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Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.

Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence’s contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure.

To develop a machine learning (ML) model that predicts disease groups or autoantibodies in patients with idiopathic inflammatory myopathies (IIMs) using muscle MRI radiomics features. Twenty-two patients with dermatomyositis (DM), 14 with amyopathic dermatomyositis (ADM), 19 with polymyositis (PM) and 19 with non-IIM were enrolled. Using 2D manual segmentation, 93 original features as well as 93 local binary pattern (LBP) features were extracted from MRI (short-tau inversion recovery [STIR] imaging) of proximal limb muscles. To construct and compare ML models that predict disease groups using each set of features, dimensional reductions were performed using a reproducibility analysis by inter-reader and intra-reader correlation coefficients, collinearity analysis, and the sequential feature selection (SFS) algorithm. Models were created using the linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machine (SVM), k-nearest neighbors (k-NN), random forest (RF) and multi-layer perceptron (MLP) classifiers, and validated using tenfold cross-validation repeated 100 times. We also investigated whether it was possible to construct models predicting autoantibody status. Our ML-based MRI radiomics models showed the potential to distinguish between PM, DM, and ADM. Models using LBP features provided better results, with macro-average AUC values of 0.767 and 0.714, accuracy of 61.2 and 61.4%, and macro-average recall of 61.9 and 59.8%, in the LDA and k-NN classifiers, respectively. In contrast, the accuracies of radiomics models distinguishing between non-IIM and IIM disease groups were low. A subgroup analysis showed that classification models for anti-Jo-1 and anti-ARS antibodies provided AUC values of 0.646–0.853 and 0.692–0.792, with accuracy of 71.5–81.0 and 65.8–78.3%, respectively. ML-based TA of muscle MRI may be used to predict disease groups or the autoantibody status in patients with IIM and is useful in non-invasive assessments of disease mechanisms.

Eosinophilic pneumonia (EP), including acute EP and chronic EP, is characterized by the massive pulmonary infiltration of eosinophils into the lung. However, the mechanisms underlying the selective accumulation of eosinophils in EP have not yet been fully elucidated. We reported that bronchoalveolar lavage fluid (BALF) from EP patients induced the transmigration of eosinophils across endothelial cells in vitro. The concentrations of eotaxin-2 (CCL24) and monocyte chemotactic protein (MCP)-4 (CCL13), which are CC chemokine receptor (CCR) 3 ligands, were elevated in the BALF of EP patients, and anti-CCR3 monoclonal antibody inhibited the eosinophil transmigration induced by the BALF of EP patients. The concentration of macrophage inflammatory protein 1β (CCL4), a CCR5 ligand that induces eosinophil migration, was increased in the BALF of EP patients. Furthermore, the concentration of interleukin (IL) 5 was increased in the BALF of EP patients, and it has been reported that anti-IL-5 antibody treatment resulted in remission and the reduction of glucocorticoid use in some cases of chronic EP. The concentrations of lipid mediators, such as leukotriene (LT) B4, damage-associated molecular pattern molecules (DAMPs), such as uric acid, or extracellular matrix proteins, such as periostin, were also increased in the BALF of EP patients. These findings suggest that chemokines, such as CCR3/CCR5 ligands, cytokines, such as IL-5, lipid mediators, such as LTB4, DAMPs, and extracellular matrix proteins may play roles in the accumulation or activation of eosinophils in EP.

Neutrophils may play an important role in the pathogenesis of severe asthma. Their infiltration into the airway is increased. Interleukin (IL)-8 is involved in this process, and is actually upregulated in the airways of patients. We have observed that in the absence of eosinophil chemoattractants, neutrophils stimulated by IL-8 augment eosinophil trans-basement membrane migration by releasing superoxide anion, matrix metalloproteinase, leukotriene B 4 and platelet-activating factor. These findings suggest that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthmatic patients, which might be a mechanism for corticosteroid resistance in severe asthma. However, the mechanisms of IL-8 upregulation in the airway are not completely understood. Several studies suggest that IL-17 (or T helper 17 cells; Th17) is involved in the IL-8 upregulation observed in severe asthma. We clarified that dopamine induces Th17 differentiation through dopamine D1-like receptor (D1-like-R), and that the D1-like-R antagonist attenuates Th17-mediated diseases like experimental autoimmune encephalomyelitis. Furthermore, we demonstrated that a D1-like-R antagonist significantly suppressed ovalbumin (OVA)-induced neutrophilic airway inflammation in OVA T cell receptor-transgenic DO11.10 mice through inhibiting Th17-mediated immune responses. Therefore, dopamine D1-like-R antagonists could become useful for treating Th17-mediated neutrophil-dominant severe asthma. As inhaled corticosteroids are known to be less effective for controlling neutrophilic inflammation, a more effective therapeutic strategy for neutrophil-dominant asthma should still be elucidated.

Allergen immunotherapy (AIT) is a specific treatment involving the administration of relevant allergens to allergic patients, with subtypes including subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). In asthma, AIT using the house dust mite (HDM) alleviates clinical symptoms and decreases airway hyper responsiveness and medication dose. In addition, AIT can improve the natural course of asthma. For example, the effects of AIT can be preserved for at least a few years, even after ending treatment. AIT may increase the remission rate of asthma in children and suppress sensitization to new allergens. If AIT is introduced in pollinosis, AIT may prevent the development of asthma. Moreover, AIT can control other allergic diseases complicated by asthma, such as allergic rhinitis, which also improves the control of asthma. The indication of HDM-SCIT for asthma is mild-to-moderate HDM-sensitized allergic asthma in a patient with normal respiratory function. To date, HDM-SLIT is applicable in Japan for allergic rhinitis, not for asthma. However, the effect of SLIT on asthma has been confirmed internationally, and SLIT is available for asthma in Japan if allergic rhinitis is present as a complication.

Allergen immunotherapy (AIT) is a treatment in which clinically corresponding allergens are administered to patients with allergic diseases, either by subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT), or by oral immunotherapy (OIT) in the case of food allergy. Since etiological allergens are administered to patients, AIT is presumed to modify mainly allergen-specific immune responses. In bronchial asthma, AIT with house dust mites (HDM) alleviates clinical symptoms, suppresses airway hyperresponsiveness, and reduces medication doses of HDM-sensitive asthmatics. Moreover, AIT can suppress the symptoms of other allergic diseases associated with asthma including allergic rhinitis. However, AIT sometimes reduces allergic symptoms not induced by the responsible allergens, such as non-targeted allergens, in clinical settings. Furthermore, AIT can suppress the spread of sensitization to new allergens that are not targeted allergens by AIT, suggesting the suppression of allergic immune responses in an allergen-nonspecific manner. In this review, the nonspecific suppression of allergic immune responses by AIT is discussed. AIT has been reported to increase regulatory T cells that produce IL-10, transforming growth factor-β, and IL-35, IL-10-producing regulatory B cells, and IL-10-producing innate lymphoid cells. These cells can suppress type-2 mediated immune responses mainly through the production of anti-inflammatory cytokines or a cell–cell contact mechanism, which may be involved in the nonspecific suppression of allergic immune responses by AIT.

In some squids, such as those in the family Loliginidae, upon copulation, females receive and store male-delivered sperm capsules, spermatangia, at two different body locations: the buccal membrane and the distal end of the oviduct. This insemination site dimorphism is associated with alternative reproductive strategies. However, in Loliolus sumatrensis , a species of Loliginidae, the females possess three insemination sites: buccal membrane (BM), basal left IV arm (ARM) and lateral head behind the left eye (EYE), therefore we studied such the unusual phenomena. We developed microsatellite markers and genotyped the paternity of each spermatangium on three sites. We found multiple paternity at every single site and simultaneous usage of all three sites by a few males. The seasonal dynamics of a population in the Seto Inland Sea revealed a set priority for the initial use of insemination sites as BM, followed by ARM and then EYE, whereas the maximum number of stored spermatangia was greater in EYE > ARM > BM. Female maturity status was correlated with the usage pattern of insemination sites but not with the number of stored spermatangia at any insemination site. These results suggest that a male squid inseminates at different locations according to female mating history and female maturity status.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis accompanied by granulomas and eosinophilic inflammation, exhibiting marked peripheral blood eosinophiliaandasthma. Neuropathy is a difficult-to-treat common manifestation that frequently remains after achieving clinical remission with current therapy in a subpopulation of patients with EGPA with or without life-threatening organ involvement. Refractory neuropathy regularly reduces the quality of life and requires glucocorticoids (GCs) and/or immunosuppressants for a long time. Long-term immunosuppressive therapy is a factor associated with a high risk of adverse effects. Mepolizumab, at three times the dose for severe asthma, provides benefits to induce the remission of relapsing or refractory EGPA and to reduce the doses of GC. Here, we present a case of EGPA successfully treated with mepolizumab at the reference dose for severe asthma. In this case, mepolizumab resolved peripheral neuropathy resistant to corticosteroids, immunosuppressants, and intravenous immunoglobulin and contributed to the improvement of comorbid chronic pulmonary aspergillosis during GC dose reduction.

One of the main factors in the deterioration of automobile three-way catalysts is the sintering of platinum group metals (PGMs). In this study, we used in situ tunneling electron microscopy (TEM) to examine the sintering of Rh particles as the temperature increases. Two types of environmental conditions were tested, namely, vacuum atmosphere with heating up to 1050 °C, and N2 with/without 1% O2 at 1 atm and up to 1000 °C. Under vacuum, Rh particles appeared to be immersed in ZrO2. In contrast, at 1 atm N2 with or without 1% O2, the sintered Rh particles appeared spherical and not immersed in ZrO2. The latter trend of Rh sintering resembles the actual engine-aged catalyst observed ex situ in this study. In the N2 atmosphere, the sintering of support material (ZrO2 or Y-ZrO2) was first observed by in situ TEM, followed by Rh particle sintering. The Rh particle size was slightly smaller on Y-ZrO2 compared to that on ZrO2. To better understand these experimental results, density functional theory was used to calculate the systems’ junction energies, assuming three layers of Rh(111) 4 × 4 structures joined to the support material (ZrO2 and Y-ZrO2). The calculated energies were consistent with the in situ TEM observations in the N2 atmosphere.