Holtzman, M.J. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. J. Clin. Invest. 122, 2741-2748

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 08/2012; 122(8):2741-8. DOI: 10.1172/JCI60325
Source: PubMed


Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.

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    • "urban or rural), household exposure to cigarette smoke, age when starting day care attendance, and the number and type of CAP episodes. We also recorded any underlying diseases possibly associated with CAP that had been diagnosed during hospitalisation or a visit to our outpatient clinic: i.e. oromotor incoordination and swallowing dysfunction predisposing to aspiration syndrome [11]; immune disorders, including atopy/allergy and primary and acquired immunodeficiency syndrome [12,13]; congenital heart defects [14]; lung and airway problems such as chronic rhinosinusitis with post-nasal drip [15], primary ciliary dyskinesia [16], recurrent wheezing [17,18], bronchial asthma [13] or middle lobe syndrome [19]; gastroesophageal reflux disease (GERD) [20]; and overweight or obesity [21]. "
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    ABSTRACT: The aim of this case--control study was to analyse the clinical characteristics of children with recurrent community-acquired pneumonia (rCAP) affecting different lung areas (DLAs) and compare them with those of children who have never experienced CAP in order to contribute to identifying the best approach to such patients. The study involved 146 children with >=2 episodes of radiographically confirmed CAP in DLA in a single year (or >=3 episodes in any time frame) with radiographic clearing of densities between occurrences, and 145 age- and gender-matched controls enrolled in Milan, Italy, between January 2009 and December 2012. The demographic and clinical characteristics of the cases and controls were compared, and a comparison was also made between the cases with rCAP (i.e. <=3 episodes) and those with highly recurrent CAP (hrCAP: i.e. >3 episodes). Gestational age at birth (p = 0.003), birth weight (p = 0.006), respiratory distress at birth (p < 0.001), and age when starting day care attendance (p < 0.001) were significantly different between the cases and controls, and recurrent infectious wheezing (p < 0.001), chronic rhinosinusitis with post-nasal drip (p < 0.001), recurrent upper respiratory tract infections (p < 0.001), atopy/allergy (p < 0.001) and asthma (p < 0.001) were significantly more frequent. Significant risk factors for hrCAP were gastroesophageal reflux disease (GERD; p = 0.04), a history of atopy and/or allergy (p = 0.005), and a diagnosis of asthma (p = 0.0001) or middle lobe syndrome (p = 0.001). Multivariate logistic regression analysis, adjusted for age and gender, showed that all of the risk factors other than GERD and wheezing were associated with hrCAP. The diagnostic approach to children with rCAP in DLAs is relatively easy in the developed world, where the severe chronic underlying diseases favouring rCAP are usually identified early, and patients with chronic underlying disease are diagnosed before the occurrence of rCAP in DLAs. When rCAP in DLAs does occur, an evaluation of the patients' history and clinical findings make it possible to limit diagnostic investigations.
    BMC Pulmonary Medicine 10/2013; 13(1):60. DOI:10.1186/1471-2466-13-60 · 2.40 Impact Factor
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    • "Recent understanding of the innate immune system suggests that it may function independently of the adaptive immune system in some cases or synergistically in others, and the relative contributions of the two systems may explain the disease heterogeneity among asthmatic patients, which might occur in patients with COPD (Holtzman, 2012). It has long been argued that asthma, chronic bronchitis, and emphysema could be considered "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses. COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage. In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections.
    Frontiers in Microbiology 10/2013; 4:293. DOI:10.3389/fmicb.2013.00293 · 3.99 Impact Factor
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    • "This systemic innate response is driven by sentinel cells such as macrophages, dendritic cells, granulocytes, and innate lymphoid cells. A recent review by Holtzman provides a comprehensive overview of both the allergic and nonallergic immune response in asthma.6 "
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    ABSTRACT: Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice - for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) - are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management.
    Targets & therapy 08/2013; 7(1):199-210. DOI:10.2147/BTT.S29976
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