Antibody-independent functions of B cells during viral infections

The humoral immune response and antibody-mediated functions of B cells during viral infections are well described. However, we have limited understanding of antibody-independent B cell functions, such as cytokine production and antigen presentation, in acute and chronic viral infections and their role in protection and/or immunopathogenesis. Here, we summarize the current literature on these antibody-independent B cell functions and identify remaining knowledge gaps. B cell subsets produce anti- and pro-inflammatory cytokines, which can have both beneficial and detrimental effects during viral clearance. As professional antigen presenting cells, B cells also play an important role in immune regulation/shaping of the developing adaptive immune responses. Since B cells primarily express TLR7 and TLR9, we specifically discuss the role of Toll-like receptor (TLR)-mediated B cell responses to viral infections and their role in augmenting adaptive immunity through enhanced cytokine production and antigen presentation. However, viruses have evolved strategies to subvert TLR signaling and additional stimulation via B cell receptor (BCR) may be required to overcome the defective TLR response in B cells. To conclude, antibody-independent B cell functions seem to have an important role in regulating both acute and chronic viral infections and may form the basis for novel therapeutic approaches in treatment of viral infections in the future

Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment

ABSTRACT: INTRODUCTION: Cross-regulation between tumor necrosis factor (TNF) and type I interferon (IFN) has been postulated to play an important role in autoimmune diseases. Therefore we determined the effect of TNF-blockade in rheumatoid arthritis (RA) on the type I IFN-response gene activity in relation to clinical response. METHODS: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA-microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative (q)PCR. RESULTS: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN-response activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN-response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN-response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR. CONCLUSIONS: Regulation of IFN-response gene activity upon TNF-blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN-response gene activity appear relevant to the clinical outcome of TNF-blockade in R

Direct Infection of B Cells by Dengue Virus Modulates B Cell Responses in a Cambodian Pediatric Cohort

Dengue is an acute viral disease caused by dengue virus (DENV), which is transmitted by Aedes mosquitoes. Symptoms of DENV infection range from inapparent to severe and can be life-threatening. DENV replicates in primary immune cells such as dendritic cells and macrophages, which contribute to the dissemination of the virus. Susceptibility of other immune cells such as B cells to direct infection by DENV and their subsequent response to infection is not well defined. In a cohort of 60 Cambodian children, we showed that B cells are susceptible to DENV infection. Moreover, we show that B cells can support viral replication of laboratory adapted and patient-derived DENV strains. B cells were permissive to DENV infection albeit low titers of infectious virions were released in cell supernatants CD300a, a phosphatidylserine receptor, was identified as a potential attachment factor or receptor for entry of DENV into B cells. In spite of expressing Fcγ-receptors, antibody-mediated enhancement of DENV infection was not observed in B cells in an in vitro model. Direct infection by DENV induced proliferation of B cells in dengue patients in vivo and plasmablast/plasma cell formation in vitro. To summarize, our results show that B cells are susceptible to direct infection by DENV via CD300a and the subsequent B cell responses could contribute to dengue pathogenesis

Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays

We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur

Impaired Antibody-Independent Immune Response of B Cells in Patients With Acute Dengue Infection

Dengue is a mosquito-borne viral disease caused by dengue virus (DENV). The disease is endemic to more than 100 countries with 390 million dengue infections per year. Humoral immune responses during primary and secondary DENV infections are well-investigated. However, the impact of DENV infection on B cell subsets and their antibody-independent functions are not well-documented. Through this study, we aimed to define the distribution of B cell subsets in the acute phase of DENV infection and characterize the effect of DENV infection on B cell functions such as differentiation into memory and plasma cells and cytokine production. In our cohort of Cambodian children, we observed decreased percentages of CD24(hi)CD38(hi) B cells and CD27(-) naive B cells within the CD19 population and increased percentages of CD27(+)CD38(hi)CD138(+) plasma cells as early as 4 days post appearance of fever in patients with severe dengue compared to patients with mild disease. Lower percentages of CD19(+)CD24(hi)CD38(hi) B cells in DENV-infected patients were associated with decreased concentrations of soluble CD40L in patient plasma and decreased platelet counts in these patients. In addition, CD19(+)CD24(hi)CD38(hi) and CD19(+)CD27(-) B cells from DENV-infected patients did not produce IL-10 or TNF-alpha upon stimulation in vitro, suggesting their contribution to an altered immune response during DENV infection. In addition, CD19(+)CD27(-) naive B cells isolated from dengue patients were refractory to TLR/anti-IgM stimulation in vitro, which correlated to the increased expression of inhibitory Fc gamma receptors (Fc gamma R) CD32 and LILRB1 on CD19(+)CD27(-) naive B cells from DENV-infected patients. Collectively, our results indicate that a defective B cell response in dengue patients may contribute to the pathogenesis of dengue during the early phase of infection

Characterization of soluble TLR2 and CD14 levels during acute dengue virus infection

Dengue virus infection results in a broad spectrum of diseases ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Hitherto, there is no consensus biomarker for the prediction of severe dengue disease in patients. Yet, early identification of patients who progress to severe dengue is pivotal for better clinical management. We have recently reported that an increased frequency of classical (CD14 ++CD16 -) monocytes with sustained high TLR2 expression in acutely infected dengue patients correlates with severe dengue development. Here, we hypothesized that the relatively lower TLR2 and CD14 expression in mild dengue patients is due to the shedding of their soluble forms (sTLR2 and sCD14) and that these could be used as indicators of disease progression. Therefore, using commercial sandwich ELISAs, we evaluated the release of sTLR2 and sCD14 by peripheral blood mononuclear cells (PBMCs) in response to in vitro dengue virus (DENV) infection and assessed their levels in acute-phase plasma of 109 dengue patients. We show that while both sTLR2 and sCD14 are released by PBMCs in response to DENV infection in vitro, their co-circulation in an acute phase of the disease is not always apparent. In fact, sTLR2 was found only in 20% of patients irrespective of disease status. In contrast, sCD14 levels were detected in all patients and were significantly elevated in DF patients when compared to DHF patients and age-matched healthy donors. Altogether, our results suggest that sCD14 may help in identifying patients at risk of severe dengue at hospital admittance. </p

Multivariate evidence-based pediatric dengue severity prediction at hospital arrival

Background: For individuals with dengue-like symptoms arriving at hospitals, early detection of those likely to progress to-or not progress to-severe dengue can be of great use. Methods: We studied 237 Cambodian children hospitalised in Kampong Cham hospital with dengue-like symptoms. Using dengue severity as primary endpoint, we ran univariate analyses and built multivariate random forest classifiers to predict this endpoint using early clinical and laboratory data. Findings: In a random forest analysis using 56 available variables we obtained AUC = 0•94, and for a sensitivity of 90%: specificity = 89%, positive predictive value (PPV) = 74%, and negative predictive value (NPV) = 96%. Platelet count, HDL cholesterol, and ultrasound pleural effusion and ascites were the four variables most associated with severe dengue outcomes. A random forest on only these four variables gave AUC = 0·88, and for a sensitivity of 90%: specificity = 82%, PPV = 64%, and NPV = 96%. Interpretation. Future severe dengue with significant vascular leakage can be correctly predicted at hospital arrival in a large majority of cases using multivariate random forests. In addition to platelet count and ultrasound pleural effusion and ascites, HDL cholesterol level on the day of admission is also a strong predictor of severe dengue

Factors of working environment on employees performance in oil palm plantation at RISDA Palong Estate, Negeri Sembilan Darul Khusus / Nurul Syafiqah Ramli

A working environment will create a pleasant atmosphere within the organization to perform well. The relationship between working environment and employees performance of central interest to research in organizational psychology. This study aims to determine the performance of employees in Risda Palong Estates and to analyse the relationship between the factor of working environment and employees performance. A number of 88 respondent was interviewed from the company Risda Palong Estates of Risda Plantation Sdn. Bhd. Several analysis are used to measure up the reliability of the questionnaire and also normality analysis are used to measure up the normal distribution of each data. Correlation analysis are also used to measure up the strength of independent variable and the dependent variable of the study. The independent variable includes job satisfaction, company policy, salary and responsiveness of working environment. The dependent variable is the performance of the employees. Regression analysis are also used to measure up in which of the independent variable mostly influence the dependent variable. The result reveals that the working environment factors have a significant effect on the performance of Risda Palong Estate. It is also indicated that employees were less satisfied by the factor company policy and salary

Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance

A cross-regulation between type I IFN and TNFα has been proposed recently, where both cytokines are hypothesized to counteract each other. According to this model, different autoimmune diseases can be viewed as disequilibrium between both cytokines. As this model may have important clinical implications, the present review summarizes and discusses the currently available clinical evidence arguing for or against the proposed cross-regulation between TNFα and type I IFN. In addition, we review how this cross-regulation works at the cellular and molecular levels. Finally, we discuss the clinical relevance of this proposed cross-regulation for biological therapies such as type I IFN or anti-TNFα treatment