Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

Background

Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen.

Methods

27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins.

Results

mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season.

Conclusion

The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.     

In vivo intranasal anti-CD23 treatment inhibits allergic responses in a murine model of allergic rhinitis

Although CD23-dependent transcytosis of IgE and IgE-derived immune complexes across respiratory epithelial cells is likely to play a pivotal role in the initiation and development of airway allergic inflammation, there is currently a lack of physiological support for this phenomena to suggest that the targeting of CD23 could be used as a means of therapeutic intervention. The present study was designed to detect the CD23 expression in the nasal mucosa of allergic rhinitis (AR) murine model by immunohistochemistry and western blotting, and to investigate whether intranasal anti-CD23 treatment could inhibit allergen-induced upper airway inflammation in the AR model. This is the first report to show that CD23 was constitutively expressed in murine nasal epithelial cells, and its expression was significantly up-regulated in the AR murine model. In vivo, the up-regulation of CD23 expression was correlated with increased serum IL-4 levels. Following intranasal anti-CD23 treatment, nasal symptoms were alleviated and histopathologic examination showed a significant decrease in eosinophilic infiltration. Meanwhile, ELISA analysis showed levels of serum leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin (OVA)-specific IgE and IL-4 also significantly decreased, as were LTC4 and OVA-specific IgE in the nasal lavage fluid. Furthermore, Western blotting analysis showed that ECP expression in the nasal mucosa was down-regulated. Finally, flow cytometric analysis revealed anti-CD23 treatment inhibited Th2 cell responses. These results indicate that intranasal anti-CD23 treatment can reduce allergic responses in a murine model of allergic rhinitis.     

Ethyl pyruvate attenuates murine allergic rhinitis partly by decreasing high mobility group box 1 release

High-mobility group box 1 (HMGB1) protein, a pro-inflammatory DNA-binding protein, meditates inflammatory responses through Toll-like receptor-4 signals and amplifies allergic inflammation by interacting with the receptor for advanced glycation end products. Previous studies have shown that HMGB1 is elevated in the nasal lavage fluids (NLF) of children suffering from allergic rhinitis (AR) and is associated with the severity of this disease. Furthermore, HMGB1 has been implicated in the pathogenesis of lower airway allergic diseases, such as asthma. Ethyl pyruvate (EP) has proven to be an effective anti-inflammatory agent for numerous airway diseases. Moreover, EP can inhibit the secretion of HMGB1. However, few studies have examined the effect of EP on AR. We hypothesized that HMGB1 plays an important role in the pathogenesis of AR and studied it using an AR mouse model. Forty BALB/c mice were divided into four groups: the control group, AR group, 50 mg/kg EP group, and 100 mg/kg EP group. The mice in the AR and EP administration groups received ovalbumin (OVA) sensitization and challenge, whereas those in the control group were given sterile saline instead of OVA. The mice in the EP administration group were given an intraperitoneal injection of EP 30 min before each OVA treatment. The number of nasal rubbings and sneezes of each mouse was counted after final treatment. Hematoxylin–eosin staining, AB-PAS staining, interleukin-4 and 13 in NLF, IgE, and the protein expression of HMGB1 were measured. Various features of the allergic inflammation after OVA exposure, including airway eosinophilia, Th-2 cytokine production, total IgE, and goblet cell hyperplasia were significantly inhibited by treatment with EP and the expression and release of HMGB1 were reduced after EP administration in a dose-dependent manner. These results indicate that HMGB1 is a potential therapeutic target of AR and that EP attenuates AR by decreasing HMGB1 expression.     

Oral administration of Lactiplantibacillus plantarum NR16 isolated from Kimchi ameliorates murine allergic rhinitis

Allergic rhinitis (AR) is a type I hypersensitivity mediated by dominant T helper 2 (Th2) response over the Th1 response after re-exposure to a specific allergen. Currently, socio-economic cost evoked by AR is quickly increasing since the prevalence of AR is gradually increasing in all ages worldwide. Several probiotic Lactobacillus strains have been described with potential immunomodulatory effects against type I hypersensitivity such as AR. Thus, the aim of the present work was to characterize basic probiotic property and immunomodulatory role of newly isolated Lactobacillus strains from Kimchi, a traditional fermented Korean food, in AR. Among the identified strains, Lactiplantibacillus plantarum NR16 revealed to be a powerful Th1 inducer since immune cells co-cultured with NR16 produced the highest quantity of interferon-γ (IFN-γ) and interleukin-12 (IL-12) but secreted a low amount of IL-4 in vitro. Therefore, NR16 was selected for the following assays conducted with mice with birch pollen–induced AR. Oral administration of NR16 reduced airway hyperresponsiveness and leukocyte infiltration in lesions of mice. In conclusion, oral administration of NR16 may mitigate symptoms of AR by inducing Th1 immune response, which might rebalance Th2/Th1 ratio by decreasing Th2 cytokine production in specific lesions of mucosa.     

Essential role of the N-terminus of murine Orai1 in store-operated Ca2+ entry

Store-operated Ca(2+) entry (SOCE) is a physiologically important process that is triggered by intracellular Ca(2+) depletion. Recently, human Orai1 (the channel-forming subunit) and STIM1 (the calcium sensor) were identified as essential molecules for SOCE. Here, we report the cloning and functional analysis of three murine orthologs of Orai1, termed Orai1, 2, and 3. Among the genes identified, Orai1 contains a distinctive proline- and arginine-rich N-terminal cytoplasmic sequence. Co-expression of STIM1 with Orai1 produced a marked effect on SOCE, while co-expression with Orai2 or Orai3 had little effect. Expression of Orai1 without its N-terminal tail had a marginal effect on SOCE, while chimeric Orai2 containing the Orai1 N-terminus produced a marked increase in SOCE. In addition, a truncated version of Orai1 containing the N-terminus without the pore-forming transmembrane domain had a dominant negative effect on SOCE. These results reveal the essential role of Orai1 and its N-terminal sequence in SOCE.     

变应性鼻炎患者口咽部菌群分析

目的研究正常人与过敏性鼻炎患者口咽部菌群差异,探讨菌群定植的变化对过敏性鼻炎发生存在的影响。方法利用PCR-DGGE方法分析正常人与过敏性鼻炎患者口咽部菌群定植,并利用切胶测序分析DGGE图谱中两组样本之间的差异菌群。结果正常人与过敏性鼻炎患者口咽部菌群定植存在显著差异,与正常组相比,过敏性鼻炎患者口咽部菌群多样性显著增大,且类杆菌门的Prevotella pallens,厚壁菌门的Veillonella atypica、Veillonella parvula、Streptococcus salivarius,变形菌门的假单胞菌属Pseudomonas fluorescens的含量均高于正常人。结论过敏性鼻炎患者口咽部菌群多样性显著高于正常人,且以厚壁菌门和变形菌门的增加为特征。     

Escaping the trap of allergic rhinitis

Rhinitis is often the first symptom of allergy but is frequently ignored and classified as a nuisance condition. Ironically it has the greatest socioeconomic burden worldwide caused by its impact on work and on daily life.However, patients appear reticent to seek professional advice, visiting their doctor only when symptoms become ‘intolerable’ and often when their usual therapy proves ineffective.Clearly, it’s time for new and more effective allergic rhinitis treatments.MP29-02 (Dymista®; Meda, Solna, Sweden) is a new class of medication for moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or intranasal corticosteroids is not considered sufficient.MP29-02 is a novel formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP). It benefits not only from the incorporation of two active agents, but also from a novel formulation; its lower viscosity, smaller droplet size, larger volume (137 μl) and wider spray angle ensure optimal coverage of, and retention on the nasal mucosa and contribute to its clinical efficacy.In clinical trials, patients treated with MP29-02 experienced twice the symptom relief as those treated with FP and AZE, who in turn exhibited significantly greater symptom relief than placebo-patients. Indeed, the advantage of MP29-02 over FP was approximately the same as that shown for FP over placebo. The advantage of MP29-02 was particularly evident in those patients for whom nasal congestion is predominant, with MP29-02 providing three times the nasal congestion relief of FP (p = 0.0018) and five times the relief of AZE (p = 0.0001). Moreover, patients treated with MP29-02 achieved each and every response up to a week faster than those treated with FP or AZE alone and in real life 1 in 2 patients reported the perception of well-controlled disease after only 3 days. MP29-02’s superiority over FP was also apparent long-term in patients with perennial allergic rhinitis or non-allergic rhinitis, with statistical significance noted from the first day of treatment, with treatment difference maintained for a full year.Taken together, these data suggest that MP29-02 may improve the lives of many of our patients, enabling them to finally escape the allergic rhinitis trap.     

Nasal hyperreactivity and inflammation in allergic rhinitis

The history of allergic disease goes back to 1819, when Bostock described his own 'periodical affection of the eyes and chest', which he called 'summer catarrh'. Since they thought it was produced by the effluvium of new hay, this condition was also called hay fever. Later, in 1873, Blackley established that pollen played an important role in the causation of hay fever. Nowadays, the definition of allergy is 'An untoward physiologic event mediated by a variety of different immunologic reactions'. In this review, the term allergy will be restricted to the IgE-dependent reactions. The most important clinical manifestations of IgE-dependent reactions are allergic conjunctivitis, allergic rhinitis, allergic asthma and atopic dermatitis. However, this review will be restricted to allergic rhinitis. The histopathological features of allergic inflammation involve an increase in blood flow and vascular permeability, leading to plasma exudation and the formation of oedema. In addition, a cascade of events occurs which involves a variety of inflammatory cells. These inflammatory cells migrate under the influence of chemotactic agents to the site of injury and induce the process of repair. Several types of inflammatory cells have been implicated in the pathogenesis of allergic rhinitis. After specific or nonspecific stimuli, inflammatory mediators are generated from cells normally found in the nose, such as mast cells, antigen-presenting cells and epithelial cells (primary effector cells) and from cells recruited into the nose, such as basophils, eosinophils, lymphocytes, platelets and neutrophils (secondary effector cells). This review describes the identification of each of the inflammatory cells and their mediators which play a role in the perennial allergic processes in the nose of rhinitis patients.