We would like to thank J. Domagala-Kulawik and colleagues for their interesting and useful comments on our previously published article on T-regulatory (Treg) cells in chronic obstructive pulmonary disease (COPD) 1.
We took great interest in the findings of the study by Fijalkowski et al. 2, which showed that the proportion of Treg cells (identified by flow cytometry with CD4/CD25/CTLA4 antibodies) was significantly decreased in COPD patients. These results support our conclusions.
Upregulation of Treg cells in central airways, as described in our article, corresponds to the the data of Fijalkowski et al. 2 of an increased Treg cell proportion in patients with inflammatory and tumourous lung disease. Inflammation in central airways is present in practically all smokers. Upregulation of Treg cells could be an adaptive reaction of the immune system to increase the peripheral tolerance against self-antigens produced by continuous irritation of airways by tobacco smoke. At the same time, these changes could be the first step towards tumour genesis, as it is now known that Treg cells decrease cellular immune anti-tumour defence 3. Opposite changes in peripheral airways in COPD patients which we reported in our article, possibly enhance the autoimmune process 1. Therefore, the events occurring in central and peripheral airways should be regarded as independent local reactions of the immune system.
We agree that lung tissue taken during surgery from patients with lung cancer may lead to confusing results. However, surgical specimens are the only available material for histopathological examination of small airways and are widely accepted in COPD studies 4.
Using flow cytometry, Fijalkowski et al. 2 found that Treg cell proportion was increased in lung cancer patients which contradicted our results. The authors suggested that Treg cell distribution could be affected by tumour stage and location.
In our study, all subjects had nonsmall cell peripherally located carcinoma at T1 stage (tumour size did not exceed 3 cm in diameter). The distribution of different histological types of tumour was similar among all the examined groups of patients including the control group. The discrepancy between our results and the results of Fijalkowski et al. 2 could be explained by the methods used for analysis. Flow cytometry of bronchoalveolar lavage (BAL) fluid provides the average proportion of cells from the lung or lobe. A histological analysis reveals the immune cell spectrum in particular tissue areas and therefore reflects local immune events. Of course, it would be intriguing to compare the picture in the areas closer to the tumour location and this could be the task for our future studies.
Other previous studies on Treg cells in COPD confirm our results. Recently, it has been shown that Treg cells are increased in the BAL fluid of healthy smokers and COPD patients, which is consistent with our study results 5. In addition, it has recently been demonstrated that Treg cells were increased within lymphocyte follicles in moderate COPD 6. Furthermore, using BAL flow cytometry, Barcelo et al. 7 showed that smokers with preserved lung function had a prominent upregulation of Treg cells that was absent in patients with COPD. In lungs of patients with emphysema the number of CD4+CD25+ positive Treg cells was decreased correlating with FOXP3 mRNA expression 8.
In our study 1, lung function testing was performed according to European Respiratory Society and British Thoracic Society guidelines for spirometry 9, and COPD staging according to Global Initiative for Chronic Obstructive Lung Disease criteria 10. In addition, COPD diagnosis was confirmed by histological examination of lung specimens stained with haematoxylin and eosin to determine structural changes in lung tissue. All COPD patients exhibited characteristic lung tissue changes. For example, in small airways goblet cell metaplasia and mucous plugging, as well as fibrosis and severe inflammation, and in lung parenchyma emphysema and fibrosis was observed. We have not discussed these features in detail in our article as they are widely accepted and used 11. Therefore, we are sure that airflow limitation was caused by COPD, but not by a solitary peripheral carcinoma.
We agree that the number of nonsmokers enrolled in our study was relatively large. We recruited these patients for a long period of time (3 yrs). All these subjects really were nonsmokers, not ex-smokers.
To conclude, we would like to thank J. Domagala-Kulawik and colleagues once more for their interesting point of view, comments, suggestions and remarks,which have allowed us to look at our study design from another point of view and provide us with new ideas.
Statement of interest
None declared.
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