Rhinosinusitis derived Staphylococcal enterotoxin B plays a possible role in pathogenesis of food allergy

BACKGROUND: Staphylococcal enterotoxin B (SEB) is a potent immunomodulator and implicated with pathogenesis of inflammatory diseases mediated by Th1 or Th2 dominant immune responses. The objective of this study is to determine a possible association between rhinosinusitis derived SEB and pathogenesis of food allergy (FA). METHODS: The study included chronic rhinosinusitis (CRS) patients with FA (N = 46) or without FA (N = 33). Controls included FA patients without CRS (N = 26) and healthy volunteers (N = 25). In CRS patients, we assessed the parameters associated with FA including prick skin test (PST) reactivity to food allergens, serum levels of allergen-specific IgE and cytokines (IL-4, IL-13, IFN-Î(3)), and the number/reactivity of food-allergen specific Th1/Th2 cells in the peripheral blood before and 2 months after sinus surgery. Changes of these parameters were evaluated in comparison with changes in SEB concentration in the sinus lavage and stool samples and also in vitro reactivity to SEB. In CRS patients with FA, we also assessed changes in reactivity to oral challenge of offending food before and after sinus surgery. RESULTS: Two months following sinus surgery, we observed statistically significant reduction in PST and oral challenge reactivity in CRS patients with FA in parallel to decrease in serum levels of Th2 cytokines (IL-4 and IL-13) and allergen specific IgE. Improvement of reactivity to food allergens was positively associated with decline in SEB concentrations in the sinus lavage and stool samples. In vitro study results also indicated a role of SEB in aggravation of Th2 skewed responses to food allergens. Such changes were not observed in CRS-non FA patients or control FA patients. CONCLUSION: The rhinosinusitis derived SEB plays a certain role in the pathogenesis of FA by augmenting and/or maintaining polarized Th2 responses. Removal of SEB-producing pathogens from the rhinosinuses may be beneficial for attenuating the FA symptoms in patients with CRS-FA

Identification and Characterization of Novel Receptor-Interacting Serine/Threonine-Protein Kinase 2 Inhibitors Using Structural Similarity Analysis.

Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis

Human Disease-Drug Network Based on Genomic Expression Profiles

BACKGROUND: Drug repositioning offers the possibility of faster development times and reduced risks in drug discovery. With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic, large-scale analysis of genomic expression profiles of human diseases and drugs to create a disease-drug network. A network of 170,027 significant interactions was extracted from the approximately 24.5 million comparisons between approximately 7,000 publicly available transcriptomic profiles. The network includes 645 disease-disease, 5,008 disease-drug, and 164,374 drug-drug relationships. At least 60% of the disease-disease pairs were in the same disease area as determined by the Medical Subject Headings (MeSH) disease classification tree. The remaining can drive a molecular level nosology by discovering relationships between seemingly unrelated diseases, such as a connection between bipolar disorder and hereditary spastic paraplegia, and a connection between actinic keratosis and cancer. Among the 5,008 disease-drug links, connections with negative scores suggest new indications for existing drugs, such as the use of some antimalaria drugs for Crohn's disease, and a variety of existing drugs for Huntington's disease; while the positive scoring connections can aid in drug side effect identification, such as tamoxifen's undesired carcinogenic property. From the approximately 37K drug-drug relationships, we discover relationships that aid in target and pathway deconvolution, such as 1) KCNMA1 as a potential molecular target of lobeline, and 2) both apoptotic DNA fragmentation and G2/M DNA damage checkpoint regulation as potential pathway targets of daunorubicin. CONCLUSIONS/SIGNIFICANCE: We have automatically generated thousands of disease and drug expression profiles using GEO datasets, and constructed a large scale disease-drug network for effective and efficient drug repositioning as well as drug target/pathway identification

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis

A case series evaluating the serological response of adult asthma patients to the 23-valent pneumococcal polysaccharide vaccine

Abstract Background Asthma is an independent risk factor for invasive pneumococcal disease; however, the immune response of adult asthma patients to pneumococcal vaccination is unknown. We explore the serologic response of patients with moderate to severe asthma to the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Methods Seventeen moderate to severe adult asthma patients that had not been vaccinated against pneumococcus over the 5 previous years were prospectively recruited from a tertiary care asthma clinic. Serum was analyzed for the presence of antibodies to five capsular polysaccharide (CP) antigens (6B, 9V, 19A, 19F, 23F) before and 4 weeks after PPSV23 vaccination. Results There was a wide variability in baseline anti-CP antibody concentrations. Other than for serotype 19A, our patients frequently have baseline anti-CP antibody concentrations below 1 µg/mL (35% for serotype 19F, 41% for serotypes 9V and 23F, and 59% for serotype 6B). All post-vaccination geometric mean antibody concentrations were significantly higher than baseline. In the 31 tests where the baseline antibody concentration was <1 µg/mL, 77.4% had at least a twofold increase post-vaccination. Despite this, a large proportion of post-vaccination anti-CP antibody concentrations remained <1 µg/mL (51.6% of tests). Nine patients had at least one anti-CP antibody concentration <1 µg/mL post-vaccination. There was no difference between these patients and the remaining eight patients in demographic or clinical variables. Conclusions Patients with moderate to severe asthma have variable baseline and low post-vaccination antibody concentrations to common CP antigens included in the PPSV23 vaccine. The clinical relevance of these observations remains to be determined since the threshold concentration in adults required for clinical protection from invasive pneumococcal disease is uncertain

Fas ligand (FasL, CD95L, APO-1L) expression in murine mast cells

Fas ligand (FasL, CD95L, Apo-1L), a type II membrane protein belonging to the tumour necrosis factor family, induces apoptosis in Fas-bearing cells. As murine mast cells have been shown to express Fas antigen, we hypothesized that mast cells might also express FasL. To explore this possibility, we first demonstrated FasL mRNA in mast cells by reverse transcription-polymerase chain reaction and FasL protein by immunoblot analysis. FasL protein was shown to be exclusively located within the cell by flow cytometry. In agreement with this observation, bone marrow cultured mast cells were unable to kill Jurkat T cells. Our results demonstrate that FasL is expressed in murine mast cells and suggest that this murine mast cell FasL is not lytic, owing to the intracellular localization