Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by FcεRIβ and the Potential Impact of FcεRIβ Splicing in Allergic Inflammation

Mast cells are tissue-resident immune cells that function in both innate and adaptive immunity through the release of both preformed granule-stored mediators, and newly generated proinflammatory mediators that contribute to the generation of both the early and late phases of the allergic inflammatory response. Although mast cells can be activated by a vast array of mediators to contribute to homeostasis and pathophysiology in diverse settings and contexts, in this review, we will focus on the canonical setting of IgE-mediated activation and allergic inflammation. IgE-dependent activation of mast cells occurs through the high affinity IgE receptor, FcεRI, which is a multimeric receptor complex that, once crosslinked by antigen, triggers a cascade of signaling to generate a robust response in mast cells. Here, we discuss FcεRI structure and function, and describe established and emerging roles of the β subunit of FcεRI (FcεRIβ) in regulating mast cell function and FcεRI trafficking and signaling. We discuss current approaches to target IgE and FcεRI signaling and emerging approaches that could target FcεRIβ specifically. We examine how alternative splicing of FcεRIβ alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting FcεRI directly and/or IgE binding to FcεRI are promising approaches to therapeutics for allergic inflammation. The characteristic role of FcεRIβ in both trafficking and signaling of the FcεRI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes FcεRIβ an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.

Precision Medicine and Childhood Asthma: A Guide for the Unwary

Many thousands of articles relating to asthma appear in medical and scientific journals each year, yet there is still no consensus as to how the condition should be defined. Some argue that the condition does not exist as an entity and that the term should be discarded. The key feature that distinguishes it from other respiratory diseases is that airway smooth muscles, which normally vary little in length, have lost their stable configuration and shorten excessively in response to a wide range of stimuli. The lungs’ and airways’ limited repertoire of responses results in patients with very different pathologies experiencing very similar symptoms and signs. In the absence of objective verification of airway smooth muscle (ASM) lability, over and underdiagnosis are all too common. Allergic inflammation can exacerbate symptoms but given that worldwide most asthmatics are not atopic, these are two discrete conditions. Comorbidities are common and are often responsible for symptoms attributed to asthma. Common amongst these are a chronic bacterial dysbiosis and dysfunctional breathing. For progress to be made in areas of therapy, diagnosis, monitoring and prevention, it is essential that a diagnosis of asthma is confirmed by objective tests and that all co-morbidities are accurately detailed.

Abatacept (Cytotoxic T Lymphocyte Antigen 4-Fragment Crystallizable) Reduces Allergic Inflammation of Ovalbumin-Sensitized Mice.

Background Abatacept (Aba) is a cytotoxic T-lymphocyte antigen-4 and fragment crystallizable fusion protein. Aba blocks B7/Cluster of differentiation 28 - cytotoxic T-lymphocyte antigen-4 costimulatory pathway, inhibits cluster of differentiation 4+ T-cell activation, and is used as an anti-inflammatory drug. Objectives We conducted this study to assess the effectiveness of Aba in the treatment of allergic rhinitis (AR) in a mouse model. Methods We divided 40 four-week-old BALB/c mice into four groups: control group ( n = 10), positive control group (AR, n = 10), Aba group (AR + Aba, n = 10), and dexamethasone group (AR + Dex, n = 10). Mice in each group were challenged intranasally with daily ovalbumin (OVA) administration. Episodes of sneezing and nose rubbing were counted. Mice were sacrificed on day 42 and cytokines were measured in nasal lavage fluid. Nasal mucosae of five mice from each group were used for reverse transcriptase-polymerase chain reaction and western blot assay. Samples were collected from five mice from each group for histological analysis. Results Symptoms of AR significantly improved in the AR + Aba and AR + Dex groups compared with the AR group. Fewer eosinophils and goblet cells were seen in the AR + Aba and AR + Dex groups compared with the AR group. Both the AR + Aba and AR + Dex groups showed a significant decrease in nasal T helper 2 cytokine levels, including interleukin (IL)-4, IL-5, IL-13 and T cell activation related IL-17A, and interferon gamma (IFN- γ). Total immunoglobulin (Ig) E and OVA-specific IgG1 levels were also significantly lower in the AR + Aba and AR + Dex groups. OVA-specific IgE level was also significantly lower in the AR + Aba than AR group. Conclusions Aba suppresses allergic inflammation and appears to be a good treatment for AR.

IL-10 AND IL-35 AS INFLAMMATION REGULATORS IN PATIENTS WITH ALLERGIC RHINITIS AND MILD ATOPIC ASTHMA

Background. Significantly less is known about the immunoregulative cytokines, especially in allergic airway disease. This study aims to present the involvement of IL-35 and IL-10 in patients with allergic rhinitis (AR) and allergic bronchial asthma (BA). Methodology. The study comprised 71 patients –AR, patients with concomitant AR and mild atopic BA, and healthy controls (HC). We examined the serum levels of IL-35 and IL-10, along with other instrumental examinations, between March and September 2021. Findings. Levels of the regulatory cytokines IL-35 and IL-10 were significantly lower in patients than in HC (87.19±11.90 vs. 96.12±1.79 pg/ml; and 30.26±17.55 vs. 111.56±65.03 pg/ml, respectively). Furthermore, threefold higher serum IL-10 levels were found in healthy subjects compared to patients (p = 0.006). No difference in the levels of interleukins was found between the studied groups. Conclusions. Our results indicate that elevated IL-35 and IL-10 may play an essential role in reducing the activity of underlying allergic inflammation in allergic respiratory diseases, although no difference in the levels of the studied cytokines was found between the different groups of patients. Therefore, we can speculate that the immunosuppressive cytokines IL-35 and IL-10 were involved in maintaining the healthy state of no inflammation.

Synaptic transmission molecules and their role in the pathogenesis of allergic rhinitis

Immune cells and molecules, as well as synaptic transmission molecules play a regulatory role in the communication pathways of the entire body when it is necessary to engage all body resources in the fight against infections or tumor cells wherever they appear. In potential allergy, the neuroimmune network controls allergen tolerance maintenance at both local and systemic levels.The review focuses on different neurotransmitters and our understanding of a balance and imbalance between the immune system and the nervous system in allergic inflammation, including allergic rhinitis. However, the pathogenesis of the two endotypes of rhinitis (conventional allergic rhinitis and local allergic rhinitis) and the impact of the neuroimmune network on it remain unresolved.

MIR-181A-5P Attenuates Ovalbumin-Induced Allergic Inflammation in Nasal Epithelial Cells by Targeting IL-33/P38 MAPK Pathway

Purpose: Chronic inflammation of the nasal mucosal tissues plays an important role in the pathogenesis of allergic rhinitis (AR). Aberrantly-expressed micro ribonucleic acid (miRNA) has been found to have strong associations with the inflammatory reactions in allergic diseases; however, its functional significance and molecular mechanism in AR remains unclear. The purpose of this study is to determine the functional role and mechanism of miR-181a-5p in AR. Methods: Allergic inflammatory reaction was induced by ovalbumin in human nasal epithelial cell line RPMI2650. The anti-inflammatory effects of miR-181a-5p were evaluated by examining pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α)) in the culture of RPMI-2650 cells stimulated by ovalbumin, using quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Luciferase assay and gain-of-function assay were used to investigate the association of miR-181a-5p and IL-33/p38 MAPK axis. Results: MiR-181a-5p was significantly downregulated in mucosal tissues of AR patients and in RPMI-2650 cells treated with ovalbumin. The overexpression of miR-181a-5p showed prominent suppression of inflammatory cytokine production in RPMI-2650 cells with the stimulation of ovalbumin. MiR-181a-5p directly targeted, and negatively regulated IL-33 to suppress the activation of p38 MAPK signalling. Conclusion: The results suggest that miR-181a-5p restricted allergic inflammation through inhibition of IL-33/p38 MAPK pathway, indicating miR-181a-5p may play an anti-inflammatory role in AR.

IL-33, an Alarmin of the IL-1 Family Involved in Allergic and Non Allergic Inflammation: Focus on the Mechanisms of Regulation of Its Activity

Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among others. It functions as an alarm signal that is released upon tissue or cellular injury. IL-33 plays a central role in the initiation and amplification of type 2 innate immune responses and allergic inflammation by activating various target cells expressing its ST2 receptor, including mast cells and type 2 innate lymphoid cells. Depending on the tissue environment, IL-33 plays a wide variety of roles in parasitic and viral host defense, tissue repair and homeostasis. IL-33 has evolved a variety of sophisticated regulatory mechanisms to control its activity, including nuclear sequestration and proteolytic processing. It is involved in many diseases, including allergic, inflammatory and infectious diseases, and is a promising therapeutic target for the treatment of severe asthma. In this review, I will summarize the literature around this fascinating pleiotropic cytokine. In the first part, I will describe the basics of IL-33, from the discovery of interleukin-33 to its function, including its expression, release and signaling pathway. The second part will be devoted to the regulation of IL-33 protein leading to its activation or inactivation.

Morphfological changes in the membranes of the trachea of guinea pigs in experimental ovalbumin-induced allergic inflammation of the airways.

Background. In recent years, there has been an increase in the number of allergic diseases of the respiratory organs, especially in children. The predictor of the further development of bronchial asthma is sensitizing at an early age to the allergens of chicken egg. The use of new knowledge about the allergenic components of the chicken egg will predict the risks and clinical features of the disease. Despite the importance, the problem of morphogenesis of allergic inflammation of the wall of the trachea is not sufficiently studied, so far many issues are not found in morphology and require further research. Objective.The aim of the study is to establish morphological changes in the tracheal membranes in experimental ovalbumin-induced allergic inflammation of the airways of guinea pigs. Methods. The thickness of tracheal wall of 48 male guinea pigs was investigated by histological, morphometric, statistical methods on the twenty-third, thirty-sixth, thirty-sixth and forty-fourth days after the initiation of the experimental ovalbumin-induced allergic inflammation of the airways. Results. We have found, that maximum statistically significant thickening is shown in the late period of tracheal mucosa in 2 times on the 44th day of observation and tracheal submucosa in the 3rd experimental group on the 36th day of observation (increasing coefficient 2) compared to the control. However, the thinning of tracheal submucosa is observed in the early period of the inflammatory process on the 23rd and 30th day of observation. It has been proved, that the allergic inflammation of the tissues of the trachea caused by the sensitization and allergization of ovalbumin leads to the change in the thickness of layers of trachea in the chronobiological aspect. Conclusion. On the 23rd and 30th days of the experiment, thinning of tracheal mucosais observed due to damage of epithelial cells. Thickening of tracheal mucosa and submucosa was found in the third and fourth groups of observation (late period of allergic inflammation) compared with animals of the intact group and the control group due to an increase in the area of loose connective tissue, which is a consequence of the continuation of the allergic inflammatory process in the trachea after the end of the experiment.