Evidence for eosinophil and IL-17 mediated inflammation in allergic rhinitis.

Background: The aim was to determine the level of inflammatory cytokines, eosinophil cationic protein and IgE in allergic rhinitis (AR) patients. Subjects and methods: Blood samples were taken from 88 AR patients and 88 healthy controls (HC). Each sample was analysed for eosinophil counts by flow cytometry, IgE by ECLIA, ECP, IL-17, and IL-33 by using ELISA test. Results: There was no significant difference between AR patients and the control group in age and gender. Levels of eosinophils, IgE, ECP, IL-17, IL-33 and the total symptom scores were significantly higher in AR patients than the HC (P = 0.0001). Serum ECP correlated with IL-17 (P = 0.041, r = 0.42), IL-33 (P = 0.0001, r = 080), and IgE levels (P = 0.017, r = 0.45) in the R patients. There was no correlation between IL-17 and IL-33. There was a correlation between symptom scores and eosinophils (P = 0.026, r = 0.52), and IgE (P = 0.001, r = 0.60) in the patients. No correlation was observed between symptom scores and ECP, IL-17, and IL-33 in the AR patient. Conclusions: Patients with AR have significant higher serum levels of ECP, IL-17, and IL-33 than healthy controls. This indicates that these markers could be used to in order to diagnose AR and to monitor disease. Inhibitory molecules to IL-17 and IL-33 may be considered as novel treatment strategies

Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.

Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses

Motor unit potential morphology differences in individuals with non-specific arm pain and lateral epicondylitis

<p>Abstract</p> <p>Background</p> <p>The pathophysiology of non-specific arm pain (NSAP) is unclear and the diagnosis is made by excluding other specific upper limb pathologies, such as lateral epicondylitis or cervical radiculopathy. The purpose of this study was to determine: (i) if the quantitative parameters related to motor unit potential morphology and/or motor unit firing patterns derived from electromyographic (EMG) signals detected from an affected muscle of patients with NSAP are different from those detected in the same muscle of individuals with lateral epicondylitis (LE) and/or control subjects and (ii) if the quantitative EMG parameters suggest that the underlying pathophysiology in NSAP is either myopathic or neuropathic in nature.</p> <p>Methods</p> <p>Sixteen subjects with NSAP, 11 subjects with LE, eight subjects deemed to be at-risk for developing a repetitive strain injury, and 37 control subjects participated. A quantitative electromyography evaluation was completed using decomposition-based quantitative electromyography (DQEMG). Needle- and surface-detected EMG signals were collected during low-level isometric contractions of the extensor carpi radialis brevis (ECRB) muscle. DQEMG was used to extract needle-detected motor unit potential trains (MUPTs), and needle-detected motor unit potential (MUP) and surface detected motor unit potential (SMUP) morphology and motor unit (MU) firing rates were compared among the four groups using one-way analysis of variance (ANOVA). Post hoc analyses were performed using Tukey's pairwise comparisons.</p> <p>Results</p> <p>Significant group differences were found for all MUP variables and for MU firing rate (<it>p</it> < 0.006). The post-hoc analyses revealed that patients with NSAP had smaller MUP amplitude and SMUP amplitude and area compared to the control and LE groups (<it>p </it>< 0.006). MUP duration and AAR values were significantly larger in the NSAP, LE and at-risk groups compared to the control group (<it>p </it>< 0.006); while MUP amplitude, duration and AAR values were smaller in the NSAP compared to the LE group. SMUP duration was significantly shorter in the NSAP group compared to the control group (<it>p </it>< 0.006). NSAP, LE and at-risk subjects had lower mean MU firing rates than the control subjects (<it>p </it>< 0.006).</p> <p>Conclusion</p> <p>The size-related parameters suggest that the NSAP group had significantly smaller MUPs and SMUPs than the control and LE subjects. Smaller MUPs and SMUPs may be indicative of muscle fiber atrophy and/or loss. A prospective study is needed to confirm any causal relationship between smaller MUPs and SMUPs and NSAP as found in this work.</p

NMR Studies of the C-Terminus of alpha4 Reveal Possible Mechanism of Its Interaction with MID1 and Protein Phosphatase 2A

Alpha4 is a regulatory subunit of the protein phosphatase family of enzymes and plays an essential role in regulating the catalytic subunit of PP2A (PP2Ac) within the rapamycin-sensitive signaling pathway. Alpha4 also interacts with MID1, a microtubule-associated ubiquitin E3 ligase that appears to regulate the function of PP2A. The C-terminal region of alpha4 plays a key role in the binding interaction of PP2Ac and MID1. Here we report on the solution structure of a 45-amino acid region derived from the C-terminus of alpha4 (alpha45) that binds tightly to MID1. In aqueous solution, alpha45 has properties of an intrinsically unstructured peptide although chemical shift index and dihedral angle estimation based on chemical shifts of backbone atoms indicate the presence of a transient α-helix. Alpha45 adopts a helix-turn-helix HEAT-like structure in 1% SDS micelles, which may mimic a negatively charged surface for which alpha45 could bind. Alpha45 binds tightly to the Bbox1 domain of MID1 in aqueous solution and adopts a structure consistent with the helix-turn-helix structure observed in 1% SDS. The structure of alpha45 reveals two distinct surfaces, one that can interact with a negatively charged surface, which is present on PP2A, and one that interacts with the Bbox1 domain of MID1

Analysing the eosinophil cationic protein - a clue to the function of the eosinophil granulocyte

Eosinophil granulocytes reside in respiratory mucosa including lungs, in the gastro-intestinal tract, and in lymphocyte associated organs, the thymus, lymph nodes and the spleen. In parasitic infections, atopic diseases such as atopic dermatitis and asthma, the numbers of the circulating eosinophils are frequently elevated. In conditions such as Hypereosinophilic Syndrome (HES) circulating eosinophil levels are even further raised. Although, eosinophils were identified more than hundred years ago, their roles in homeostasis and in disease still remain unclear. The most prominent feature of the eosinophils are their large secondary granules, each containing four basic proteins, the best known being the eosinophil cationic protein (ECP). This protein has been developed as a marker for eosinophilic disease and quantified in biological fluids including serum, bronchoalveolar lavage and nasal secretions. Elevated ECP levels are found in T helper lymphocyte type 2 (atopic) diseases such as allergic asthma and allergic rhinitis but also occasionally in other diseases such as bacterial sinusitis. ECP is a ribonuclease which has been attributed with cytotoxic, neurotoxic, fibrosis promoting and immune-regulatory functions. ECP regulates mucosal and immune cells and may directly act against helminth, bacterial and viral infections. The levels of ECP measured in disease in combination with the catalogue of known functions of the protein and its polymorphisms presented here will build a foundation for further speculations of the role of ECP, and ultimately the role of the eosinophil

The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis

A gluten-free diet (GFD) is currently the only available therapy for coeliac disease (CD)