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Exacerbation of Mycobacterium avium pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses.

ABSTRACT: Accumulating evidence suggests that two chronic respiratory diseases, nontuberculous mycobacterium (NTM)-pulmonary disease (PD) and allergic asthma, are frequently present together and that they likely influence the disease development and progression of each other. However, their precise interactions regarding the pathogenesis of comorbid diseases versus that of individual diseases are not well understood. In this study, comorbid diseases (i.e., Mycobacteria avium (Mav) pulmonary infection (PI) (Mav-PI) and ovalbumin-induced allergic asthma) were established in mice in different orders and at different time periods. Individual disease-specific characteristics, including alterations in immune cell populations and antigen-specific immune responses, were analyzed and compared. To assess Mav-PI pathogenesis, lung inflammation and bacterial burden levels were also determined. Allergic asthma induction in the presence of Mav-PI markedly aggravated Mav-PI pathogenesis by increasing the bacterial burden and the severity of lung inflammation. Interestingly, the general outcome of allergic asthma with goblet cell hyperplasia was alleviated at a chronic stage in the comorbid mouse model. Overall, the increase in the number of Mav CFUs was inversely correlated with the Mav-specific Th17 response, as confirmed by comparing BALB/c and C57BL/6J mice. Overall, the pathogenesis of existing Mav-PI is more severely affected by allergen exposure than vice versa. This Mav-PI exacerbation is associated with disruption of Mav-specific Th17 responses. This study provides the first evidence that the Mav-specific Th17 response plays an important role in the control of Mav pathogenesis in the presence of allergic asthma, indicating that targeting the Th17 response has therapeutic potential for NTM-PD accompanied by allergic asthma.

SUBMITTER: Bak Y

PROVIDER: S-EPMC8496529 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chronic comorbid conditions are common in adults with asthma, and some may influence a patient's asthma exacerbation risk. We explored associations between eighteen chronic comorbid conditions and asthma exacerbation occurrence in adults with asthma in a cross-sectional study nested within a cohort study using data from the two-yearly US National Health and Nutrition Examination Survey (NHANES) program. Data of 2387 adults with self-reported doctor-diagnosed current asthma from the 2007 to 2018 NHANES surveys were selected. Investigated chronic comorbidities were: angina pectoris; congestive heart failure; coronary heart disease; depression; diabetes mellitus; soft and hard drug use; gastroesophageal reflux; gout; history of heart attack; history of stroke; hypercholesterolemia; hypertension; kidney failure; liver conditions; obesity; rheumatoid arthritis; and thyroid problems. Outcome was defined as asthma exacerbation category: no, moderate, or severe exacerbation(s) in the past year. Ordinal logistic regression analysis with correction for potential confounders was used to estimate odds ratios (OR) for moderate or severe exacerbations. Observed associations with increased severe asthma exacerbation occurrence were: obesity (OR = 1.67; 95% confidence interval 1.24, 2.26), and rheumatoid arthritis (OR = 1.55; 1.04, 2.30). History of stroke (OR = 1.95; 1.22, 3.11) and rheumatoid arthritis (OR = 1.33; 1.00, 1.75) showed associations with increased moderate exacerbation occurrence. Age-stratified analysis showed soft drug use, obesity, depression, thyroid problems, and rheumatoid arthritis to be associated with moderate and/or severe exacerbation occurrence in one or more 10-year age strata. In conclusion, several chronic comorbid conditions were associated with asthma exacerbation occurrence, which confirms but also complements previous studies. Our observations contribute to understanding exacerbation risk estimation and, ultimately, personalized asthma management.

Project description:BackgroundAirway remodeling in patients with asthma, which leads to a decline in pulmonary function, is likely the result of repeated exacerbations often provoked by aeroallergen exposures. Aeroallegen exposure triggers a stereotypic response orchestrated by growth factor cytokines and other protein mediators. This results in a late-phase allergic reaction characterized by vascular permeability, recruitment of activated leukocytes, and activation of structural cells of the airway. The spectrum of protein mediators and their functions are incompletely understood.MethodsBronchoalveolar lavage fluid (BALF) samples were obtained from 12 volunteers who exhibited robust eosinophilic recruitment following segmental bronchial provocation with allergen (SBP-Ag). We systematically identified and quantified proteins in BALF using high-performance liquid chromatography-high-resolution mass spectrometry (LC-MS/MS) followed by pathway analysis and correlations with airway physiology.ResultsPairwise analysis of protein abundance in BALF pre- vs post-SBP-Ag revealed that 55 proteins were upregulated and 103 proteins were downregulated. We observed enrichment of groups of proteins mapping to hemostasis/fibrin clot, platelet activation, lipoprotein assembly, neutrophil degranulation proteins, and acute-phase inflammation-airway remodeling pathways. The abundances of F2 and Fibrinogen γ (FGG) correlated with eosinophil numbers, whereas SERPINA3 negatively correlated with change in FeNO. The coagulation proteins F2 and KNG negatively correlated with FN1 an index of airway remodeling. Interestingly, patients with lower FEV1 showed distinct allergen-induced patterns of 8 BALF proteins, including MUC1, alarmins (HSPB1), and actin polymerization factors.ConclusionsProtein abundance of the fibrin formation cascade, platelet activation and remodeling are associated with late-phase leukocyte numbers and markers of remodeling. Patients with lower FEV1 have distinct dynamic responses to allergen.

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Exacerbation of Mycobacterium avium pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses.

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