Chronic granulomatous disease (CGD) is an uncommon congenital immunodeficiency seen approximately in 1 of 250,000 individuals. It is caused by a profound defect in a burst of oxygen consumption that ...normally accompanies phagocytosis in all myeloid cells (neutrophils, eosinophils, monocytes, and macrophages). This “respiratory burst” involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide, which in turn gives rise to hydrogen peroxide, hypochlorous acid, and hydroxyl radicals. These oxygen derivatives play a critical role in the killing of pathogenic bacteria and fungi. As a result of the failure to activate the respiratory burst in their phagocytes, the majority of CGD patients suffer from severe recurrent infections and rather unexplained prolonged inflammatory reactions that may result in granulomatous lesions. Both may cause severe organ dysfunction depending on the tissues involved. Preventive measures as well as rapid (invasive) diagnostic procedures are required to successfully treat CGD. Hematopoietic stem cell transplantation may be a serious option in some of the patients.
Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous ...spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best‐defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non‐type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point‐of‐care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
Background Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. Objective We sought to determine differential gene and protein expression in ...sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. Methods Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. Results Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13–induced TH 2 signature and IL-1 receptor–like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. Conclusion IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH 2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.
Severe adult-onset asthma: A distinct phenotype Amelink, Marijke, MD; de Groot, Jantina C., MD; de Nijs, Selma B., MSc ...
Journal of allergy and clinical immunology,
08/2013, Letnik:
132, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Background Some patients with adult-onset asthma have severe disease, whereas others have mild transient disease. It is currently unknown whether patients with severe adult-onset asthma represent a ...distinct clinical phenotype. Objective We sought to investigate whether disease severity in patients with adult-onset asthma is associated with specific phenotypic characteristics. Methods One hundred seventy-six patients with adult-onset asthma were recruited from 1 academic and 3 nonacademic outpatient clinics. Severe refractory asthma was defined according to international Innovative Medicines Initiative criteria, and mild-to-moderate persistent asthma was defined according to Global Initiative for Asthma criteria. Patients were characterized with respect to clinical, functional, and inflammatory parameters. Unpaired t tests and χ2 tests were used for group comparisons; both univariate and multivariate logistic regression were used to determine factors associated with disease severity. Results Apart from the expected high symptom scores, poor quality of life, need for high-intensity treatment, low lung function, and high exacerbation rate, patients with severe adult-onset asthma were more often nonatopic (52% vs 34%, P = .02) and had more nasal symptoms and nasal polyposis (54% vs 27%, P ≤ .001), higher exhaled nitric oxide levels (38 vs 27 ppb, P = .02) and blood neutrophil counts (5.3 vs 4.0 109 /L, P ≤ .001) and sputum eosinophilia (11.8% vs 0.8%, P ≤ .001). Multiple logistic regression analysis showed that increased blood neutrophil (odds ratio, 10.9; P = .002) and sputum eosinophil (odds ratio, 1.5; P = .005) counts were independently associated with severe adult-onset disease. Conclusion The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation. This suggests that severe adult-onset asthma has a distinct underlying mechanism compared with milder disease.
Cadherin-related family member 3 (CDHR3) was identified earlier as a susceptibility locus for recurrent severe exacerbations in patients with early childhood asthma.2 The single nucleotide ...polymorphism rs6967330 in CDHR3 results in a tyrosine (CDHR3-Y529) instead of a cysteine at position 529, which facilitated enhanced cell-surface expression.2 In a groundbreaking study from Bochkov et al,3 it was subsequently shown that transfection of CDHR3 mediated rhinovirus C binding and replication. Modeling of the CDHR3 structure suggested potential binding sites for the capsid proteins VP1 and VP2 of rhinovirus C. Mapping of the rhinovirus C binding site or sites on CDHR3 revealed that extracellular domain 1 is the likely docking site for all rhinovirus C types, which was also supported by the capacity of extracellular domain 1–containing proteins/peptides to inhibit rhinovirus C infection of susceptible cells.4 Sequence analysis of a rhinovirus C strain that displayed improved binding and replication in in vitro cultures showed that a mutation in the viral capsid protein VP1 was indeed responsible for the improved binding.5 Together, these data are highly suggestive of CDHR3 being the docking site for rhinovirus C types, but independent confirmation is still required. Everman et al6 and Basnet et al9 showed independently that the CDHR3 high-risk genotype in primary airway epithelial cells resulted in enhanced infection with rhinovirus C. By using expression quantitative trait locus analyses on nasal brushings from 431 asthmatic and 242 healthy control children, Everman et al6 found that the rs6967330 A allele, which is associated with increased human rhinovirus-C infection in primary airway epithelial cells, was also associated with greater CDHR3 expression levels.
Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an ...involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.
Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.
In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.
Oxidative stress is a common feature of obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Lung macrophages are key innate immune cells that can generate ...oxidants and are known to display aberrant polarization patterns and defective phagocytic responses in these diseases. Whether these characteristics are linked in one way or another and whether they contribute to the onset and severity of exacerbations in asthma and COPD remain poorly understood. Insight into oxidative stress, macrophages, and their interactions may be important in fully understanding acute worsening of lung disease. This review therefore highlights the current state of the art regarding the role of oxidative stress and macrophages in exacerbations of asthma and COPD. It shows that oxidative stress can attenuate macrophage function, which may result in impaired responses toward exacerbating triggers and may contribute to exaggerated inflammation in the airways.
PDF
