[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunology of asthma and chronic obstructive pulmonary disease

Nature Reviews Immunology volume 8, pages 183–192 (2008)Cite this article

Key Points

  • Asthma and chronic obstructive pulmonary disease (COPD) are both associated with chronic inflammation of the respiratory tract and with increased inflammation during disease exacerbations. However, the inflammatory pattern differs between these two diseases.

  • The inflammation in asthma mainly involves the proximal airways, whereas in COPD inflammation mainly occurs in the peripheral airways and the lung parenchyma.

  • Asthma is typically characterized by activated mucosal mast cells, an infiltration of eosinophils and activated T helper 2 (TH2) cells, whereas in COPD macrophages, neutrophils and type 1 cytotoxic T (TC1) cells predominate.

  • These distinct patterns reflect differences in the mechanisms that drive the inflammatory response, with responses being driven by allergens in asthma and by chronic inhaled irritants, such as cigarette smoke, in COPD.

  • The pattern of inflammatory mediators produced also differs between the two diseases. In asthma, there are increased levels of mediators, such as histamine and cysteinyl leukotrienes, that cause bronchoconstriction and of TH2-type cytokines (such as interleukin-4 (IL-4), IL-5, IL-9 and IL-13), which orchestrate the inflammatory response through activation of the transcription factors GATA3 (GATA-binding protein 3) and NFAT (nuclear factor of activated T cells). By contrast, in COPD, there is an increase in the levels of nonspecific cytokines, such as IL-6 and tumour-necrosis factor, and chemokines that are associated with monocytic and neutrophilic inflammation (such as CXCL8, CXCL1 and CCL2).

  • In severe asthma and asthmatics who smoke, the inflammatory pattern changes to become more similar to that seen in COPD, with more involvement of the peripheral airways, increased infiltration of neutrophils and CD8+ T cells.

  • Differences in inflammatory patterns affect the response of these two diseases to therapy. Mild asthma is very responsive to corticosteroids, as these drugs suppress the multiple inflammatory genes that are activated through recruitment of the enzyme histone deacetylase 2 (HDAC2). However, in COPD and severe asthma, corticosteroids fail to suppress inflammation owing to a reduction in HDAC2 activity and expression. In the future, specific immunosuppressants may be a useful approach to therapy.

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved. As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases. However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations. This has important implications for the development of new therapies.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inflammatory and immune cells involved in asthma.
Figure 2: Inflammatory and immune cells involved in chronic obstructive pulmonary disease (COPD).
Figure 3: Contrasting histopathology of asthma and chronic obstructive pulmonary disease (COPD).
Figure 4: Interactions between TH1 and TH2 cells in asthma.
Figure 5: TH17 cells and airway inflammation.
Figure 6: CD8+ T cells in chronic obstructive pulmonary disease (COPD).

Similar content being viewed by others

References

  1. Barnes, P. J. Chronic obstructive pulmonary disease: a growing but neglected epidemic. PLoS Med. 4, e112 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mannino, D. M. & Buist, A. S. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370, 765–773 (2007). A comprehensive recent review of the various risk factors involved in COPD and the current global prevalence of the disease.

    Article  PubMed  Google Scholar 

  3. Pearce, N. et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62, 758–766 (2007). This paper provides the most recent data showing the worldwide prevalence of asthma.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kraft, M. Asthma and chronic obstructive pulmonary disease exhibit common origins in any country! Am. J. Respir. Crit. Care Med. 174, 238–240 (2006).

    Article  PubMed  Google Scholar 

  5. Barnes, P. J. Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases. Am. J. Respir. Crit. Care. Med. 174, 240–243 (2006).

    Article  PubMed  Google Scholar 

  6. Barnes, P. J. Mechanisms in COPD: differences from asthma. Chest 117, 10S–14S (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Jeffery, P. K. Comparison of the structural and inflammatory features of COPD and asthma. Chest 117, 251S–260S (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Wenzel, S. E. Asthma: defining of the persistent adult phenotypes. Lancet 368, 804–813 (2006). This paper provides a discussion of the different phenotypes of asthma that are discussed in this Review.

    Article  CAS  PubMed  Google Scholar 

  9. Phelan, P. D., Robertson, C. F. & Olinsky, A. The Melbourne Asthma Study: 1964–1999. J. Allergy Clin. Immunol. 109, 189–194 (2002).

    Article  PubMed  Google Scholar 

  10. Barnes, P. J., Chung, K. F. & Page, C. P. Inflammatory mediators of asthma: an update. Pharmacol. Rev. 50, 515–596 (1998).

    CAS  PubMed  Google Scholar 

  11. Barnes, P. J. Mediators of chronic obstructive pulmonary disease. Pharm. Rev. 56, 515–548 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Hart, L. A., Krishnan, V. L., Adcock, I. M., Barnes, P. J. & Chung, K. F. Activation and localization of transcription factor, nuclear factor-κB, in asthma. Am. J. Respir. Crit. Care Med. 158, 1585–1592 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Caramori, G. et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 58, 348–351 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Benayoun, L., Druilhe, A., Dombret, M. C., Aubier, M. & Pretolani, M. Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med. 167, 1360–1368 (2003). This study quantifies the changes in airway smooth muscle that occur in asthmatic patients.

    Article  PubMed  Google Scholar 

  15. Siddiqui, S. et al. Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis. J. Allergy Clin. Immunol. 120, 813–819 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Ordonez, C. L. et al. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am. J. Respir. Crit. Care Med. 163, 517–523 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Hogg, J. C. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364, 709–721 (2004).

    Article  PubMed  Google Scholar 

  18. Hogg, J. C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645–2653 (2004). An important study quantifying the inflammation in small airways in patients with differing severity of COPD.

    Article  CAS  PubMed  Google Scholar 

  19. Caramori, G. et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 45, 477–484 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Majo, J., Ghezzo, H. & Cosio, M. G. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur. Respir. J. 17, 946–953 (2001). A demonstration of increased numbers of CD8+ T cells in the lung parenchyma of patients with COPD and their relationship to apoptosis of type I pneumocytes.

    Article  CAS  PubMed  Google Scholar 

  21. Taraseviciene-Stewart, L. et al. Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc. Am. Thorac. Soc. 3, 687–690 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Ohnishi, K., Takagi, M., Kurokawa, Y., Satomi, S. & Konttinen, Y. T. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab. Invest. 78, 1077–1087 (1998).

    CAS  PubMed  Google Scholar 

  23. Tuder, R. M., Yoshida, T., Arap, W., Pasqualini, R. & Petrache, I. State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective. Proc. Am. Thorac. Soc. 3, 503–510 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reber, L., Da Silva, C. A. & Frossard, N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 533, 327–340 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Brightling, C. E. et al. Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346, 1699–1705 (2002). This paper shows that mast-cell numbers are present in the airway smooth muscle of asthmatic patients, whereas this is not seen in non-asthmatic subjects or patients with eosinophilic bronchitis who do not have asthma.

    Article  PubMed  Google Scholar 

  27. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2144–2148 (2000). This study reports a surprising finding that blocking IL-5 in asthmatic patients does not reduce the response to allergen or airway hyper-responsiveness despite a profound reduction in circulating and sputum eosinophils.

    Article  CAS  PubMed  Google Scholar 

  28. Flood-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Green, R. H. et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57, 875–879 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Keatings, V. M., Collins, P. D., Scott, D. M. & Barnes, P. J. Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 153, 530–534 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Traves, S. L., Smith, S. J., Barnes, P. J. & Donnelly, L. E. Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J. Leukoc. Biol. 76, 441–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Barnes, P. J. Macrophages as orchestrators of COPD. COPD 1, 59–70 (2004).

    Article  PubMed  Google Scholar 

  33. Meyer, E. H., DeKruyff, R. H. & Umetsu, D. T. T cells and NKT cells in the pathogenesis of asthma. Annu. Rev. Med. 59, 281–292 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Kay, A. B. The role of T lymphocytes in asthma. Chem. Immunol. Allergy. 91, 59–75 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Ho, I. C. & Pai, S. Y. GATA-3 — not just for Th2 cells anymore. Cell Mol. Immunol. 4, 15–29 (2007).

    CAS  PubMed  Google Scholar 

  36. Barnes, P. J. Role of GATA-3 in allergic diseases. Curr. Mol. Med. (in the press) (2008).

  37. Caramori, G. et al. Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies. Eur. Respir. J. 18, 466–473 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Nakamura, Y. et al. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J. Allergy Clin. Immunol. 103, 215–222 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Maneechotesuwan, K. et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J. Immunol. 178, 2491–2498 (2007). This study shows that in human T cells GATA3 translocates to the nucleus after phosphorylation by p38 MAPK, which is activated by TCR and co-receptor activation.

    Article  CAS  PubMed  Google Scholar 

  40. Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002). This paper shows that the lack of T-bet results in eosinophilic inflammation in mouse lungs and a reduction in T cells expressing T-bet in the airways of asthmatic patients.

    Article  CAS  PubMed  Google Scholar 

  41. Hwang, E. S., Szabo, S. J., Schwartzberg, P. L. & Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J. & Nakanishi, K. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation. J. Immunol. 179, 4415–4423 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Usui, T. et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 203, 755–766 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

    Article  CAS  Google Scholar 

  45. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Komai-Koma, M. et al. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37, 2779–2786 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Grumelli, S. et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 1, 75–83 (2004). This study shows that the numbers of T H 1 and T C 1 cells, both of which express CXCR3, are increased in the lung parenchyma of patients with COPD.

    Article  CAS  Google Scholar 

  48. Saetta, M. et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 165, 1404–1409 (2002).

    Article  PubMed  Google Scholar 

  49. Costa, C. et al. CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest 133, 26–33 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Barczyk, A. et al. Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 117, 1484–1492 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Kurashima, K. et al. Asthma severity is associated with an increase in both blood CXCR3+ and CCR4+ T cells. Respirology 11, 152–157 (2006).

    Article  PubMed  Google Scholar 

  52. Larche, M. Regulatory T cells in allergy and asthma. Chest 132, 1007–1014 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, J. H. et al. The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin. Exp. Immunol. 148, 53–63 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Smyth, L. J., Starkey, C., Vestbo, J. & Singh, D. CD4-regulatory cells in COPD patients. Chest 132, 156–163 (2007).

    Article  PubMed  Google Scholar 

  56. Wan, Y. Y. & Flavell, R. A. Regulatory T cells, transforming growth factor-β, and immune suppression. Proc. Am. Thorac. Soc. 4, 271–276 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stockinger, B. & Veldhoen, M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19, 281–286 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Bullens, D. M. et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir. Res. 7, 135 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Laan, M., Lotvall, J., Chung, K. F. & Linden, A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br. J. Pharmacol. 133, 200–206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 8 November 2007 (doi:10.1146/annurev.immunol.26.021607.090316).

    Article  CAS  PubMed  Google Scholar 

  63. Wolk, K. & Sabat, R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17, 367–380 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Akbari, O. et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117–1129 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Vijayanand, P. et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 1410–1422 (2007). A careful study showing that there is no increase in i NKT cells in asthma or COPD in contrast to reference 64.

    Article  CAS  PubMed  Google Scholar 

  66. Saetta, M. et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 157, 822–826 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Xanthou, G., Duchesnes, C. E., Williams, T. J. & Pease, J. E. CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11. Eur. J. Immunol. 33, 2241–2250 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Chrysofakis, G. et al. Perforin expression and cytotoxic activity of sputum CD8+ lymphocytes in patients with COPD. Chest 125, 71–76 (2004).

    Article  PubMed  Google Scholar 

  69. van Rensen, E. L. et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am. J. Respir. Crit. Care Med. 172, 837–841 (2005).

    Article  PubMed  Google Scholar 

  70. Cho, S. H., Stanciu, L. A., Holgate, S. T. & Johnston, S. L. Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+ and CD8+ T cells in atopic asthma. Am. J. Respir. Crit. Care Med. 171, 224–230 (2005).

    Article  PubMed  Google Scholar 

  71. Gould, H. J., Beavil, R. L. & Vercelli, D. IgE isotype determination: epsilon-germline gene transcription, DNA recombination and B-cell differentiation. Br. Med. Bull. 56, 908–924 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Avila, P. C. Does anti-IgE therapy help in asthma? Efficacy and controversies. Annu. Rev. Med. 58, 185–203 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Takhar, P. et al. Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J. Allergy Clin. Immunol. 119, 213–218 (2007). An important study demonstrating that IgE is produced locally in the airways of patients with non-atopic (intrinsic) asthma.

    Article  CAS  PubMed  Google Scholar 

  74. Agusti, A., Macnee, W., Donaldson, K. & Cosio, M. Hypothesis: does COPD have an autoimmune component? Thorax 58, 832–834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sullivan, A. K. et al. Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema. Am. J. Respir. Crit. Care Med. 172, 590–596 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lee, S. H. et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nature Med. 13, 567–569 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Hammad, H. & Lambrecht, B. N. Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin. Immunol. 118, 331–336 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Allakhverdi, Z. et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204, 253–258 (2007). This study highlights an important role for TSLP released from airway epithelial cells in the activation of mast cells, providing a link between environmental factors and mast-cell activation in asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu, Y. J. Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Soler, P., Moreau, A., Basset, F. & Hance, A. J. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am. Rev. Respir. Dis. 139, 1112–1117 (1989).

    Article  CAS  PubMed  Google Scholar 

  82. Francus, T., Klein, R. F., Staiano-Coico, L., Becker, C. G. & Siskind, G. W. Effects of tobacco glycoprotein (TGP) on the immune system. II. TGP stimulates the proliferation of human T cells and the differentiation of human B cells into Ig secreting cells. J. Immunol. 140, 1823–1829 (1988).

    CAS  PubMed  Google Scholar 

  83. Rogers, A. V., Adelroth, E., Hattotuwa, K., Dewar, A. & Jeffery, P. K. Bronchial mucosal dendritic cells in smokers and ex-smokers with COPD: an electron microscopic study. Thorax 63, 108–114 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Wenzel, S. E. & Busse, W. W. Severe asthma: lessons from the Severe Asthma Research Program. J. Allergy. Clin. Immunol. 119, 14–21 (2007).

    Article  PubMed  Google Scholar 

  85. Jatakanon, A. et al. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 160, 1532–1539 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Thomson, N. C., Chaudhuri, R. & Livingston, E. Asthma and cigarette smoking. Eur. Respir. J. 24, 822–833 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Papi, A. et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162, 1773–1777 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Brightling, C. E. et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 60, 193–198 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wark, P. A. & Gibson, P. G. Asthma exacerbations. 3: pathogenesis. Thorax 61, 909–915 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Celli, B. R. & Barnes, P. J. Exacerbations of chronic obstructive pulmonary disease. Eur. Respir. J. 29, 1224–1238 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Papi, A., Luppi, F., Franco, F. & Fabbri, L. M. Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 3, 245–251 (2006).

    Article  PubMed  Google Scholar 

  92. Barnes, P. J. How corticosteroids control inflammation. Br. J. Pharmacol. 148, 245–254 (2006). A review of the molecular mechanisms involved in the anti-inflammatory actions of corticosteroids and a discussion of the mechanisms of corticosteroid resistance in airway diseases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ito, K. et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967–1976 (2005). This paper shows that HDAC2 activity and expression are reduced in peripheral lungs, airways and alveolar macrophages of COPD patients, and that this is associated with an increase in inflammatory gene expression.

    Article  CAS  PubMed  Google Scholar 

  94. Barnes, P. J. Reduced histone deacetylase in COPD: clinical implications. Chest 129, 151–155 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Barnes, P. J., Ito, K. & Adcock, I. M. A mechanism of corticosteroid resistance in COPD: inactivation of histone deacetylase. Lancet 363, 731–733 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Cosio, B. G. et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood monocytes in asthma. Am. J. Respir. Crit. Care Med. 170, 141–147 (2004).

    Article  PubMed  Google Scholar 

  97. Hew, M. et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am. J. Respir. Crit. Care Med. 174, 134–141 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Barnes, P. J. Theophylline: new perspectives on an old drug. Am. J. Respir. Crit. Care Med. 167, 813–818 (2003).

    Article  PubMed  Google Scholar 

  99. Finegold, I. Allergen immunotherapy: present and future. Allergy Asthma Proc. 28, 44–49 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Alexander, A., Barnes, N. C. & Kay, A. B. Cyclosporin A in chronic severe asthma: a double-blind placebo-controlled trial. Am. Rev. Respir. Dis. 143, A633 (1991).

    Google Scholar 

  101. Evans, D. J., Cullinan, P. & Geddes, D. M. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst. Rev. 2, CD002993 (2001).

    Google Scholar 

  102. Tamaoki, J. et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 356, 273–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Edwards, J. C. & Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Rev. Immunol. 6, 394–403 (2006).

    Article  CAS  Google Scholar 

  104. Barnes, P. J. New therapies for asthma. Trends Mol. Med. 12, 515–520 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Barnes, P. J. & Hansel, T. T. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 364, 985–996 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Barnes, P. J. Transcription factors in airway diseases. Lab. Invest. 86, 867–872 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Duan, W. et al. Inhaled p38α mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am. J. Respir. Crit. Care Med. 171, 571–578 (2005).

    Article  PubMed  Google Scholar 

  108. Smit, J. J. & Lukacs, N. W. A closer look at chemokines and their role in asthmatic responses. Eur. J. Pharmacol. 533, 277–288 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Donnelly, L. E. & Barnes, P. J. Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol. Sci. 27, 546–553 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Saetta, M. et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin. Exp. Allergy 26, 766–774 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Zhu, J. et al. Exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am. J. Respir. Crit. Care Med. 164, 109–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Gamble, E. et al. Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur. Respir. J. 30, 467–471 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Retamales, I. et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am. J. Respir. Crit. Care Med. 164, 469–473 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Humbert, M. et al. The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol. Today 20, 528–533 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Jahnsen, F. L. et al. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 56, 823–826 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lukacs, N. W., Hogaboam, C. M. & Kunkel, S. L. Chemokines and their receptors in chronic pulmonary disease. Curr. Drug Targets Inflamm. Allergy 4, 313–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Chung, K. F. & Barnes, P. J. Cytokines in asthma. Thorax 54, 825–857 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chung, K. F. Cytokines in chronic obstructive pulmonary disease. Eur. Respir. J. 34, 50S–59S (2001).

    Article  CAS  Google Scholar 

  119. Montuschi, P. et al. Increased 8-Isoprostane, a marker of oxidative stress, in exhaled condensates of asthmatic patients. Am. J. Respir. Crit. Care Med. 160, 216–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Paredi, P., Kharitonov, S. A. & Barnes, P. J. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med. 162, 1450–1454 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Montuschi, P. et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 162, 1175–1177 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Rahman, I., Biswas, S. K. & Kode, A. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533, 222–239 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW3 6LY, UK

    Peter J. Barnes

Authors
  1. Peter J. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Peter Barnes's homepage

Glossary

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants, such as coal dust, and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Atopic (extrinsic) asthma

The commonest form of asthma in which the patients are atopic (as indicated by a positive skin-prick test and the presence of IgE to common inhalant allergens, such as house-dust mites) and have allergic inflammation of the airways.

Non-atopic (intrinsic) asthma

An uncommon form of asthma that is more likely to be severe and characterized by negative skin-prick tests. The airway inflammation is similar to that of atopic asthma and may be mediated by local rather than systemic IgE production.

Emphysema

Destruction of the alveolar walls, resulting in decreased gas exchange and contributing to airflow limitation by loss of alveolar attachments to the small airways that serve to keep the airways open during expiration.

Pseudostratification

Increased proliferation of airway epithelial cells in chronic obstructive pulmonary disease, as a result of the release of epithelial-cell growth factors, which lead to increased thickness of the epithelial-cell layer.

Type I pneumocytes

Flat alveolar cells that make up most of the epithelial-cell layer of the alveolar wall and that are responsible for gas exchange in the alveoli.

Bronchoconstrictor

An agent that induces contraction of airway smooth muscle and thereby narrows the airways, thus reducing the flow of air.

Airway hyper-responsiveness

Increased narrowing of the airways, initiated by exposure to a defined stimulus that usually has little or no effect on airway function in normal individuals. This is a defining physiological characteristic of asthma.

TH2 cells

(T helper 2 cells). The definition of a CD4+ T cell that has differentiated into a cell that produces the cytokines interleukin-4 (IL-4), IL-5 and IL-13, thereby supporting humoral immunity and counteracting TH1-cell responses. An imbalance of TH1–TH2-cell responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

TH1 cells

(T helper 1 cells). The definition of a CD4+ T cell that has differentiated into a cell that produces the cytokines interferon-γ and tumour-necrosis factor, thereby promoting cell-mediated immunity.

Regulatory T cells

A specialized type of CD4+ T cells that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and a subset of these cells is characterized by expression of CD25 and the transcription factor forkhead box P3 (FOXP3).

Allergic rhinitis

Allergic inflammation that is caused by the pollen of specific seasonal plants, such as grasses (causing hay fever), and house dust (causing perennial rhinitis) in people who are allergic to these substances. It is characterized by sneezing, and a runny and blocked nose.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Invariant natural killer T (iNKT) cells

Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T-cell receptor α-chains with an invariant sequence. Typically, these cells co-express cell-surface markers that are encoded by the natural killer (NK) locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.

Type 1 cytotoxic T (TC1) and TC2 cells

A designation that is used to describe subsets of CD8+ cytotoxic T cells. TC1 cells typically secrete interferon-γ and granulocyte/macrophage colony-stimulating factor, and have strong cytotoxic capacity, whereas TC2 cells secrete interleukin-4 (IL-4) and IL-10 and are less effective killers.

Immunoglobulin class switching

The somatic-recombination process by which the class of immunoglobulin expressed by activated B cells is switched from IgM to IgG, IgA or IgE.

Corticosteroids

Anti-inflammatory drugs that are derived from cortisol secreted by the adrenal cortex and that are effective in suppressing inflammation in asthma but not in chronic obstructive pulmonary disease.

FEV1

(Forced expiratory volume in 1 second). The amount of air that can be forcibly exhaled in 1 second, measured in litres. It is used as a measurement of airway obstruction in asthma and chronic obstructive pulmonary disease.

Theophylline

A drug that is used at high doses as a bronchodilator in the treatment of asthma and chronic obstructive pulmonary disease. However, it is now less widely used as the high doses can have side effects, including nausea, headaches, cardiac arrhythmias and seizures. More recently, it has been shown to have anti-inflammatory effects at lower doses and may reverse corticosteroid resistance by increasing the activity of histone deacetylase.

Cyclosporin A and tacrolimus

Calcineurin inhibitors that are used to prevent transplant rejection and that function by inhibiting nuclear factor of activated T cells (NFAT).

Rapamycin

An immunosuppressive drug that, in contrast to calcineurin inhibitors, does not prevent T-cell activation but blocks interleukin-2-mediated clonal expansion by blocking mTOR (mammalian target of rapamycin).

Mycophenolate mofetil

An immunosuppressant that inhibits purine synthesis and has an inhibitory effect on T cells and B cells. It is currently used to treat transplant rejection and rheumatoid arthritis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barnes, P. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8, 183–192 (2008). https://doi.org/10.1038/nri2254

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2254

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing