Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma

Journal of Allergy and Clinical Immunology

Available online 24 September 2013

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Measures of gene expression in sputum cells can identify T_H2-high and T_H2-low subtypes of asthma

• Michael C. Peters, MD^{a, b},
• Zesemayat K. Mekonnen, BA^b,
• Shaopeng Yuan, BS^b,
• Nirav R. Bhakta, MD, PhD^{a, b},
• Prescott G. Woodruff, MD, MPH^{a, b},
• John V. Fahy, MD, MSc^{a, b, ,}

• ^a Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
• ^b Cardiovascular Research Institute, University of California, San Francisco, Calif

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Background

The 3-gene signature of periostin, chloride channel accessory 1 (CLCA1), and Serpin β2 (SERPINB2) in airway epithelial brushings is used to classify asthma into T_H2-high and T_H2-low endotypes. Little is known about the utility of gene profiling in sputum as a molecular phenotyping method.

Objective

We sought to determine whether gene profiling in sputum cells can identify T_H2-high and T_H2-low subtypes of asthma.

Methods

In induced sputum cell pellets from 37 asthmatic patients and 15 healthy control subjects, PCR was used to profile gene expression of the epithelial cell signature of IL-13 activation (periostin, CLCA1, and SERPINB2), T_H2 genes (IL4, IL5, and IL13), and other genes associated with airway T_H2 inflammation.

Results

Gene expression levels of CLCA1 and periostin, but not SerpinB2, were significantly higher than normal in sputum cells from asthmatic subjects. Expression levels of IL-4, IL-5, and IL-13 were also significantly increased in asthmatic patients and highly correlated within individual subjects. By combining the expression levels of IL-4, IL-5, and IL-13 in a single quantitative metric (“T_H2 gene mean”), 26 (70%) of the 37 asthmatic patients had T_H2-high asthma, which was characterized by more severe measures of asthma and increased blood and sputum eosinophilia. T_H2 gene mean values tended to be stable when initial values were very high or very low but fluctuated above or below the T_H2-high cutoff when initial values were intermediate.

Conclusion

IL-4, IL-5, and IL-13 transcripts are easily detected in sputum cells from asthmatic patients, and their expression levels can be used to classify asthma into T_H2-high and T_H2-low endotypes.

Key words

• Asthma;
• phenotypes;
• T_H2 cell;
• mast cells;
• eotaxin;
• inflammation;
• sputum;
• cytokines;
• eosinophils;
• IL-4;
• IL-5;
• IL-13;
• IL-17

Abbreviations used

• BME, β-Mercaptoethanol;
• CLCA1, Chloride channel accessory 1;
• CPA3, Carboxypeptidase A3;
• Feno, Fraction of exhaled nitric oxide;
• LABA, Long-acting β-agonist;
• RIN, RNA integrity number;
• SerpinB2, Serpin β2;
• UCSF, University of California, San Francisco