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| ==Immune Response== | | ==Immune Response== |
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| F1.large.jpg | Schematic representation of a vicious circle of events which occurs during chronic bronchial infection. IL: interleukin; TNF: tumour necrosis factor; LT: leukotriene; MMP: matrix metalloproteinase <br> [http://erj.ersjournals.com/content/31/2/396/F1.large.jpg <font size="-2">''European Respiratory Journal''</font>] | | F1.large.jpg | Schematic representation of a vicious circle of events which occurs during chronic bronchial infection. IL: interleukin; TNF: tumour necrosis factor; LT: leukotriene; MMP: matrix metalloproteinase <br> [http://erj.ersjournals.com/content/31/2/396/F1.large.jpg <font size="-2">''European Respiratory Journal''</font>] |
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| Immunohistological analysis of bronchial biopsy specimens from nine patients with bronchiectasis and four control subjects was performed with a panel of monoclonal antibodies selected to show lymphocyte and macrophage subsets and signs of cellular activation. The cells taking part in the inflammatory response in the bronchial wall of patients with bronchiectasis were almost exclusively mononuclear cells, most of them T lymphocytes. B lymphocytes were observed in biopsy specimens from only two out of nine patients. CD8+ T cells outnumbered CD4+ cells in all patients in aRATIO ranging from 2:1 to 10:1. Most T lymphocytes also strongly expressed CD7 antigen and a proportion of them expressed HLA-DR. Most of the lymphocytic infiltration occurred just beneath the basement membrane of the epithelium, though intraepithelial and submucosal infiltration was also seen. Non-lymphoid mononuclear cells expressing the phenotype of dendritic cells and macrophages were found dispersed throughout the infiltrate, most of them expressing HLA-DR. These observations support the hypothesis that cell mediated immunological reactions contribute to the inflammation associated with bronchiectasis.
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| Furthermore, lung histopathology shows infiltrating CD4 and CD8 cells, the latter predominating. T cell infiltrates are activated (HLA-DR+) and located mainly in the lamina propria [28]. There are also activated macrophages and dendritic cells. In a disease with chronic neutrophilia, one has to consider the possibility of excessive or dysregulated IL-17 release as a driver. While there is considerable focus on the role of Th17 cells in resistance to bacterial infection [29,30], it is likely that much IL-17 release may derive from other sources, including γδ T cells iNK T and NK cells. In line with this, the airway submucosa of non-cystic fibrosis (CF) bronchiectasis and CF patients show enhanced levels of IL-17+ cells, both innate and adaptive [31]. Furthermore, IL-17+ cells were correlated with neutrophilia, making them potential candidates in driving the vicious cycle of infection and inflammation in bronchiectasis.
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| In King's laboratory, Holdsworth and colleagues focused on baseline immune parameters in bronchiectasis patients compared to controls and the innate and adaptive immune response to non-typable H. influenzae[32,33]. Most aspects of baseline, systemic, cellular immunity were normal in this patient group, although minor subsets were outside the normal range either for CD4 numbers or for neutrophil oxidative burst.
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| Genotypic analysis of HLA-C and killer immunoglobulin-like receptors (KIR) has been used across a wide range of infectious, inflammatory and autoimmune disease phenotypes to elucidate the potential contribution of NK cell activation programmes in disease susceptibility [34,35]. From such studies has come the concept that, depending both on inheritance of predominantly activating or inhibitory KIR genomic repertoires and on differential inheritance of the cognate HLA class I ligands, humans may be considered to have an inherent potential for NK cell activation ranged across a spectrum of activation [36]. Susceptibility to viral infection, including hepatitis CVIRUS (HCV) and HIV, has tended to be associated with inhibitory genotypes, while susceptibility to autoimmune and inflammatory pathology has often been associated with activating genotypes. Analysis of KIR and HLA class I genotypes appears informative with respect to susceptibility to idiopathic bronchiectasis: HLA-Cw*03 alleles and, in particular, HLA-C group 1 homozygosity were associated with increased risk of bronchiectasis [37,38]. Approximately half the bronchiectasis cohort were homozygous for HLA-C group 1 compared with a quarter of controls. Homozygosity effects of this type are reminiscent of several other NK cell disease studies, in which homozygotes missing ligands for inhibitory receptors are predicted to have fewer NK cells under inhibitory control [39,40]. Bronchiectasis patients encompass a significantly increased number of individuals expressing only HLA-C group 1 with 2DS1 and/or 2DS2 stimulatory KIRs – a combination that would be considered at the extreme end of the activation spectrum for NK cells. This model will acquire greater nuance and complexity as we gain the ability to factor in both polymorphic KIR variability and copy number variability [41,42]. Specific, functional data addressing the hypothesis based on the genotypic data are not yet available. Certainly, NK cells play a critical role at the innate–adaptive interface during lung infection, and are implicated in immunity to many of the key pathogens implicated in the respiratory infections of these patients [43,44].
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D.
Overview
Bronchiectasis involves bronchi that are permanently dilated, inflamed, and easily collapsible. This results in airflow obstruction and impaired clearance of secretions.
Pathophysiology
- Dilation of the bronchial walls results in airflow obstruction and impaired clearance of secretions because the dilated areas interrupt normal air pressure of the bronchial tubes, causing sputum to pool inside the dilated areas instead of being pushed upward.[1]
- The pooled sputum provides an environment conducive to the growth of infectious pathogens. Therefore, that particular area is vulnerable to infections.
- The more infections that the lungs experience, the more damaged the alveoli in the lung become.
- With more damage to the lung tissue, the bronchial tubes become more inelastic and dilated. This creates a perpetual, destructive cycle within this disease.
- The most widely known model of the development of bronchiectasis is Cole’s “vicious cycle hypothesis”. In this model, Cole proposed that an environmental insult often on a background of genetic susceptibility impaired muco-ciliary clearance resulting in persistence of microbes in the sinobronchial tree and microbial colonization. The microbial infection caused chronic inflammation resulting in tissue damage and impaired mucociliary motility. In turn this led to more infection with a cycle of progressive inflammation causing lung damage. The current view is that the two factors required for the development of this condition are persistent infection and a defect in host defense.[2]
- The biopsies indicate that the infiltrate contains neutrophils, T lymphocytes and macrophages. The sputum contains elastase, interleukin-8, tumor necrosis factor a (TNF-a), and prostanoids.
Immune Response
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Schematic representation of a vicious circle of events which occurs during chronic bronchial infection. IL: interleukin; TNF: tumour necrosis factor; LT: leukotriene; MMP: matrix metalloproteinase
European Respiratory Journal
References
Template:WikiDoc Sources
Schematic representation of a vicious circle of events which occurs during chronic bronchial infection. IL: interleukin; TNF: tumour necrosis factor; LT: leukotriene; MMP: matrix metalloproteinase
