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Activation of Neutrophils in Cutaneous T-Cell Lymphoma

Authors' Affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: David A. Jones, Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Room 671, Boston, MA 02115. Phone: 617-525-5558; Fax: 617-525-5571; E-mail: dajones{at}partners.org.

	Abstract

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Purpose: Cutaneous T-cell lymphoma (CTCL) is a spectrum of disease of unknown etiology defined by infiltrates of activated and malignant T cells in the skin. In working with blood from CTCL patients, we noticed frequent activation of neutrophils; therefore, we tested the hypothesis that neutrophils are activated in CTCL subjects compared with normal healthy controls.

Experimental Design: Using peripheral blood of 44 subjects with CTCL and 15 normal controls, we examined three measures of neutrophil activation. These are the presence of neutrophils of reduced buoyant density, the presence of primed neutrophils in a stimulated chemiluminescence assay, and changes in surface markers by flow cytometry. In addition, we tested plasma interleukin-8 (IL-8) and leukotriene B₄ (LTB₄) levels using ELISA.

Results: A significantly larger fraction of hypodense neutrophils was observed in CTCL subjects compared with normals (10.6 ± 1.7% versus 1.5 ± 0.4%). Stimulated chemiluminescence was also significantly increased in CTCL, and analysis of neutrophil surface markers using flow cytometry showed significantly increased CD11b and CD66b and decreased CD62L, consistent with neutrophil activation. These changes were present even in early stages of CTCL. We further found that plasma IL-8 and LTB₄ levels are elevated in CTCL, which could form a feedback loop contributing to disease pathophysiology.

Conclusions: CTCL is associated with systemic neutrophil activation, even in early disease, and a feedback loop between neutrophils and T cells mediated by IL-8 and LTB₄ is a potential contribution to the pathophysiology of CTCL.

Skin lesions have an infiltration of atypical lymphocytes. In early disease, many of these atypical lymphocytes seem to be activated reactive lymphocytes, but in more advanced disease a dominant malignant clone can usually be shown by molecular methods. Malignant clones most frequently have a phenotype of memory helper T cells expressing the cutaneous lymphocyte antigen and are associated with a type 2 cytokine profile. Neutrophils are occasionally present in the infiltrate of skin lesions but are not a prominent feature. The mechanism of immunosuppression in CTCL is unknown but recent work in our laboratory has provided an initial measure of this effect using spectra-type analysis (2): We showed that despite relatively normal numbers of lymphocytes, the diversity in the T-cell receptor repertoire becomes highly contracted in CTCL. This T-cell receptor repertoire contraction could be found in many patients with early-stage disease, suggesting a more widespread immune system dysregulation than was previously suspected.

Over the past 1 or 2 years, we have noticed that peripheral blood samples of CTCL patients frequently have neutrophils that fail to separate completely from the peripheral blood mononuclear cells (PBMC) using density gradient separation. This can result from an increased number of activated neutrophils that have a reduced buoyant density ("hypodense" neutrophils; ref. 3). We did not see this with normal healthy controls drawn and processed under identical conditions. Based on this finding of hypodense neutrophils in numerous CTCL blood samples, we formally tested the hypothesis that peripheral blood neutrophils are activated in CTCL and here show that this hypothesis seems to be true. In addition to a density shift, we found that peripheral blood neutrophils in CTCL patients are primed for generation of an enhanced respiratory burst and have an activated surface marker phenotype.

Abnormalities in peripheral blood neutrophils of CTCL patients have not been previously reported. However, previous work has shown CXCL8/interleukin-8 (IL-8) production in CTCL skin lesions (4, 5) and by clonal CTCL cells (6, 7), so we further tested for elevated plasma IL-8 levels. The activated neutrophils could, in turn, generate elevated levels of leukotriene B₄ (LTB₄), which has recently been shown to enhance recruitment of T cells to inflamed tissues, including skin (8, 9); thus, we tested plasma LTB₄ levels as well. Plasma levels of both IL-8 and LTB₄ showed significant elevations in CTCL subjects compared with normal controls, providing an initial suggestion as to how activated neutrophils may contribute to the pathophysiology of CTCL.

	Materials and Methods

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Subjects. Forty-four subjects with a biopsy-confirmed diagnosis of CTCL were recruited from the Cutaneous Oncology Clinic of the Dana-Farber Cancer Institute and Brigham and Women's Hospital, and informed consent was obtained according to an institutional review board–approved study protocol. Fifteen healthy control volunteers were also recruited for comparison. For initial studies, frozen aliquots of a previously acquired set of blood samples from 34 CTCL subjects and 14 normal controls were used (these were also acquired according to an institutional review board–approved study protocol). Occasional subjects or controls were prospectively excluded because of viral upper respiratory tract infection, suspected or proven skin lesion superinfection, or any other active infection that was felt could potentially activate neutrophils. Skin-directed treatments for stage I and II disease included topical corticosteroids, topical nitrogen mustard, narrow-band UVB, psoralen plus UVA, and topical bexarotene. Most subjects receiving systemic therapy were treated with extracorporeal photopheresis and/or oral bexarotene, although IFN--2b, corticosteroids, and denileukin diftitox were also used in some subjects.

Blood processing. For initial studies, heparinized venous whole blood was centrifuged (250 x g, 20 minutes, room temperature) through Ficoll-Hypaque (1.077 g/mL, Histopaque; Sigma, St. Louis, MO) and the interface cells were collected and washed once with room temperature Dulbecco's PBS without divalent cations (Invitrogen, Carlsbad, CA), followed by storage over liquid nitrogen in medium with 10% human serum AB and 10% DMSO. For all subsequent studies, venous blood was drawn from the antecubital vein through a 21-G needle into heparinized Vacutainer tubes (BD, Franklin Lakes, NJ). There was a delay between blood drawing and processing of CTCL samples (average 2.5 hours), and we matched this delay (and also the needles and tubes) when processing normal control samples (average delay 2.8 hours). Blood was maintained at room temperature until processing because temperature shifts are known to cause neutrophil activation. Blood was diluted 1:1 with room temperature Dulbecco's PBS without divalent cations and spun through a two-layer discontinuous Percoll gradient of 1.080 and 1.100 g/mL densities. The 1.080 g/mL interface yields PBMCs and hypodense neutrophils, and the 1.100 g/mL interface yields normodense granulocytes. Interface cells were recovered and diluted directly in buffers for flow cytometry and chemiluminescence assays. We avoided further washing of the cells because pelleting neutrophils can result in activation.

Plasma for the LTB₄ and IL-8 assays was recovered as the upper layer of the Percoll centrifugation and centrifuged at 10,000 x g for 10 minutes at 4°C, then stored at –80°C before use in ELISA assays.

Flow cytometry. Two-color flow cytometric analysis was done on three fractions per subject [whole blood, PBMC with hypodense polymorphonuclear (PMN) and normodense PMN fractions] by using the following monoclonal antibodies against neutrophil surface markers: CD16-phycoerythrin–conjugated antibody, CD11b-FITC–conjugated antibody, CD62L-FITC–conjugated antibody (BD Biosciences, San Diego, CA), CD66b-FITC–conjugated antibody (Beckman Coulter, Fullerton, CA), and appropriate isotype-matched control antibodies. Measurements were made using a FACScan flow cytometer (BD Biosciences) with CellQuest software. Whole blood staining was done using PharmLyse buffer (BD PharMingen, San Diego, CA) according to the protocol of the manufacturer.

Chemiluminescence assay. Following separation over Percoll, cells in each fraction were stained with gentian violet in 1% acetic acid and counted using a hemacytometer. The chemiluminescence assay was done using 20,000 neutrophils diluted in 1 mL of Dulbecco's PBS (with 9 mmol/L calcium, 4.9 mmol/L magnesium, and 0.1% glucose) with 150 µmol/L luminol and 10^–7 mol/L fMLP (Sigma). Peak chemiluminescence was measured for each fraction (whole blood, hypodense fraction, and normodense PMN fraction) using a Wallac Trilux 1450 MicroBeta Liquid Scintillation and Luminescence Counter (Wallac Oy, Turku, Finland) using MicroBeta software.

ELISA assays. LTB₄ levels were determined using the average value of two dilutions (1:10 and 1:5) of purified plasma from CTCL subjects and normal controls using a LTB₄ EIA kit (Cayman Chemical, Ann Arbor, MI) according to the instructions of the manufacturer. IL-8 levels were determined for CTCL subjects and normal controls according to the instructions of the manufacturer using two ELISA kits, which had different measurable ranges [IL-8 Ultrasensitive kit (Biosource International, Camarillo, CA) and human IL-8 ELISA kit (R&D Systems, Minneapolis, MN)].

Statistics. Significance for differences between data sets was tested by the Mann-Whitney nonparametric test using a cutoff value of P < 0.05. Correlations were analyzed using the Spearman correlation coefficient with a cutoff value of P < 0.05. Calculations were done using GraphPad Prism software (GraphPad Software, San Diego, CA).

	Results

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Cutaneous T-cell lymphoma subjects have increased numbers of hypodense neutrophils. Figure 1A shows representative fluorescence-activated cell sorting plots of our initial observation of an increased number of hypodense neutrophils localizing with the interface cells (PBMC) of a CTCL patient (bottom) compared with a normal control (top). CD16 staining was done to confirm the presence of neutrophils (Fig. 1B), as was Wright-Giemsa staining of cytospin preparations (data not shown). Flow cytometry in some CTCL subjects also showed CD16-negative hypodense granulocytes that were confirmed as eosinophils by Wright-Giemsa staining (data not shown).

View larger version (45K): [in this window] [in a new window]   Fig. 1. Representative flow cytometry plots using PBMCs of normal (top) and CTCL (bottom) subjects. A, scatter plot for CTCL subject shows population of cells that is absent in plot for normal control. B, staining with CD16 confirms identity of these cells as neutrophils.

View larger version (17K): [in this window] [in a new window]   Fig. 2. CTCL subjects have increased numbers of hypodense neutrophils localizing with interface cells (PBMCs) following density gradient centrifugation. A, results after centrifugation over Ficoll using frozen PBMC samples from a previously studied set of subjects and controls. B, results after centrifugation over Percoll using fresh samples from a new set of subjects and controls.

The mechanism of this type of density shift has not been reported in neutrophils; however, in eosinophils, this is believed to result from a combination of cell swelling and degranulation (11–13). To investigate these effects, we measured the scatter properties of neutrophils in whole blood following CD16 staining. We used backgating of the CD16⁺ neutrophil population to measure mean forward scatter and side scatter of neutrophils and found that mean forward scatter was significantly higher for CTCL subjects than normal controls (675.7 ± 9.8 versus 614.6 ± 11.6, P = 0.001, data not shown). Mean side scatter, on the other hand, was not different. These results suggest that cell swelling is a more prominent contribution to the density shift than degranulation.

This analysis also showed a single bell-shaped distribution of forward scatter values in CTCL neutrophils rather than two peaks. This indicates that there is no subset of hypodense neutrophils that is distinct from a majority normodense population and that the cutoff density of 1.080 g/mL selects the least dense fraction of neutrophils from a continuous distribution that is shifted with activation. Similarly, cell surface marker expression analysis in whole blood showed shifted distributions of staining intensity in CTCL rather than the development of a separate subpopulation of activated neutrophils (data not shown). Because density and activation varies on a continuous distribution, the number of neutrophils defined as hypodense is arbitrary. We chose to use a commonly used Percoll density of 1.080 g/mL for separation, which showed 10% of CTCL neutrophils have a lower density than 1.080 g/mL. A higher Percoll density (e.g., 1.085 g/mL) will yield a greater percentage of neutrophils copurifying with PBMCs.

Hypodense neutrophils are primed and activated in cutaneous T-cell lymphoma subjects. The properties of hypodense neutrophils have not been widely reported in the literature, but by analogy to hypodense eosinophils, likely reflect increased neutrophil activation. The functional activity of neutrophils is modulated on several levels. Two particularly important aspects are the "priming" of neutrophils to undergo a respiratory burst and the activation of neutrophils to mobilize granule contents. Priming is shown in assays of the production of reactive oxygen species, such as chemiluminescence or cytochrome reduction. In these assays, unprimed neutrophils generate little activity on low-level stimulation, whereas primed neutrophils will generate a larger burst. Degranulation can be measured by observing released proteases or by the mobilization of granule membrane proteins to the cell surface. Examples of the latter are CD66b, which is detected on the cell surface primarily after granule mobilization, and CD11b (a component of the integrin Mac-1), which is expressed on resting neutrophils and also mobilized in larger amounts to the surface from granules upon activation. CD62L (the adhesion molecule L-selectin) is proteolytically shed from the surface of neutrophils on activation; thus, CD62L expression decreases with activation.

We sought to confirm that the hypodense neutrophils are primed and/or activated using separated fractions of hypodense and normodense neutrophils from CTCL subjects. Figure 3A shows results of the fMLP-stimulated chemiluminescence assay and Fig. 3B shows flow cytometry analysis of surface marker expression, confirming that the hypodense fraction is more highly primed as well as more highly activated than the normodense fraction.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Hypodense neutrophils are primed and activated in CTCL subjects. A, PMNs stimulated with a low level of fMLP showed a 6-fold increase in respiratory burst activity for hypodense PMNs compared with normodense PMNs. B, expression of CD11b and CD66b was higher in hypodense PMNs compared with normodense PMNs, and CD62L expression was lower in hypodense versus normodense PMNs, confirming an activated phenotype.

View larger version (18K): [in this window] [in a new window]   Fig. 4. Neutrophils in whole blood of CTCL subjects are primed and activated compared with normal controls. A, stimulated chemiluminescence was 3-fold higher for PMNs in CTCL subjects compared with normal controls. B, expression of CD11b and CD66b was higher, and expression of CD62L was lower, in CTCL subjects compared with normal controls as measured by flow cytometry.

View larger version (22K): [in this window] [in a new window]   Fig. 5. Subgroup analysis by CTCL stage and treatment. CTCL subjects with earlier-stage disease (stage I/II) have higher levels of neutrophil activation compared with subjects with more advanced disease (stage III/IV). Subjects receiving skin-directed therapy had higher numbers of activated neutrophils compared with subjects receiving systemic therapy. The lower levels of activated neutrophils seen in advanced-stage subjects may be more related to the immunosuppressive systemic therapies they were receiving.

View larger version (17K): [in this window] [in a new window]   Fig. 6. CTCL subjects have increased plasma levels of LTB4 and IL-8. A, CTCL subjects, particularly those with early-stage disease receiving skin-directed therapy only, showed elevated levels of LTB4. B, CTCL subjects also showed elevated IL-8 levels compared with normal controls.

	Discussion

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Neutrophil activation in CTCL is potentially important for several reasons. First, these data suggest that systemic priming and activation of neutrophils are present even in early-stage disease, emphasizing that the often mild clinical skin disease occurs in the context of significant systemic immune system dysregulation. Although we were initially surprised by this finding, it is consistent with our previous demonstration of significant contractions in the T-cell receptor repertoire in early-stage CTCL (2). Another group has also observed a suggestion of innate immunity differences between CTCL patients and normal healthy controls (14). In their experiments using a CpG Toll-like receptor 9 agonist and other stimuli to generate a therapeutic antitumor response in CTCL, CTCL patients had a blunted response to the Toll-like receptor 9 agonist, IFN-, and IL-15 when compared with normal healthy controls.

Second, the presence of activated neutrophils or elevations in IL-8 or LTB₄ could potentially correlate with prognosis or other clinical variables in the same way that eosinophilia and infiltration of skin lesions with eosinophils are markers of a poor prognosis (15, 16). The mechanism that underlies eosinophil activation is unknown but presumably reflects a cytokine imbalance associated with Th2 skewing, and such a cytokine imbalance could be related to priming and activation of neutrophils as well. Correlating these or other related measures with clinical variables will be a focus of future work. At this point, it has proved difficult to make such correlations because we included a highly heterogeneous patient population with a variety of clinical presentations and treatments as well as varying clinical courses (i.e., disease that was improving, worsening, or staying the same) at the time of blood sampling. As shown in Fig. 5, there seems to be a consistent trend toward less neutrophil activation in advanced stages, but advanced-stage disease is closely linked with the use of systemic treatments. Because the subjects with advanced CTCL that we studied were all actively receiving systemic treatments, it is not possible to determine whether the lower levels of neutrophil activation seen in our CTCL subjects with advanced disease are attributable to disease stage or to disease treatment. We believe it is likely that this decrease in neutrophil activation is due to systemic treatments with immunosuppressive effects, but will need to confirm this in future work by testing advanced-stage subjects before treatment. As shown in Figs. 5 and 6, there also seems to be less neutrophil activation, IL-8 and LTB₄, in subjects who are in remission compared with those having clinically evident active disease at the time of the blood draw. Nonetheless, subjects in clinical remission still showed somewhat higher levels of activated neutrophils compared with normal controls.

Third, the activated neutrophils could be directly involved in the pathophysiology of CTCL. There are many possibilities for such involvement (17). The elevated LTB₄ levels shown in Fig. 6A are one reasonable possibility and this is supported by the recent finding that LTB₄ can modulate the adhesive properties of CD4⁺ T cells expressing the high affinity LTB₄ receptor (BLT1; ref. 8). In a mouse model of skin inflammation, LTB₄ was a key mediator of T cell homing to skin (9), and LTB₄ is therefore an attractive potential contribution to the skin tropism exhibited in CTCL. It is interesting that this would likely be a systemic effect rather than local production of LTB₄ because there are generally relatively few neutrophils in CTCL skin lesions. The elevations in plasma IL-8 shown in Fig. 6B may indicate a mechanism for systemic neutrophil priming and activation in CTCL. However, it is important to note that detailed in vitro culture experiments will be required to verify that the observed concentrations of IL-8 (and likewise LTB₄) are sufficient to produce the observed effects. Also of potential importance is the oxidative stress associated with neutrophil activation. Reactive oxygen species can lead to T-cell dysfunction (3) and could be related to the immunosuppression and loss of T-cell receptor diversity seen in CTCL.

Activation of peripheral blood neutrophils is seen in several disease processes and is not specific to CTCL. Among skin diseases, psoriasis and dermatitis herpetiformis show evidence of systemic neutrophil activation (18–20), but not atopic dermatitis or superficial skin cancer (19). This correlates well with the neutrophilic infiltrates in psoriasis and dermatitis herpetiformis skin lesions but not in atopic dermatitis and skin cancers. Advanced adenocarcinoma patients also show systemic activation of neutrophils, which correlates with impaired T-cell function in these patients (3). Although these various disease processes are associated with the presence of neutrophil activation, it is likely that the mechanisms involved in each case are different, especially with regard to neutrophil-T cell interactions. Further work investigating the causes and effects of neutrophil activation in CTCL should lead to significant added insight into this complex disease.

	Acknowledgments

 
We thank Carrie Wechsler, study coordinator in the Department of Cutaneous Oncology, Dana-Farber Cancer Institute.

	Footnotes

 
Grant support: Specialized Program of Research Excellence grant in skin cancer from the National Cancer Institute (all authors), and a Clinical Research Fellowship from the Doris Duke Charitable Foundation, Harvard Medical School PASTEUR Program, and the Harvard Medical School Office of Enrichment Programs (D.S. Goddard).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 1/05; revised 8/22/05; accepted 9/ 6/05.

	References

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