Significant increase of CD57+ cells in pulmonary lymphoid follicles of COPD patients

J. Olloquequi, J.F. Montes, A. Prats, E. Rodríguez, M.A. Montero, J. García-Valero, J. Ferrer
European Respiratory Journal 2011 37: 289-298; DOI: 10.1183/09031936.00201509

Abstract

Although the presence of pulmonary lymphoid follicles (LFs) has been associated with the progression of chronic obstructive pulmonary disease (COPD), there is no information regarding the pattern of vascularisation, expression of addressins or inflammatory cell densities within these structures in COPD.

Histological and immunohistochemical techniques were used to assess the prevalence, structure, localisation, vascularisation and cell proliferation/apoptosis of LFs, as well as the follicular density of B- and T-lymphocytes, macrophages, dendritic cells and CD57+ cells, in lung tissue of nine nonsmokers, 18 smokers without COPD, 16 smokers with moderate COPD and 16 patients with very severe COPD.

The density of CD57+ cells within LFs of COPD patients was significantly increased compared to that of nonsmokers and smokers without COPD (p<0.05). Moreover, the percentage of LF profiles with cell apoptosis was also significantly higher in COPD patients (p = 0.03). By contrast, no significant differences among groups were observed in the follicular densities of other inflammatory cells, nor in the distribution of blood and lymphatic vessels within LFs.

Since CD57+ cells are important effectors of cytotoxicity and immune regulation, an increase in their follicular density supports the hypothesis of local immune dysfunction in COPD.

Chronic obstructive pulmonary disease (COPD) is characterised by progressive and not fully reversible airflow limitation, associated with an abnormal inflammatory response of the lung to noxious particles and gases, mainly cigarette smoke 1. The main pathological features of COPD are found in both peripheral airways and lung parenchyma, as well as in pulmonary vasculature.

It is now established that COPD is a chronic inflammatory condition resulting from complex interactions between cells belonging to the innate and adaptive immune systems. Recently, this inflammatory process has been associated with the development of ectopic lymphoid follicles (LFs) in lungs of COPD patients 2–7, which are similar to the tertiary lymphoid tissue found in other inflammatory or autoimmune diseases 8, 9.

Since LFs were described in the airways of COPD patients 2, increasing attention has been focused on the study of these structures and their possible role in the pathogenesis of COPD. Progression of COPD from Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 to stage 4 is associated with the number of bronchioles containing LFs 3. Furthermore, although the nature of the stimuli that trigger the formation of LFs remains unknown, an oligoclonal process in follicular B-lymphocytes of COPD patients and mice with emphysema has been reported, which suggests an antigen-specific proliferation in these structures 4.

Conversely, despite increased numbers of macrophages, dendritic cells, natural killer cells and lymphocytes having been reported in lung tissue of COPD patients 10, 11, few data are available on the follicular densities of these cells and the molecules involved in their recruitment to LFs in COPD, especially at the most severe stages of the disease. Indeed, only one study reported a higher percentage of T-regulatory cells within LFs of moderate COPD patients compared with smokers and nonsmokers 5, but no information is available regarding vascular supply, lymphatic drainage or the follicular densities of other key inflammatory cells in subjects with and without COPD. Moreover, there are no studies examining which addressins are involved in the migration of inflammatory cells from the blood into the LFs in COPD.

The purpose of the present study is to examine the prevalence, localisation, vascularisation, addressin expression and inflammatory cell densities of LFs in lung tissue of moderate and very severe COPD patients compared to nonsmokers and smokers without COPD.

METHODS

Subjects

The study population comprised 59 subjects who underwent lung resection for non-obstructive peripheral lung tumours or were subjected to double lung transplantation for very severe COPD. The Ethics Committee of Vall d’Hebron Hospital (Barcelona, Spain) approved the study and written informed consent was obtained from all of the patients. Subjects were classified into four clinical groups according to their smoking habits (smokers and nonsmokers) and COPD severity 1: nine nonsmoking patients (never-smokers) with normal lung function; 18 asymptomatic smokers with normal lung function; 16 smokers with moderate COPD (GOLD stage 2); and 16 smokers with very severe COPD (GOLD stage 4) undergoing lung transplantation.

Standard procedures 12 and equipment (Masterlab; Jaeger, Würzburg, Germany) were used to assess pulmonary function in all patients, including measurements of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), residual volume, total lung capacity and carbon monoxide diffusing capacity of the lung (DL,CO). All subjects had been free of acute lung infections and none had received chemotherapy before surgery.

Sample processing

The resected lungs or lobes obtained during surgery were immediately inflated with 4% formaldehyde prior to immersion in fixative for 24 h. After fixation, surgical specimens were serially sliced into 1-cm axial sections and the severity of emphysema was graded using the panel grid described by Thurlbeck et al. 13. Subsequently, 2×2×1-cm randomly selected tissue blocks were excised, embedded in paraffin, cut into serial 4-μm sections and mounted on positively charged slides (Starfrost Plus; Menzel-Gläser, Braunschweig, Germany). One section per block was stained with haematoxylin and eosin.

Immunohistochemistry

The following antibodies were used at the indicated dilutions: polyclonal anti-CD3 (DakoCytomation, Glostrup, Denmark; 1:400), monoclonal anti-CD4 (Novocastra, Newcastle, UK; 1:50), monoclonal anti-CD8 (DakoCytomation; 1:100), monoclonal anti-CD20cy (DakoCytomation; 1:800), monoclonal anti-CD57 (DakoCytomation; 1:80), monoclonal anti-follicular dendritic cell (DakoCytomation; 1:20), monoclonal anti-CD83 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA; 1:30), monoclonal anti-CD68 (DakoCytomation; 1:50), monoclonal anti-platelet–endothelial cell adhesion molecule (PECAM)-1 (DakoCytomation; 1:200), monoclonal anti-podoplanin (Abcam, Cambridge, UK; 1:150), monoclonal anti-mucosal addressin cell adhesion molecule (MAdCAM)-1 (AbD Serotec, Kidlington, UK; 1:30), monoclonal anti- peripheral node addressin (PNAd) (BD Biosciences, Franklin Lakes, NJ, USA; 1:50), monoclonal anti-Ki-67 (DakoCytomation; 1:150), monoclonal anti-Bcl-6 (DakoCytomation; 1:60), and polyclonal anti-cleaved caspase 3 (Cell Signaling Technology, Danvers, MA, USA; 1:200).

Immunostaining was performed using the avidin–biotin complex (ABC) immunoperoxidase method (Vectastain Elite ABC kit; Vector Laboratories, Burlingame, CA, USA) with a 3,3’-diaminobenzidine tetrahydrochloride (DAB) reaction. For double immunostaining of CD3 and CD57 antigens, the sections were first incubated with polyclonal anti-CD3. After DAB development, this marker was amplified with a nickel ammonium sulphate solution, which permitted obtention of a differentiating black colour for T-cells. Following this amplification, the sections were incubated with monoclonal anti-CD57, with DAB development giving a brown colour. Hence, this design permitted differentiation between CD3+CD57+ cells (double-stained with black and brown) and CD3−CD57+ cells (brown-stained).

Assessment of LFs

Following the criteria previously described by Elliot et al. 14, LFs were defined as focal collections of >50 lymphomononuclear cells with a cell density (cells per millimetre squared) more than 10 times that of the surrounding tissue. Haematoxylin and eosin staining was used to assess the presence and location of LFs in samples from all patients. Furthermore, two sections per subject were analysed for each antibody.

For the assessment of cell densities, a point-counting method described previously was used 15. Briefly, at least six fields were randomly and systematically sampled in order to assess cell densities in follicular tissue by using a grid with a known area attached to the eyepiece of the microscope. The number of points hitting each LF profile were counted and converted into square millimetres using a conversion factor calculated for the specific magnification used. In each field, the number of cells was determined by counting the cell profiles that were not in vessels or intersected by the exclusion lines. Mean patient values were obtained by averaging the results of all LFs. Cell densities were expressed as the number of cells per square millimetre of tissue examined.

In addition, the percentage of patients with positive staining for vascular structures and addressins within LFs was determined by considering two different locations of these markers: either at the LF periphery or inside it. The percentage of patients with positive staining for the markers of proliferation and apoptosis in LFs were also averaged. The cases were coded and the measurements made without knowledge of clinical data.

Statistical analysis

The descriptive statistical analysis included mean±sem for each parameter. Clinical data were compared between groups using ANOVA. The prevalence, vascularisation, proliferation and apoptosis of LFs were compared between case groups using the Chi-squared test. Differences in LF cell densities were analysed using the Kruskal–Wallis test. When differences were significant, the Kruskal–Wallis test was followed by the Mann–Whitney U-test for comparison between groups. The significance level was set at p<0.05. All analyses were performed using Statgraphics Centurion XV (StatPoint, Inc., Warrenton, VA, USA).

RESULTS

Demographic and clinical data

Table 1 shows the characteristics of the patient groups. The four clinical groups were similar with regard to age, and no significant difference was found in cumulative cigarette consumption among smokers with and without COPD. By contrast, the values of FEV1, FEV1/FVC and DL,CO were significantly different in COPD patients, the very severe COPD subjects showing the lowest values. Additionally, as expected, there was a significantly increased macroscopic emphysema degree (% predicted) in COPD patients, especially those at a very severe GOLD stage (table 1).

View this table:
Table 1– Clinical and demographic data

LF assessment

Structure and localisation

The presence of at least one LF was observed in 89% of samples studied, their prevalence ranging 83–100% in the four clinical groups, without significant differences among them (table 1). LFs were characterised by a high density of mononuclear infiltrates without a fibrous covering layer. Furthermore, anthracotic granules were frequently located at the periphery of LFs, especially in patients with very severe COPD (fig. 1a).

Figure 1–
Figure 1–

Vascularisation and addressins of lung lymphoid follicles (LFs). a) Haematoxylin–eosin staining of a LF in an arteriolar adventitia. Anthracotic granules were frequently found in the periphery of the lymphoid masses (arrow). A lymphatic vessel surrounds the LF (asterisk). b) Immunolocalisation of platelet–endothelial cell adhesion molecule (PECAM)-1 in lung LFs. Blood vessels were found inside and in the periphery of lymphoid masses. PECAM-1 was expressed in both the flat constitutive and high endothelial venule (HEV) phenotypes of endothelial cells. c) Immunolocalisation of podoplanin in lung LFs. Detail of a peripheral lymphatic vessel that penetrates into the lymphoid mass. d) Immunolocalisation of peripheral node addressin (PNAd) in lung LFs. PNAd was expressed in both HEVs and conventional vessels. e) Immunolocalisation of mucosal addressin cell adhesion molecule (MAdCAM)-1 in a Peyer’s patch (positive control). f) Immunolocalisation of MAdCAM-1 in lung LFs. None of the LF profiles was MAdCAM-1-positive. Immunostained sections were counterstained with Friedlander's haematoxylin. Scale bars: a, d and e) 100 μm; b, c and f) 50 μm.

LFs were essentially distributed within three tissue compartments: bronchiolar and arteriolar adventitias, and parenchymal interstitium. Occasionally, some samples showed LFs in bronchial adventitias and lobular septa, which were not included in further analyses because of their low frequency.

No significant differences among groups were observed in the frequency of LFs present in each compartment. However, it is interesting to note that nonsmokers showed a higher prevalence of bronchiolar LFs, whereas, in COPD patients, the arteriolar compartment was more frequently infiltrated by LFs (fig. 1a).

Vascularisation

The presence and distribution of blood vessels in LFs was determined by the immunolocalisation of PECAM-1 (fig. 1b). It was found that 95% of LF sections were positive for this marker, and there were no significant differences in the number of positive profiles among clinical groups. Blood vessels were found in both the centre of the LF and also the adjacent connective tissue, both the flat and the high endothelial venule (HEV) phenotypes of endothelial cells being observed (fig. 1b).

The immunolocalisation of podoplanin permitted assessment of the presence of lymphatic vessels in the LFs (fig. 1c). The results showed that lymphatic endothelium was detected in around half (56%) of the LFs, without significant differences among groups. When the distribution of lymphatic vessels was assessed in these LFs, it was observed that only 12% showed lymphatic irrigation inside the LFs (fig. 1c), whereas 91% of the LFs had surrounding lymphatic vessels lying on the connective tissue of their periphery. No significant differences among groups were observed in the distribution of lymphatic vessels.

Vascular addressins

In order to determine which addressin was expressed by the vessels of lung LFs, immunolocalisation of PNAd and MAdCAM-1 was carried out in the pulmonary samples. It was found that 35% of LFs in lung samples were PNAd-positive, although no significant difference was found among clinical groups. It is noteworthy that PNAd expression was demonstrated not only in HEVs but also in conventional endothelium of LFs (fig. 1D), as well as in some adventitial vessels of bronchioles and arterioles without tertiary lymphoid tissue.

Regarding the PNAd distribution in LFs, it was found that 82% showed peripheral PNAd-positive vessels, whereas 54% showed a central localisation, without significant differences among clinical groups. Nevertheless, severe COPD patients showed a higher number of LFs with central PNAd staining than the other groups (fig. 2).

Figure 2–
Figure 2–

Percentage of lung lymphoid follicles (LFs) with peripheral node addressin (PNAd)+ central vessels. Data are presented as mean±sem. Very severe chronic obstructive pulmonary disease patients showed a higher percentage of LFs with central PNAd staining, although no significant differences among groups were found (p>0.05). NS: nonsmokers; Mod: moderate; VS: very severe.

In order to assess the reactivity of lung LFs for MAdCAM-1, a section of a small intestine with a Peyer’s patch was used as positive control (fig. 1e). It was found that none of the pulmonary LF profiles were MAdCAM-1-positive, whatever the location or clinical group considered (fig. 1f).

Cell densities

CD3+, CD4+ and CD8+ cells and B-lymphocytes, as well as macrophages and CD57+ and dendritic cells were immunostained in order to assess whether, among clinical groups, there were qualitative or quantitative differences in the main inflammatory cells constituting the LFs.

All LFs were characterised by a central core of B-lymphocytes, the most abundant follicular cells (fig. 3a), and a peripheral zone mainly infiltrated by T-lymphocytes (fig. 3b). Among these, CD4+ and CD8+ T-cells (fig. 3c and d) were distributed diffusely, in either the follicular core or surrounding germinal centres. In every case, both B- and T-lymphocytes were found in close contact with blood and lymphatic vessels.

Figure 3–
Figure 3–

Immunolocalisation of the main cell types inside lung lymphoid follicles (LFs). a) B-lymphocytes were the most abundant cells within LFs, and followed a central distribution. b) T-lymphocytes were mainly found in the follicular periphery, with CD4+ cells the most abundant subset (c). Both CD4+ and CD8+ (d) cells were also found in the follicular core. e) Macrophages were diffusely distributed through the lymphoid aggregates, whereas the presence of mature dendritic cells was sparse in most LF profiles (f). g) CD57+ cells were found in both the periphery and the centre of LFs, and their density was significantly higher in LFs of COPD patients than in those of patients without COPD (h). Sections were counterstained with Friedlander’s haematoxylin, except one (c), which was counterstained with eosin. Scale bars; a, d, e and g) 100 μm; b and c) 125 μm; f) 250 μm; and h) 250 μm.

Macrophages, mature dendritic cells and CD57+ cells were diffusely distributed in most of the LF profiles (fig. 3e–h). By contrast, isolated follicular dendritic cells were only found in samples belonging to very severe COPD patients.

Importantly, when the cell densities of LFs were compared, it was found that COPD patients showed a significantly higher density of CD57+ cells than did nonsmokers and smokers without COPD (p<0.05) (table 2, and figs 3g and h, and 4). By contrast, no significant differences in the densities of the other cell types were found (table 2).

View this table:
Table 2– Lymphoid follicle cell densities

Additionally, in order to differentiate the subpopulations of CD57+ cells, double immunostaining of CD3 and CD57 antigens was performed in the present series (fig. 5). Subsequently, the follicular density of both the CD57+CD3- and CD57+CD3+ subpopulations was assessed. The results showed that the mean ratio of CD57+CD3- cells to CD57+CD3+ plus CD57+CD3- cells in LFs was 0.23. No significant differences among the clinical groups were found (0.21 in nonsmokers, 0.33 in smokers without COPD, 0.16 in moderate COPD patients and 0.29 in very severe COPD patients).

Figure 5–
Figure 5–

Double immunostaining of CD3 and CD57 antigens on lymphoid follicles (LFs). a) Representative micrograph of double immunostaining of CD3 (black) and CD57 (brown) antigens on a LF of a COPD patient. b) Immunostaining of CD57 (brown) on a control consecutive section (3 μm apart) of the same LF. Arrows indicate CD3+CD57- cells, circles CD3-CD57+ cells and squares CD3+CD57+ cells. Scale bars = 20 μm.

Proliferation and apoptosis

In order to examine whether or not LFs were active in terms of proliferation and/or apoptosis, the percentage of samples with positive cell staining for Bcl-6, Ki-67 and activated caspase 3 in at least one LF was determined.

Only two LF profiles of a nonsmoker and a very severe COPD patient were positive for Bcl-6 staining (fig. 6a). By contrast, the Ki-67 staining (fig. 6b) demonstrated proliferation in the majority of LFs (ranging 56–91%), without significant differences among groups.

Figure 6–
Figure 6–

Proliferation and apoptosis in lung lymphoid follicles (LFs). a) Immunolocalisation of Bcl-6 in a LF of a nonsmoker. Immunolocalisation of Ki-67 (b) and activated caspase 3 (c) in consecutive sections of a LF from a very severe chronic obstructive pulmonary disease patient. Sections were counterstained with eosin (a) and Friedlander’s haematoxylin (b and c). Scale bars = 50 μm.

Regarding apoptosis, COPD patients showed a significantly higher percentage of samples with positive staining for activated caspase 3 than the other groups (p<0.05) (Figs. 4 and 6c). Indeed, 25% of moderate COPD patients and 30% of very severe COPD patients showed activated caspase 3 staining, whereas no LFs with positive staining were found in nonsmokers and smokers without COPD (fig. 4).

Figure 4–
Figure 4–

Follicular CD57+ cell density (□) and apoptosis (caspase 3+ lymphoid follicles (LFs); ░). Data are presented as mean±sem. Moderate (Mod) and very severe (VS) chronic obstructive pulmonary disease (COPD) patients showed a significantly higher density of follicular CD57+ cells and a significantly higher percentage of LF profiles with apoptosis than nonsmokers (NS) and smokers without COPD. *: p<0.05 versus NS; #: p<0.05 versus smokers without COPD.

DISCUSSION

For a long time, the presence of LFs has been associated with COPD progression 3, but only recently has some attention been paid to the study of the cellular and molecular patterns of this tertiary lymphoid tissue in COPD patients 5, 6. Following this research line, the present work represents a complete study of LFs, including their prevalence, vascularisation, cell composition and proliferation/apoptosis in patients with moderate and very severe COPD. The present results show, for the first time, that COPD patients exhibit a significant increase in the follicular density of CD57+ cells compared to nonsmokers and smokers without COPD. Moreover, the percentage of LF profiles with cell apoptosis is also significantly increased in COPD patients.

A principal objective of the present study was to quantify the main cellular types inside LFs in order to compare their densities among clinical groups. Importantly, the results showed a significant and specific increase in the follicular density of CD57+ cells in patients with COPD. This finding adds new knowledge about the role that LFs could play in the disease, since there is evidence pointing toward CD57 as a marker of lung inflammation 16, or even as a marker of general immune dysfunction, independent of the underlying disease 17. Moreover, it has recently been demonstrated that CD57 antigen is also a marker of terminally differentiated cells with a high cytolytic potential 18. Indeed, Chattopadhyay et al. 18 reported that CD57 expression was strongly correlated with simultaneous expression of pro-apoptotic molecules, such as granzyme A, granzyme B and perforin. Thus an increased density of the follicular CD57+ cells in COPD patients may explain the high percentage of LF profiles with cell apoptosis that was observed in the moderate and very severe COPD groups.

Apart from their cytotoxicity, Kim et al. 19 showed that a subset of CD57+ cells present in germinal centres of human lymphoid tissues induces B-cell differentiation and immunoglobulin production. In addition, Laffont et al. 20 demonstrated that natural killer cells act as regulators of alloreactive T-cell priming in allotransplantation by killing allogeneic dendritic cells in draining lymph nodes.

Recently, there has been increased interest in a better understanding of the pathophysiological role of LFs in COPD. There are several observations pointing to the fact that these structures could arise in response to chronic bacterial and viral colonisation or even against neo- or self-antigens, which have been hypothesised to be present in lungs of COPD patients 7. In this respect, the higher density of follicular CD57+ cells found in COPD groups is noteworthy, since CD57 antigen is expressed by many cells during chronic immune activation 21 or under clinical conditions, such as infections or immune dysfunction 17.

By contrast, although previous data of Plumb et al. 5 indicated an increase in CD4+ T-cells in parenchymal LFs of moderate COPD patients, the present results do not show any significant difference in the follicular densities of B-cells, T-cells, macrophages or mature dendritic cells among clinical groups.

Another objective of the present study was to examine the structure and localisation of LFs in order to find existing differences between subjects with and without COPD. We have stated that LFs were located in both the adventitia of airways and the parenchyma of pulmonary samples, as previously described 2–6, 14. However, the presence of LFs was also observed in the connective tissue of lobular septa and in the arteriolar adventitia, the later compartment being the most frequently occupied by LFs in COPD patients. This finding reveals that LF development is not restricted to the connective tissue of airways and parenchymal interstitium, other lung compartments also being susceptible to infiltration by these cellular aggregates.

Hogg et al. 3 reported an association between the number of small airways containing LFs and COPD severity. However, when the number and distribution of LF profiles for each compartment (small airways, arterioles and parenchyma) were compared, no significant differences were found among clinical groups. After data analysis, we considered that one factor interfering with these results could be the inhaled corticosteroid treatment given to most COPD patients (see table 1). Correspondingly, Hogg et al. 22, found a negative association between steroid therapy and the percentage of airways containing LFs.

Although no data are available regarding the effect of inhaled steroids on infiltrated CD57+ cells, it has been shown that steroid therapy drastically reduces lymphocyte numbers in the airways 23. Moreover, CD57 levels in patients with relapsing–remitting multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis appear to be influenced by corticosteroid therapy, which reduces these lymphocyte counts 24. Hence, if inhaled steroids could have influenced the present results, their hypothetical effect would make the differences found in the follicular density of CD57+ cells more remarkable.

Immunolocalisation of PECAM revealed that LFs of subjects with and without COPD exhibit a defined pattern of vascularisation, adding further information to previous studies that reported a high number of vascular structures in lung lymphoid masses of smokers 25, subjects with idiopathic pulmonary fibrosis 26 and subjects with asthma 14. Conversely, the immunolocalisation of podoplanin showed that most LF profiles did not present lymphatic vessels inside, suggesting that these LFs lack their own lymphatic drainage. This could be related to the absence of the fibrous covering that is characteristic of tertiary lymphoid tissue 27.

The addressins PNAd and MAdCAM-1 are expressed in HEVs of lymph nodes and Peyer’s patches, respectively, and play a key role in lymphocyte homing, permitting the passage of lymphocytes from the blood into secondary lymphoid tissues 28. To the best of our knowledge, this is the first study to provide data regarding the expression of PNAd and MAdCAM-1 in LFs of COPD patients. The results showed that 35% of the LF profiles were PNAd+, the very severe COPD patients showing the highest number of LF profiles with central PNAd staining. Conversely, none of the LF profiles showed positive staining for MAdCAM-1. These results add new knowledge to previous studies reporting the expression of PNAd in LFs of patients with idiopathic pulmonary fibrosis 26 and to others reporting an absence of MAdCAM-1 expression in bronchus-associated lymphoid tissue of mice 29. This specific expression of PNAd correlates with that which is characteristic of the ectopic lymphoid tissue found in chronic inflammatory diseases 30, 31.

Finally, following exhaustive analysis of LFs from COPD patients and control groups, no significant differences were found in the prevalence, vacularisation and cell composition of this ectopic lymphoid tissue, except for CD57+ cells. Therefore, the specific increase in these immune cells within LFs of diseased subjects permits us to conclude that CD57+ cells could play a key role in COPD pathogenesis.

Acknowledgments

The authors thank the personnel of the Thoracic Surgery Dept of Hospital Vall d’Hebron (Barcelona, Spain) who provided biological specimens. They also thank M. Sevillano (Dept de Biologia Cel·lular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain) for technical assistance and G. Gannaway (Dept de Didàctica I Organització Educativa (Facultat de Pedagogia, Universitat de Barcelona) for linguistic advice.

Footnotes

  • Support Statement

    This study was supported by grants from the Health Research Fund (Madrid, Spain; FIS 04/0635), Catalan Society of Pneumology (Barcelona, Spain; Beca SOCAP 2006) and the Spanish Society of Pulmonology and Thoracic Surgery (Barcelona, Spain; 2005). J. Olloquequi is funded by a researcher training fellowship from the Commission for Universities and Research of the Departament of Innovation, Universities and Enterprise of the Generalitat of Catalonia (Barcelona, Spain) and the European Social Fund (Brussels, Belgium).

  • Statement of Interest

    None declared.

  • Received December 22, 2009.
  • Accepted May 12, 2010.

REFERENCES

  1. ↵
    Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. NHLBI/WHO workshop Report. Updated 2007. Gig Harbor, Medical Communications Resources, Inc., 2008.
  2. ↵
    1. Bosken CH,
    2. Hards J,
    3. Gatter K,
    4. et al
    . Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry. Am Rev Respir Dis 1992; 145: 911–917.
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Hogg JC,
    2. Chu F,
    3. Utokaparch S,
    4. et al
    . The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 2645–2653.
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. van der Strate BW,
    2. Postma DS,
    3. Brandsma CA,
    4. et al
    . Cigarette smoke-induced emphysema: a role for the B cell? Am J Respir Crit Care Med 2006; 173: 751–758.
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Plumb J,
    2. Smyth LJ,
    3. Adams HR,
    4. et al
    . Increased T-regulatory cells within lymphocyte follicles in moderate COPD. Eur Respir J 2009; 34: 89–94.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Kelsen SG,
    2. Aksoy MO,
    3. Georgy M,
    4. et al
    . Lymphoid follicle cells in chronic obstructive pulmonary disease overexpress the chemokine receptor CXCR3. Am J Respir Crit Care Med 2009; 179: 799–805.
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Brusselle GG,
    2. Demoor T,
    3. Bracke KR,
    4. et al
    . Lymphoid follicles in (very) severe COPD: beneficial or harmful? Eur Respir J 2009; 34: 219–230.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Drayton DL,
    2. Liao S,
    3. Mounzer RH,
    4. et al
    . Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 2006; 7: 344–353.
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Pabst R
    . Plasticity and heterogeneity of lymphoid organs. What are the criteria to call a lymphoid organ primary, secondary or tertiary? Immunol Lett 2007; 15, 112: 1–8.
    OpenUrl
  10. ↵
    1. Di Stefano A,
    2. Caramori G,
    3. Ricciardolo FL,
    4. et al
    . Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin Exp Allergy 2004; 34: 1156–1167.
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Tsoumakidou M,
    2. Demedts IK,
    3. Brusselle GG,
    4. et al
    . Dendritic cells in chronic obstructive pulmonary disease: new players in an old game. Am J Respir Crit Care Med 2008; 177: 1180–1186.
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Crapo R,
    2. Hankinson J,
    3. Irvin C,
    4. et al
    . Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med 1995; 152: 1107–1136.
    OpenUrlCrossRefPubMedWeb of Science
  13. ↵
    1. Thurlbeck WM,
    2. Dunnill MS,
    3. Hartung W,
    4. et al
    . A comparison of three methods of measuring emphysema. Hum Pathol 1970; 1: 215–226.
    OpenUrlPubMed
  14. ↵
    1. Elliot JG,
    2. Jensen CM,
    3. Mutavdzic S,
    4. et al
    . Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma. Am J Respir Crit Care Med 2004; 169: 712–718.
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    1. De Magalhães Simões S,
    2. dos Santos MA,
    3. da Silva Oliveira M,
    4. et al
    . Inflammatory cell mapping of the respiratory tract in fatal asthma. Clin Exp Allergy 2005; 35: 602–611.
    OpenUrlCrossRefPubMedWeb of Science
  16. ↵
    1. Palmer BE,
    2. Mack DG,
    3. Martin AK,
    4. et al
    . CD57 expression correlates with alveolitis severity in subjects with beryllium-induced disease. J Allergy Clin Immunol 2007; 120: 184–191.
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Focosi D,
    2. Petrini M
    . CD57 expression on lymphoma microenvironment as a new prognostic marker related to immune dysfunction. J Clin Oncol 2007; 25: 1289–1291.
    OpenUrlFREE Full Text
  18. ↵
    1. Chattopadhyay PK,
    2. Betts MR,
    3. Price DA,
    4. et al
    . The cytolytic enzymes granyzme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression. J Leukoc Biol 2009; 85: 88–97.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Kim JR,
    2. Lim HW,
    3. Kang SG,
    4. et al
    . Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination. BMC Immunol 2005; 6: 3–
    OpenUrlCrossRefPubMedWeb of Science
  20. ↵
    1. Laffont S,
    2. Seillet C,
    3. Ortaldo J,
    4. et al
    . Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells. Blood 2008; 112: 661–671.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Tarazona R,
    2. DelaRosa O,
    3. Alonso C,
    4. et al
    . Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech Ageing Dev 2000; 121: 77–88.
    OpenUrlCrossRefPubMedWeb of Science
  22. ↵
    1. Hogg JC,
    2. Chu FS,
    3. Tan WC,
    4. et al
    . Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med 2007; 176: 454–459.
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Reid DW,
    2. Wen Y,
    3. Johns DP,
    4. et al
    . Bronchodilator reversibility, airway eosinophilia and anti-inflammatory effects of inhaled fluticasone in COPD are not related. Respirology 2008; 13: 799–809.
    OpenUrlCrossRefPubMedWeb of Science
  24. ↵
    1. Stricker RB,
    2. Winger EE
    . Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunol Lett 2001; 76: 43–48.
    OpenUrlCrossRefPubMedWeb of Science
  25. ↵
    1. Richmond I,
    2. Pritchard GE,
    3. Ashcroft T,
    4. et al
    . Bronchus associated lymphoid tissue (BALT) in human lung: its distribution in smokers and non-smokers. Thorax 1993; 48: 1130–1134.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Marchal-Sommé J,
    2. Uzunhan Y,
    3. Marchand-Adam S,
    4. et al
    . Cutting edge: nonproliferating mature immune cells form a novel type of organized lymphoid structure in idiopathic pulmonary fibrosis. J Immunol 2006; 176: 5735–5739.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Carragher DM,
    2. Rangel-Moreno J,
    3. Randall TD
    . Ectopic lymphoid tissues and local immunity. Semin Immunol 2008; 20: 26–42.
    OpenUrlCrossRefPubMedWeb of Science
  28. ↵
    1. Ebert LM,
    2. Schaerli P,
    3. Moser B
    . Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol Immunol 2005; 42: 799–809.
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    1. Xu B,
    2. Wagner N,
    3. Pham LN,
    4. et al
    . Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by l-selectin/PNAd, α4β1 integrin/VCAM-1, and LFA-1 adhesion pathways. J Exp Med 2003; 197: 1255–1267.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Uchimura K,
    2. Rosen SD
    . Sulfated l-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol 2006; 27: 559–565.
    OpenUrlCrossRefPubMedWeb of Science
  31. ↵
    1. Suzawa K,
    2. Kobayashi M,
    3. Sakai Y,
    4. et al
    . Preferential induction of peripheral lymph node addressin on high endothelial venule-like vessels in the active phase of ulcerative colitis. Am J Gastroenterol 2007; 102: 1499–1509.
    OpenUrlCrossRefPubMedWeb of Science
Back to top
View this article with LENS
Email
Print
Citation Tools

Significant increase of CD57+ cells in pulmonary lymphoid follicles of COPD patients
J. Olloquequi, J.F. Montes, A. Prats, E. Rodríguez, M.A. Montero, J. García-Valero, J. Ferrer
European Respiratory Journal Feb 2011, 37 (2) 289-298; DOI: 10.1183/09031936.00201509
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

Subjects