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  • Review Article
  • Published:

Immunology of asthma and chronic obstructive pulmonary disease

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.

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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).

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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.

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

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