Pathogenesis of severe asthma: cytokines determine the phenotypes

What is severe asthma?

Patients with severe asthma have the following characteristics:

- asthma symptoms which are difficult to control
- require high dosages of medication
- continue to experience persistent symptoms, asthma exacerbations or airflow obstruction.

Severe asthma - differential diagnosis and management (click to enlarge the image):



Severe asthma is not a single phenotype.

There are several subtypes of severe asthma based on the prediminant cytokine profile:

- IL-4/IL-13 signalling pathway accounts for allergen-associated symptoms and high serum immunoglobulin E (IgE) levels. These patients are generally responsive to anti-IgE treatment (omalizumab, Xolair).

- IL-5/IL-33 signalling pathway is likely to play a key role in patients resistant to high doses of inhaled corticosteroid but responsive to systemic corticosteroids and anti-IL5 therapy.

IL-33 is a new member of the IL-1 cytokine family that promotes Th2 inflammation. Video: Interleukin-1 binding to its receptor on a cell surface:



- IL-17 signalling pathway is thought to contribute to 'neutrophilic asthma'.

- Th1 cytokines such as IL-18 and IFN-γ may also in severe asthma pathogenesis. They are traditionally viewed as players in the defence mechanism against viral and intracellular bacterial infection.


T helper cells (click to enlarge the image).

Steroids are the most effective anti-asthma drugs available, yet severe asthma patients are typically resistant to the effects of glucocorticoids.

Glucocorticoid receptor (GR) dysfunction and histone deacetylase activity (HDAC) reduction are likely to contribute to steroid resistance in severe asthma patients.

 References:

Pathogenesis of severe asthma. Poon AH, Eidelman DH, Martin JG, Laprise C, Hamid Q. Clin Exp Allergy. 2012 May;42(5):625-37. doi: 10.1111/j.1365-2222.2012.03983.x.

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