Marcia A. Chan

Omalizumab may decrease IgE synthesis by targeting membrane IgE+ human B cells.

BackgroundOmalizumab, is a humanized anti-IgE monoclonal antibody used to treat allergic asthma. Decreased serum IgE levels, lower eosinophil and B cell counts have been noted as a result of treatment. In vitro studies and animal models support the hypothesis that omalizumab inhibits IgE synthesis by B cells and causes elimination of IgE-expressing cells either by induction of apoptosis or induction of anergy or tolerance.MethodsWe examined the influence of omalizumab on human tonsillar B cell survival and on the genes involved in IgE synthesis. Tonsillar B cells were stimulated with IL-4 plus anti-CD40 antibody to induce class switch recombination to IgE production in the presence or absence of omalizumab. Cell viability was assessed and RNA extracted to examine specific genes involved in IgE synthesis.ConclusionsWe found that omalizumab reduced viable cell numbers but this was not through induction of apoptosis. IL-4R and germline Cϵ mRNA levels were decreased as well as the number of membrane IgE+ cells in B cells treated with omalizumab. These data suggest that omalizumab may decrease IgE synthesis by human B cells by specifically targeting membrane IgE-bearing B cells and inducing a state of anergy.

CD23-mediated cell signaling in human B cells differs from signaling in cells of the monocytic lineage

CD23 is the low affinity receptor for IgE and in B cells CD23 has been proposed to play a role in the regulation of IgE synthesis. CD23 is expressed also on other cell types including monocytes/macrophages, eosinophils, follicular dendritic cells and intestinal epithelial cells none of which is capable of expressing IgE. The diverse nature of the expressing cells suggests that either the CD23-mediated signal transduction pathway may be different among the cell types or biological outcomes differ in different cells in response to the same signaling pathway. To address this issue, the CD23 signaling pathway was analyzed and compared in primary tonsillar B cells and in the monocytic cell lines U937 and THP-1. Activation of the tyrosine kinase Fyn and the serine/threonine kinase Akt were only observed in B cells. These results suggest that the CD23-mediated signal transduction pathways in human B cells and human monocytes are different.

Home dust microbiota is disordered in homes of low-income asthmatic children

Abstract Objective: Exposure to microorganisms has repeatedly been found to influence development of atopic diseases, such as asthma. Innovative techniques have been developed that can comprehensively characterize microbial communities. The objective of this study was to characterize the home microbiota of asthmatic children utilizing 16S rRNA-based phylogenetic analysis by microarray. Methods: In this cross-sectional study, DNA was extracted from home dust and bacterial 16S rRNA genes amplified. Bacterial products were hybridized to the PhyloChip Array and scanned using a GeneArray scanner (Affymetrix, Santa Clara, CA). The Adonis test was used to determine significant differences in the whole microbiome. Welch’s t-test was used to determine significant abundance differences and genus-level richness differences. Results: Nineteen homes were included in the analysis (14 asthma and five no asthma). About 1741 operational taxonomic units (OTUs) were found in at least one sample. Bacterial genus richness did not differ in the homes of asthmatics and non-asthmatics (p = 0.09). The microbial profile was significantly different between the two groups (p = 0.025). All the top 12 OTUs with significant abundance differences were increased in homes of asthmatics and belonged to one of the five phyla (p = 0.001 to p = 7.2 × 10−6). Nearly half of significant abundance differences belonged to the phylum Cyanobacteria or Proteobacteria. Conclusions: These results suggest that home dust has a characteristic microbiota which is disturbed in the homes of asthmatics, resulting in a particular abundance of Cyanobacteria and Proteobacteria. Further investigations are needed which utilize high-throughput technology to further clarify how home microbial exposures influence human health and disease.

Nicotinamide Phosphoribosyltransferase Attenuates Methotrexate Response in Juvenile Idiopathic Arthritis and In Vitro

Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX. Inhibition of NAMPT in cell culture by either siRNA‐based gene silencing or pharmacological inhibition with FK‐866 was found to result in a fourfold increase in the pharmacological activity of MTX. Collectively, these findings provide evidence that NAMPT inhibits the pharmacological activity of MTX and may represent a predictive biomarker of response, as well as a therapeutic target, in the treatment of JIA with MTX.

Immunoendocrine alterations following Marine Corps Martial Arts training are associated with changes in moral cognitive processes

Combined physical and psychological stress events have been associated with exacerbated endocrine responses and increased alterations in immune cell trafficking when compared to exercise stress alone. Military training programs are rigorous in nature and often purposefully delivered in environments combining high levels of both physical and mental stress. The objective of this study was to assess physiological and cognitive changes following U.S. Marine Corps Martial Arts training. Seven active-duty, male Marines were observed during a typical Marine Corps Martial Arts training session. Immune parameters, including immunomodulatory cytokines, and hormone concentrations were determined from blood samples obtained at baseline, immediately post training (IP) and at 15min intervals post-training to 1h (R15, R30, R45, R60). Assessments of cognitive moral functioning (moral judgment and intent) were recorded at intervals during recovery. There were significant fluctuations in immunoendocrine parameters. Peak endocrine measures were observed within the IP-R15 time interval. Distributions of circulating immune cells were significantly altered with neutrophils and all lymphocyte subsets elevated at IP. IFN-γ and IL-17a exhibited small, non-significant, parallel increases over the recovery period. Moral functioning was informed by different social identities during the recovery resulting in changes in moral decision-making. These data demonstrate that the Marine Corps Martial Arts Program induces significant alterations in lymphocyte and leukocyte distributions, but does not shift the balance of Th1/Th2 cytokines or induce a systemic inflammatory response. The program does, however, induce alterations in moral decision-making ability associated with the observed endocrine responses, even suggesting a potential interaction between ones social identities and endocrine responses upon moral decision-making.

Cytokine Biomarkers of Disease Activity and Therapeutic Response after Initiating Methotrexate Therapy in Patients with Juvenile Idiopathic Arthritis

To evaluate the relationship between plasma cytokine levels with disease activity and therapeutic response in patients with juvenile idiopathic arthritis (JIA) after initiating methotrexate (MTX) therapy.

DNA methylation levels associated with race and childhood asthma severity

ABSTRACT Objective: Asthma is a common chronic childhood disease worldwide. Socioeconomic status, genetic predisposition and environmental factors contribute to its incidence and severity. A disproportionate number of children with asthma are economically disadvantaged and live in substandard housing with potential indoor environmental exposures such as cockroaches, dust mites, rodents and molds. These exposures may manifest through epigenetic mechanisms that can lead to changes in relevant gene expression. We examined the association of global DNA methylation levels with socioeconomic status, asthma severity and race/ethnicity. Methods: We measured global DNA methylation in peripheral blood of children with asthma enrolled in the Kansas City Safe and Healthy Homes Program. Inclusion criteria included residing in the same home for a minimum of 4 days per week and total family income of less than 80% of the Kansas City median family income. DNA methylation levels were quantified by an immunoassay that assessed the percentage of 5-methylcytosine. Results: Our results indicate that overall, African American children had higher levels of global DNA methylation than children of other races/ethnicities (p = 0.029). This difference was more pronounced when socioeconomic status and asthma severity were coupled with race/ethnicity (p = 0.042) where low-income, African American children with persistent asthma had significantly elevated methylation levels relative to other races/ethnicities in the same context (p = 0.006, Hedges g = 1.14). Conclusion: Our study demonstrates a significant interaction effect among global DNA methylation levels, asthma severity, race/ethnicity, and socioeconomic status.