The dual aspects of IgD in the development of tolerance and the pathogenesis of allergic diseases

The cell-surface form of IgD is co-expressed with IgM on mature, naïve B cells as B-cell receptors. The secreted IgD antibody (Ab) is found in relatively modest concentrations in the blood and other body fluids as it has a relatively short serum half-life. IgD Abs produced in the upper-respiratory mucosa presumably participate in host defense against pathogens. The allergen-mediated cross-linkage of basophil-bound IgD Ab enhances type 2 cytokine secretion; IgD Ab may also interfere with IgE-mediated basophil degranulation, suggesting dual and opposing roles of IgD Ab in allergen sensitization and the development of allergen immune tolerance. We recently demonstrated that children with egg allergies who avoided all forms of egg have lower ovomucoid-specific IgD and IgG₄ Ab levels than those who only partially avoided egg products and that different mechanisms may regulate allergen-specific IgD Ab production compared to allergen-specific IgG₄ Ab production. The relationship between antigen-specific IgD Ab levels and the clinical improvement of asthma and food allergies suggests that antigen-specific IgD Ab affects the process of outgrowing allergies. We discuss the possibility that allergen-specific IgD Ab production reflects low-affinity, allergen-specific IgE production as children outgrow a food allergy.     

Gut microbiota and allergic diseases in children

The gut microbiota resides in the human gastrointestinal tract, where it plays an important role in maintaining host health. The human gut microbiota is established by the age of 3 years. Studies have revealed that an imbalance in the gut microbiota, termed dysbiosis, occurs due to factors such as cesarean delivery and antibiotic use before the age of 3 years and that dysbiosis is associated with a higher risk of future onset of allergic diseases. Recent advancements in next-generation sequencing methods have revealed the presence of dysbiosis in patients with allergic diseases, which increases attention on the relationship between dysbiosis and the development of allergic diseases. However, there is no unified perspective on the characteristics on dysbiosis or the mechanistic link between dysbiosis and the onset of allergic diseases. Here, we introduce the latest studies on the gut microbiota in children with allergic diseases and present the hypothesis that dysbiosis characterized by fewer butyric acid-producing bacteria leads to fewer regulatory T cells, resulting in allergic disease. Further studies on correcting dysbiosis for the prevention and treatment of allergic diseases are warranted.     

IL-24: A new player in the pathogenesis of pro-inflammatory and allergic skin diseases

Interleukin (IL)-24 is a member of the IL-20 family of cytokines and is produced by various types of cells, such as CD4⁺ T cells, NK cells, mast cells, keratinocytes, bronchial epithelial cells, and myofibroblasts. Previous studies suggest that IL-24 plays an essential role in the pathogenesis of pro-inflammatory autoimmune disorders such as psoriasis, arthritis, and inflammatory bowel diseases. However, the role of IL-24 in the pathogenesis of allergic diseases has been elusive. It has already been reported that IL-24 is involved in the pathogenesis of allergic lung and skin diseases. Moreover, we have recently revealed for the first time the pivotal functions of IL-24 in IL-13–mediated skin barrier dysfunction in atopic dermatitis (AD), which is known to be a characteristic of AD caused by Th2 cytokines such as IL-4 or IL-13. In this review, we show recent advances in the basic characteristics of IL-24 and its novel functions in the pathogenesis of allergic skin inflammation, focusing on AD. A better understanding of the role of IL-24 in allergic diseases can lead to the development of new therapeutic options.     

Decreased intracellular histamine concentration and basophil activation in anaphylaxis

BackgroundHistamine is a crucial mediator in the development of anaphylaxis. Although histamine is promptly degraded because of its short half-life in plasma, basophils, which release histamine, remain in the blood for days. To explore basophils as a potential marker and their involvement in the pathogenesis of anaphylaxis, we evaluated the intracellular histamine concentration and the degree of basophil activation in anaphylaxis patients.MethodsWe conducted a case–control study enrolling anaphylaxis patients and healthy controls. Basophil activation was evaluated by flow cytometry using up-regulation of CD203c expression.ResultsWe enrolled 23 patients and measured their blood histamine concentration. Basophil activation was analyzed in seven of 23 patients. The median intracellular histamine concentrations at admission were significantly lower in patients compared with controls (16.4 ng/mL [interquartile range {IQR}, 2.70 to 34.0] vs. 62.3 ng/mL [IQR, 46.0 to 85.1]; p < 0.0001). The median basophil number at admission was also significantly lower in patients compared with controls (2.21 cell/μL [IQR, 0.75 to 12.3] vs. 21.0 cell/μL [IQR, 19.5 to 28.9]; p = 0.027). CD203c expression was not up-regulated in any of the seven patients in vitro, but it was up-regulated in response to anti-IgE stimulation in vitro in two patients at admission and four patients at follow-up.ConclusionsAnaphylaxis is associated with a decrease in intracellular histamine, and a reduced number and reactivity of peripheral basophils. Impaired basophil function and a decrease in their number and intracellular histamine levels in the circulation may reflect the underlying mechanism, suggesting that basophils may be a marker of anaphylaxis.     

Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye

Biologics applying antibodies against IgE, IL-5, IL-5 receptor α, IL-4 receptor α, and IL-13 have dramatically improved recent treatment outcomes in allergic diseases including asthma, rhinitis, and atopic dermatitis. However, these drugs have not been approved for ocular allergic diseases such as allergic conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. Although the putative mechanisms suggest that these drugs should have beneficial effects in patients with ocular allergies and some studies have reported such beneficial effects, various adverse ocular symptoms have also been observed in clinical trials and off-label use studies. Since ocular allergic diseases have distinct pathogeneses, each biologic drug must be examined regarding specific effects on each ocular allergy. For example, IgE-mediated type 1 hypersensitivity plays a critical role in allergic conjunctivitis. By contrast, T cells and eosinophilic and non-IgE-mediated type 2 inflammation play important roles in vernal keratoconjunctivitis. Allergists must fully understand the effects of each drug on the eye. This review outlines both potential therapeutic and adverse effects of various biologics on allergic diseases of the eye.     

Cysteinyl leukotriene metabolism of human eosinophils in allergic disease

Eosinophils are multifaceted immune cells with diverse functions that enhance allergic inflammation. Cysteinyl leukotrienes (cys-LTs), mainly synthesized in eosinophils, are a class of inflammatory lipid mediators produced via multiple enzymatic reactions from arachidonic acid. Multiple clinical studies have reported dysregulated fatty acid metabolism in severe asthma and aspirin-exacerbated respiratory diseases. Therefore, understanding the mechanism responsible for this metabolic abnormality has attracted a lot of attention. In eosinophils, various stimuli (including cytokines, chemokines, and pathogen-derived factors) prime and/or induce leukotriene generation and secretion. Cell–cell interactions with component cells (endothelial cells, epithelial cells, fibroblasts) also enhance this machinery to augment allergic responses. Nasal polyp-derived eosinophils from patients with eosinophilic rhinosinusitis present a characteristic fatty acid metabolism with selectively higher production of leukotriene D₄. Interestingly, type 2 cytokines and microbiome components might be responsible for this metabolic change with altered enzyme expression. Here, we review the regulation of fatty acid metabolism, especially cys-LT metabolism, in human eosinophils toward allergic inflammatory status.     

Evaluation of magnesium oxide and zinc oxide nanoparticles against multi-drug-resistance Mycobacterium tuberculosis

ObjectiveThe current study has evaluated the MICs and MBCs of ZnONPs, MgONPs, and MgONPs-ZnONPs against H₃₇Rv Mtb and MDR-Mtb.MethodsMixture, magnesium oxide nanoparticles (NPs) and zinc oxide (MgONPs-ZnONPs) were prepared. The microplate alamar blue (MABA) assay and the proportion method were used to evaluate of anti-tubercular activity against MDR-MTB. MTT test was done to MgONPs-ZnONPs against Vero and HepG₂ cell lines.ResultsThe MIC of MgONPs and ZnONPs were 0.195 and 0.468 μg mL^?1 against 10⁴ of H₃₇Rv Mtb. As well, 0.166 μg mL^?1 of MgONPs-ZnONPs was able to inhibit 10^?4 H₃₇Rv Mtb. The MIC of MgONPs against 10⁴ concentrations of MDR-Mtb was 12.5 μg mL^?1. The MIC of MgONPs/ZnONPs against 10⁴ concentrations of MDR-Mtb reached to 0.664 μg mL^?1. The MBC value of ZnONPs increased to 1.875 μg mL^?1 against 10^?4 concentrations of MDR-Mtb. Testing showed that the MBCs of MgONPs/ZnONPs reached to 1.328 μg mL^?1 against 10⁴ concentrations of MDR-Mtb. The IC₅₀ against MDR-TB was 0.779 μg mL^?1 for ZnONPs and 0.883 μg mL^?1 for MgONPs-ZnONPs. The MgONPs-ZnONPs was not toxic to Vero cell lines however ZnONPs could inhibit the Vero and HepG₂ cell lines.ConclusionWe found that ZnONPs and mixture MgONPs-ZnONPs not only have higher bactericide behavior but might have also synergistic effects against MDR-TB.     

J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with MAFLD

Background and aimsZinc is an essential trace element that plays an important role in maintaining health, and affecting gene expression, signal transduction and regulation of apoptosis. It is uncertain whether serum zinc levels are altered in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). We aimed to investigate the association between serum zinc levels and the severity of hepatic necro-inflammation (HN) in patients with MAFLD.Methods and resultsLiver disease severity was graded histologically using the NAFLD activity score. HN was defined as the sum of ballooning and lobular inflammation. We used a smooth function regression model to analyze the relationship between serum zinc levels and HN. A total of 561 (76.5% men) patients with biopsy-confirmed MAFLD were enrolled. They had a mean age of 41.3 years, and a mean serum zinc level of 17.0 ± 4.1 μmol/L. Compared to those with mild hepatic necro-inflammation (MHN, grades 0–2; n = 286), patients with severe hepatic necro-inflammation (SHN, grades 3–5; n = 275) had lower serum zinc concentrations (16.3 ± 4.2 vs. 17.6 ± 4.0 μmol/L; p < 0.001). However, a threshold saturation effect analysis showed that there was an inflection in serum zinc levels at 24 μmol/L. After adjustment for potential confounders, serum zinc levels <24 μmol/L were inversely associated with SHN (adjusted-odds ratio 0.88, 95%CI 0.83–0.93; p < 0.001), whereas serum zinc levels >24 μmol/L were positively associated with SHN (adjusted-odds ratio 1.42, 95%CI: 1.03–1.97; p = 0.035).ConclusionsThere is a J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with biopsy-proven MAFLD.     

Diversities of allergic pathologies and their modifiers: Report from the second DGAKI-JSA meeting

In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host–pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.     

Role of serum periostin in the management of asthma and its comorbidities

Type-2 airway inflammation is a major characteristic of asthma. Assessing its degree of severity is, therefore, essential in asthma management. Periostin, a matricellular protein belonging to the fasciclin family, is a key molecule linking type-2 airway inflammation and airway remodeling. Fortunately, periostin can be detected in the blood and used to provide sustaining airway information on type-2 inflammation and remodeling. Serum periostin is elevated in the eosinophilic/type 2 subtype of severe asthma, and its levels remain relatively stable and reflect genetic backgrounds. This suggests that serum periostin may serve as a marker of geno-endophenotype with type-2 airway inflammation and thus could be a predictive marker of the long-term prognosis of asthma under treatment. As expected, serum periostin is particularly elevated in comorbidities associated with the eosinophilic/type 2 subtype of severe asthma, including eosinophilic chronic rhinosinusitis, aspirin-exacerbated respiratory diseases, allergic bronchopulmonary aspergillosis, and eosinophilic granulomatosis with polyangiitis. Conversely, serum periostin levels are relatively lower in the overweight/obese. Serum periostin measurements may help to significantly improve the management of patients with severe asthma.     

Perspective on the clone library method for infectious diseases

Recently, culture-independent molecular methods, such as DNA sequencing techniques targeting the 16S-ribosomal RNA (rRNA) gene and/or other housekeeping genes with Sanger method-based technologies, next generation sequencing (NGS), and metagenomic analysis, have been developed for detecting microorganisms in the human body; these can provide information on microbiomes of samples from individuals with or without infectious diseases. Determining the bacterial species is crucial in identifying causative bacteria of upper and lower respiratory tract infections, especially for Streptococcus species, but NGS analysis is often not precise enough to identify bacteria at the species level. This review briefly introduces previous observations of the microbiome of samples from various respiratory and other infections assessed using the clone library method with Sanger sequencing of the 16S-rRNA gene. On analysis of 16S-rRNA gene-sequence data of bronchoalveolar lavage fluid obtained from pneumonia lesions in patients with bacterial pneumonia and lung abscess, anaerobes are often detected in non-elderly patients with pneumonia, and the detection rate of Staphylococcus aureus in patients with hospital-acquired pneumonia is lower than that previously reported. Analysis of pleural effusion samples from patients with pleurisy indicated a more important role of anaerobes than previous believed. The other topics reviewed include microbiomes of nontuberculous mycobacteriosis and lower respiratory tract infections in children with permanent tracheostomy due to neuromuscular disorders, in nasal discharge, in bacterial vaginosis, in the intracystic fluid of postoperative maxillary cyst, and in bacterial conjunctivitis; urine microbiota in urethritis; fecal microbiota; and newly detected infectious organisms in the human respiratory tract.     

The Role of Invasive Hemodynamics in Guiding Contemporary Transcatheter Valvular Interventions

Recent advances in transcatheter interventions have refueled the interest in utilizing invasive hemodynamics in the catheterization laboratory. The authors review contemporary invasive techniques used to confirm valve disease and guide transcatheter valve interventions. They also discuss the available data and the remaining questions on the role of invasive hemodynamics in current practice and in the future.     

Protective Role of Tacrolimus,Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study

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Molecular mechanism of asthma and its novel molecular target therapeutic agent

Asthma is a chronic disease with major public health ramifications owing to its high morbidity and mortality rates, especially in severe and recurrent cases. Conventional therapeutic options could partially alleviate the burden of asthma, yet a novel approach is needed to completely control this condition. To do so, a comprehensive understanding of the molecular mechanism underlying asthma is essential to recognize and treat the major pathways that drive its pathophysiology. In this review, we will discuss the molecular mechanism of asthma, in particular focusing on the type of inflammatory responses it elicits, namely type 2 and non-type 2 asthma. Furthermore, we will discuss the novel therapeutic options that target the aberrant molecules found in asthma pathophysiology. We will specifically focus on the role of novel monoclonal antibody therapies recently developed, such as the anti-IgE, IL-5, IL-5Rα, and IL-4Rα antibodies, drugs that have been extensively studied preclinically and clinically.     

Identification of the major allergenic proteins from silkworm moth (Bombyx mori) involved in respiratory allergic diseases

Introduction and ObjectivesMoths are a significant source of indoor and outdoor aeroallergens. High prevalence of IgE-mediated sensitization was demonstrated in a group of patients with allergic respiratory diseases. There are no studies on adult stage of these moth species allergens involved in allergic respiratory reactions - the aim of this study.Material and Methods36 participants were included in an experimental study, submitted to skin prick test with Bombyx mori wing extract and six other common allergens, as well as Western blot analysis with incubated nitrocellulose membrane impregnated with silkworm moth extract and human IgE-antibody. The participants were divided into 3 groups: 1) 21 allergic patients whose skin prick test was positive to Bombyx mori wing extract, 2) eight allergic patients whose skin prick test was positive to mite and negative to Bombyx mori extract 3) seven negative non-allergic subjects.ResultsAmong the 21 participants from group 1, 19 serum samples reacted to Bombyx mori extract by Western blot. All of them reacted to a protein at 80 kDa and five other proteins (66, 50, 45, 37 and 30 kDa) were identified in more than 50% of the individuals tested, considered as major allergenic proteins. Sera from seven out of eight patients sensitized to house dust mite demonstrated IgE-reactivity to Bombyx mori extract by Western blot analysis. Serum samples from healthy participants did not react at all.ConclusionSix major reactive proteins by immunoblot analysis from moth’s wings sensitized patients can be potential allergens. The one at 80 kDa is the major protein, seen in all IgE-reactive patients from group 1 and in none from group 2, yet to be identified. Future studies should be conducted to better characterize these proteins.