sCD14, and CMV immunoglobulin G levels were measured in duplicate with human enzyme-linked immunosorbent assay kits. We found significantly higher sCD163 plasma levels in HIV+CMV+ compared with HIV+CMV- subjects and healthy donors. This augmentation was confirmed also when subjects positive for hepatitis C virus-Ab were excluded from analysis. Interestingly, a correlation between anti-CMV immunoglobulin G levels and sCD163, tumor necrosis factor-alpha, interleukin-6, and sCD14 in HIV+CMV+ subjects was found. CMV coinfection could be a major driver of monocyte/macrophage activation in virally suppressed HIV+ individuals and might explain the increased risk of non-AIDS morbidity/mortality in HIV/CMV-coinfected subjects.

Effect of Antiretroviral Therapy on the Memory and Activation Profiles of B Cells in HIV-Infected African Women.

Human immunodeficiency virus infection induces a wide range of effects in B cells, including skewed memory cell differentiation, compromised B cell function, and hypergammaglobulinemia. However, data on the extent to which these B cell abnormalities can be reversed by antiretroviral therapy (ART) are limited. To investigate the effect of ART on B cells, the activation (CD86) and differentiation (IgD, CD27, and CD38) profiles of B cells were measured longitudinally in 19 HIV-infected individuals before (median, 2 mo) and after ART initiation (median, 12 mo) and compared with 19 age-matched HIV-uninfected individuals using flow cytometry. Twelve months of ART restored the typical distribution of B cell subsets, increasing the proportion of naive B cells (CD27-IgD+CD38-) and concomitantly decreasing the immature transitional (CD27-IgD+CD38+), unswitched memory (CD27+IgD+CD38-), switched memory (CD27+IgD-CD38- or CD27-IgD-CD38-), and plasmablast (CD27+IgD-CD38high) subsets. However, B cell activation was only partially normalized post-ART, with the frequency of activated B cells (CD86+CD40+) reduced compared with pre-ART levels (p = 0.0001), but remaining significantly higher compared with HIV-uninfected individuals (p = 0.0001). Interestingly, unlike for T cell activation profiles, the extent of B cell activation prior to ART did not correlate with HIV plasma viral load, but positively associated with plasma sCD14 levels (p = 0.01, r = 0.58). Overall, ART partially normalizes the skewed B cell profiles induced by HIV, with some activation persisting. Understanding the effects of HIV on B cell dysfunction and restoration following ART may provide important insights into the mechanisms of HIV pathogenesis.

TLR4/CD14 Variants-Related Serologic and Immunologic Dys-Regulations Predict Severe Sepsis in Febrile De-Compensated Cirrhotic Patients.

Genetic variants and dysfunctional monocyte had been reported to be associated with infection susceptibility in advanced cirrhotic patients. This study aims to explore genetic predictive markers and relevant immune dysfunction that contributed to severe sepsis in febrile acute de-compensated cirrhotic patents. Polymorphism analysis of candidate genes was undergone in 108 febrile acute de-compensated cirrhotic patients and 121 healthy volunteers. Various plasma inflammatory/regulatory cytokines, proportion of classical (CD 16-, phagocytic) and non-classical (CD16+, inflammatory) monocytes, lipopolysaccharide (LPS)-stimulated toll-like receptor 4 (TLR4) and intracellular/extracellular cytokines on cultured non-classical monocytes, mCD14/HLA-DR expression and phagocytosis of classical monocytes were measured. For TLR4+896A/G variant allele carriers with severe sepsis, high plasma endotoxin/IL-10 inhibits HLA-DR expression and impaired phagocytosis were noted in their classical monocyte. In the same group, increased non-classical monocyte subset, enhanced LPS-stimulated TLR4 expression and TNFα/nitrite production, and systemic inflammation [high plasma soluble CD14 (sCD14) and total nitric oxide (NOx) levels] were noted. For CD14-159C/T variant allele carriers with severe sepsis, persist endotoxemia inhibited mCD14/HLA-DR expression and impaired phagocytosis of their classical monocyte. In the same group, increased non-classical monocyte subset up-regulated TLR4-NFκB-iNOS and p38MAPK pathway, stimulated TNFα/nitrite production and elicited systemic inflammation. In febrile acute de-compensated cirrhotic patients, TLR4+896A/G and CD14-159C/T polymorphisms-related non-classical and classical monocytes dysfunction resulted in increased severe sepsis risk. Malnutrition, high plasma endotoxin and sCD14 levels, single TLR4+896A/G or CD14-159C/T variant allele carriers and double variant allele carriers are significant predictive factors for the development of severe sepsis among them.

Gag-Specific CD4 T Cell Proliferation, Plasmacytoid Dendritic Cells, and Ethnicity in Perinatally HIV-1-Infected Youths: The ANRS-EP38-IMMIP Study.

In perinatally HIV-1-infected youths living in France, we previously reported that Gag-specific CD4 and CD8 T cell proliferation is more frequently detected in patients of black ethnicity than in those of other ethnicities. We observed that black patients had higher levels of dendritic cells (DCs) than other patients. We aimed at studying the association of DC levels with Gag-specific T cell proliferation. The ANRS-EP38-IMMIP study is an observational study of youths aged between 15 and 24 years who were perinatally infected with HIV. A single blood sample was drawn for virological and immunological assays. Data from cART-treated 53 youths with undetectable plasma HIV RNA were analyzed. Gag-specific T cell proliferation was assessed by using a CFSE-based test. Peripheral blood myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were phenotyped by flow cytometry. Plasma markers were quantified by ELISA or multiplex assays. Logistic regression was used for univariate and multivariate analyses. Patients with Gag-specific CD4 T cell proliferative responses had significantly higher percentages and absolute counts of mDCs and pDCs in the peripheral blood than nonresponding patients. Gag-specific CD4 and CD8 T cell proliferation was associated with lower plasma sCD14 levels. Plasma levels of IFN-α, TRAIL, and chemokines involved in T cell migration to secondary lymphoid organs were not associated with T cell proliferation. Multivariate analysis confirmed the association between Gag-specific CD4 T cell proliferation and pDC levels. In conclusion, DC levels are a robust correlate of the presence of Gag-specific T cell proliferation in successfully treated youths.

Abstract 3441: Associations between lipopolysaccharide (LPS) and LPS pathway biomarkers and gallbladder cancer are modulated by markers of systemic inflammation

Abstract Little is known about gallbladder cancer (GBC) etiology. Gallstones (GS) are a critical factor in GBC pathogenesis. Bacterial infections, such as Salmonella Typhi and Helicobacter pylori, also may contribute to the development of GBC. We previously observed strong associations between inflammation markers and GBC vs. GS patients and hypothesized that bacterial infections may explain in part associations between GBC and inflammation. In the current study of 41 GBC cases and 124 GS patients from Shanghai, China, we evaluated relationships between GBC and the bacterial infection-related proteins plasma lipopolysaccharide (LPS) and two LPS-pathway proteins, soluble CD14 (sCD14) and lipid binding protein (LBP), as measured by ELISA. Further, we explored the extent to which these associations were mediated through systemic inflammation. Logistic regression was conducted to assess associations of GBC with plasma LPS, sCD14, and LBP levels. To evaluate mediation through inflammation, an inflammation score was calculated by summing the value of 15 previously measured GBC-associated serum inflammation markers (β-coefficient multiplied by 1 if above the median or 0 if below the median) and included in the models. sCD14 and LBP levels (above vs. below the median) were strongly associated with GBC [Odds Ratio (95% Confidence Interval): 2.75 (1.27-6.29) for sCD14 and 2.83 (1.32-6.46) for LBP]. The highest vs. lowest tertiles of sCD14 and LBP were associated with a five-fold increased risk of GBC. These associations were attenuated when the inflammation score was entered into the model. Plasma LPS demonstrated a borderline association after adjustment for inflammation score [OR (95% CI): 2.46 (0.96-6.56)]. In contrast, the ORs for inflammation score remained &amp;gt;20 after adjusting for each bacteria-related marker. These findings suggest that bacterial infections may contribute to GBC etiopathogenesis through inflammatory pathways. LPS, sCD14, and LBP and Gallbladder Cancer Relative to Gallstone ControlsLPSSex &amp; Age Adjusted OR (95% CI)Sex, Age, &amp; Inflammation Score Adjusted OR (95% CI)Detectable Level1.001.00Undetectable Level1.81 (0.85-3.80)2.46 (0.96-6.56)sCD14Sex, Age, &amp; Batch Adjusted OR (95% CI)Sex, Age, Batch, &amp; Inflammation Score Adjusted OR (95% CI)Below Median1.001.00Above Median2.75 (1.27-6.29)1.05 (0.39-2.83)1st Tertile1.001.002nd Tertile1.42 (0.45-4.71)0.44 (0.10-1.80)3rd Tertile5.27 (1.98-16.06)1.37 (0.38-5.04)p-trend0.00060.25LBPSex, Age, &amp; Batch Adjusted OR (95% CI)Sex, Age, Batch, &amp; Inflammation Score Adjusted OR (95% CI)Below Median1.001.00Above Median2.83 (1.32-6.46)1.63 (0.64-4.28)1st Tertile1.001.002nd Tertile1.95 (0.61-6.99)1.53 (0.37-7.01)3rd Tertile5.01 (1.84-16.25)2.09 (0.58-8.71)p-trend0.00080.25 Citation Format: Alison L. Van Dyke, Troy J. Kemp, Amanda F. Corbel, Bin Zhu, Yu-Tang Gao, Bingsheng Wang, Asif Rashid, Ming-Chang Shen, Allan Hildesheim, Ann W. Hsing, Ligia A. Pinto, Jill Koshiol. Associations between lipopolysaccharide (LPS) and LPS pathway biomarkers and gallbladder cancer are modulated by markers of systemic inflammation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3441.

56 Impairment of CD163 receptor are associated with increased levels of TNF- α and IL-1 β in plasma from pregnant women with preeclampsia

Introduction Preeclampsia (PE) is a pregnancy-specific syndrome characterized by a systemic inflammatory response that polarizes peripheral blood monocytes to the M1 phenotype. CD163 is a scavenger receptor expressed by monocytes/macrophages which may shed from their cell membrane after proteolytic cleavage producing soluble CD163 molecule (sCD163) that plays a role in the modulation of inflammatory response. Objectives This study aimed at evaluate expression of CD163 on monocytes and the levels of sCD163 as well as pro- and anti-inflammatory cytokines in plasma of pregnant women with the severe and mild forms of PE. Methods Fifty-six women with preeclampsia, 28 normotensive pregnant women matched for gestational age and 20 healthy non-pregnant women were included. Preeclamptic women were classified according to the disease severity as mild ( n = 28) or severe ( n = 28) PE. Plasma levels of sCD163, tumor necrosis factor-alpha (TNF- α ), Interleukin-1 beta (IL-1 β ), IL-10 and transforming growth factor beta (TGF- β 1) were determined by enzyme-linked immunosorbent assay, and CD163 expression by monocytes was assessed by flow cytometry. Differences between groups were compared by parametric analysis of variance with significance level set at 5%. Results Monocytes from preeclamptic women showed lower expression of CD163 receptor compared with normotensive pregnant and non-pregnant women. Plasma levels of sCD163 were also significantly lower in pregnant women with severe or mild PE than in normotensive pregnant women. No significant differences were detected between both groups of PE in relation to this parameter. A positive correlation was observed between sCD163 and IL-10 concentration in plasma from normotensive pregnant women ( r = 0.5829; p = 0.0111). The values of IL-1 β , TGF- β 1 and TNF- α were higher in severe PE than in mild PE and normotensive pregnant women. Both groups of preeclamptic women showed decreased plasma levels of IL-10. A negative correlation was observed between concentrations of sCD163 and IL-1 β ( r = −0.4251; p = 0.0341) and between sCD163 and TNF- α ( r = −0.5075; p = 0.0096) in the group of severe PE. Conclusions The results showed that decreased plasma levels of sCD163 could possibly be explained by the lower expression of CD163 by monocytes from preeclamptic women. The association between the pro-inflammatory cytokine profile and the lower concentration of sCD163 and IL-10 in plasma from pregnant women with severe PE suggests an impairment in the modulation of the inflammatory response in this preeclamptic group. Financial support – FAPESP 2013/12260-7.