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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1050-1054, (2002)
© 2002 American Thoracic Society

Articles

Alteration of Balance between Myeloid Dendritic Cells and Plasmacytoid Dendritic Cells in Peripheral Blood of Patients with Asthma

Hiroyuki Matsuda, Takafumi Suda, Hideo Hashizume, Koushi Yokomura, Kazuhiro Asada, Kenichiro Suzuki, Kingo Chida and Hirotoshi Nakamura

Second Division, Department of Internal Medicine, and Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Correspondence and requests for reprints should be addressed to Kingo Chida, M.D., Ph.D., 3600 Handa-cho, Hamamatsu, Shizuoka, 431-3192 Japan. E-mail: chidak11{at}hama-med.ac.jp

ABSTRACT

Asthma, a well-known helper T cell Type 2 (Th2)-mediated disease, has a polarized immune response toward a Th2 phenotype. However, the factors causing the Th2 polarization remain to be fully determined in this disease. Dendritic cells (DCs) are the most potent antigen-presenting cells that play a central role in initiating the primary immune response. In human blood, two functional distinct subsets of DCs, myeloid DCs and plasmacytoid DCs, have been identified. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) are also called Type 1 DCs (DC1) and Type 2 DCs (DC2), respectively, because mDCs and pDCs were shown to preferentially differentiate naive T cells into Th1 and Th2 cells, respectively. In asthma, it can thus be speculated that an altered balance of mDCs to pDCs toward pDCs may contribute to the Th2 polarization. To clarify this, we examined the numbers of mDCs and pDCs in the peripheral blood of 44 patients with asthma and 38 normal subjects, using multicolor flow cytometry. We found that the patients with asthma had a significantly higher number of pDCs, resulting in a significant decrease in the ratio of mDCs to pDCs compared with normal subjects. These data indicate that the patients with asthma had a polarization of the mDC:pDC balance toward pDCs, which may be involved in producing the Th2-dominant immune phenotype in asthma.

Key Words: asthma • dendritic cells • myeloid dendritic cells • plasmacytoid dendritic cells • DC1 • DC2

Asthma is a chronic disease associated with abnormal lung physiology, including reversible airway obstruction and bronchial hyperreactivity. Infiltration of activated eosinophils in the airways was considered to be central to the pathophysiology of asthma (1, 2). Studies of asthma in humans as well as its animal models have also highlighted a critical role of Type 2 CD4+ T helper (Th2) cells as orchestrators of this disease (3, 4). Th2 cells produce interleukin (IL)-4, IL-5, and IL-13, which promote IgE production and eosinophil activation, both of which play a role in the pathogenesis of asthma (5). Indeed, CD4+ T cells producing these cytokines have been identified in bronchoalveolar lavage and airway biopsies, suggesting that patients with asthma show an apparent immune polarization toward a Th2 phenotype (3, 6, 7). However, the factors causing the Th2 polarization in asthma remain to be fully determined.

The specific cytokine profile of T cells, Th1- or Th2-type, can be induced by a variety of factors, including the genetic background, the nature of the antigenic stimulus, the cytokine microenvironment, and costimulatory signals (5). During the early steps in stimulating naive T cells, the first activation signal is the presentation of antigen-derived peptides by antigen-presenting cells (APCs). This initial interaction between naive T cells and APCs is also thought to critically determine the types of resulting immune responses. Interestingly, the subsets of APCs, such as those that have the capacity to produce high amounts of prostaglandin E2, were shown to preferentially induce Th2 cell development (5, 8–10). In contrast, APCs secreting a large amount of IL-12 potentially induce a Th1 response (11). These data suggest that distinct subsets of APCs may promote different types of T cell responses. In allergic diseases, APCs involved in responses against allergens may be functionally polarized toward Th2-inducing APCs.

Dendritic cells (DCs) are the most potent APCs that play a central role in initiating the primary immune response (12, 13). In humans, two distinct subsets of DCs, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), have been identified (14–17). mDCs, derived from myeloid precursors, express myeloid cell markers CD13 and CD33, and require exogenous granulocyte-macrophage colony-stimulating factor for their survival (18, 19). mDCs, also called Type 1 DCs (DC1), produce high levels of IL-12 when stimulated with tumor necrosis factor-{alpha} or CD40 ligand and drive a potent Th1-polarized immune response (20, 21). On the other hand, pDCs, which originate from lymphoid precursors, show a plasma cell-like morphology and a lack of myeloid cell markers, and express high amounts of IL-3 receptor {alpha} chain (CD123), which is necessary for their survival and differentiation (15–17). pDCs, also called Type 2 DCs (DC2), can elicit an IL-4-independent Th2 polarization of naive T cells (14). On the basis of these distinct properties of the DC subtypes, mDCs and pDCs were considered to be specialized APCs inducing a Th1 and Th2 response, respectively. In asthma, it is suggested that increased pDCs relative to mDCs may be involved in the Th2-biased immune responses.

To clarify whether the balance between mDCs and pDCs can be altered in asthma, we examined the numbers of mDCs and pDCs and the ratio of mDCs to pDCs in the peripheral blood of patients with asthma. We found a significant increase in the number of pDCs, resulting in a marked decrease in the mDC:pDC ratio in patients with asthma compared with normal subjects. These data suggest that a Th2 predisposition of immune responses in asthma may be associated with a polarized mDC:pDC balance toward pDCs.

METHODS

Study Subjects
The subjects included 44 patients with asthma, consisting of 31 patients with atopic asthma and 13 patients with nonatopic asthma. Thirty-eight healthy nonatopic volunteers were also studied as control subjects. All patients in this study were recruited from the Hamamatsu University School of Medicine (Hamamatsu, Japan) teaching hospital and gave informed consent before entering the study. Patients with asthma were meticulously defined by (1) a clear clinical history with current symptoms and (2) evidence of more than 20% reversibility of FEV1 either spontaneously or after inhaling ß2-agonists and/or a methacholine provocation test with a provocative concentration causing a 20% decrease in FEV1 (PC20) of 10 mg/ml or less. Patients with atopic asthma were defined as having a positive radioallergosorbent test (RAST) response of more than 0.70 international units/ml to more than one of the common aeroallergens. Patients with nonatopic asthma and control subjects had negative RAST responses to the common aeroallergens. All patients with asthma were in stable condition. Forty-one patients received inhaled glucocorticoids. Nineteen patients were treated with beclomethasone dipropionate (BDP) (mean daily dose, 600 ± 51 µg), and 22 were treated with fluticasone propionate (FP) (mean daily dose, 473 ± 43 µg). All subjects were nonsmokers and had not taken oral glucocorticoids before the study.

Monoclonal Antibodies
Phycoerythrin (PE)-conjugated anti–IL-3 receptor {alpha} chain (CD123), PE-conjugated anti-CD11c, peridinin chlorophyll protein (PerCP)-conjugated anti–HLA-DR, and fluorescein isothiocyanate (FITC)-conjugated lineage cocktail 1 (lin 1) were purchased from Becton Dickinson (San Jose, CA). The lin 1 contains monoclonal antibody (mAb) clones against CD3 (T cells), CD14 (monocytes/macrophages), CD16 (natural killer cells), CD19 (B cells), CD20 (B cells), and CD56 (natural killer cells). PE- and PerCP-conjugated isotype control murine mAbs were obtained from Becton Dickinson.

Flow Cytometric Analysis
Peripheral blood cells obtained from the subjects were analyzed by three-color flow cytometry. All blood samples from patients with asthma and control subjects were collected in the morning. To minimize selective cell loss during the preparation procedure, the cells were first stained with mAbs followed by lysing the erythrocytes. Briefly, the blood cells were incubated with PE-, PerCP-, and FITC-conjugated mAbs for 20 minutes at room temperature. The erythrocytes were then lysed with FACS lysing solution (Becton Dickinson). After washing with PBS, the stained cells were analyzed with a FACSCaliber flow cytometer (Becton Dickinson). DCs were defined as the cells positive for PerCP-conjugated anti-HLA-DR mAb and negative for FITC-conjugated lin 1. Anti-CD11c or anti-CD123 mAb conjugated with PE was used for further identification of the mDC and pDC subsets. The number of total white blood cells in the samples was determined using an automated cell counter. The absolute number of mDCs and pDCs was calculated from the white blood cell count multiplied by the proportion of each subset within the white blood cells, as determined by flow cytometric analysis. The ratio of mDCs to pDCs was determined by dividing the absolute number of mDCs by that of pDCs in each subject.

Measurement of Serum Cytokines
The serum levels of granulocyte colony-stimulating factor (G-CSF) and IL-3 were measured with an enzyme immunoassay kit from Immuno-Biological Laboratory (Fujioka, Japan) and an ELISA kit from R&D Systems (Minneapolis, MN), respectively.

Statistical Analysis
The unpaired Student t test and the {chi}2 test were used for statistical analysis with the StatView statistical program (Abacus Concepts, Berkeley, CA). A p value of less than 0.05 was considered significant. All values are expressed as the means ± SEM unless otherwise specified.

RESULTS

Clinical Characteristics
Details of the study population are shown in Table 1 . Between normal control subjects and patients with asthma, there was no significant difference in age or sex proportion. The blood eosinophil counts were significantly higher in bronchial asthma than in normal control subjects (p = 0.0001). Between patients with atopic asthma and patients with nonatopic asthma, patients with atopic asthma were significantly younger than patients with nonatopic asthma. The proportion of females was significantly higher among patients with nonatopic asthma than among patients with atopic asthma. No difference was found in the total serum IgE levels or blood eosinophil counts between patients with atopic asthma and patients with nonatopic asthma.


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  		TABLE 1. Clinical characteristics of study subjects

 
Identification of mDCs and pDCs in Human Peripheral Blood
For gating lin–HLA-DR+ cells, whole peripheral blood cells were stained with anti-HLA-DR mAb and the Lineage Cocktail (Figure 1A) . In the gated cells, we further analyzed the expression of CD11c and CD123 to determine the two distinct DC lineages. As previously reported (15–19), mDCs and pDCs were defined as lin-HLA-DR+CD11c+ and lin-HLA-DR+CD123+ cells, respectively. Representative profiles of CD11c and CD123 expression by peripheral blood dendritic cells (PBDCs) from a normal subject are shown in Figure 1B, which clearly indicates the two DC subsets, HLA-DRbrightCD11cbright and HLA-DRbrightCD123bright DCs.



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  		Figure 1. Phenotype of blood DCs in normal subjects and patients with asthma. Peripheral blood samples were collected from normal subjects and patients with asthma. The cells were stained with PerCP-conjugated anti-HLA-DR, PE-conjugated anti-CD11c or anti-IL3R{alpha} (CD123), and FITC-conjugated lineage markers (lin) containing anti-CD3, -CD15, -CD16, -CD19, -CD20, and -CD56. After lysis of erythrocytes, the cells were analyzed by three-color flow cytometry. Dendritic cells were characterized by positive HLA-DR and negative lineage markers in the R1 region (a). The DCs were further analyzed for the expression of CD11c and CD123. mDCs and pDCs were defined as lin-HLA-DR+CD11c+ and lin-HLA-DR+CD123+ cells, respectively. Representative profiles of the blood DC subsets of a control subject and a patient with asthma are shown (b and c, respectively). The numbers indicate the percentage of double-positive cells for R1-gated cells.

 
Number of Blood mDCs and pDCs in Patients with Asthma and in Normal Subjects
Figures 1b and 1c show typical profiles of CD11c and CD123 expression by blood DCs from a normal subject and from a patient with asthma, respectively. There was no difference in the numbers of total PBDCs or mDCs between the patients with asthma and the normal subjects (21.6 ± 1.3 versus 20.1 ± 1.5/µl and 15.8 ± 1.0 versus 17.2 ± 1.4/µl, respectively) (Figure 2) . However, the number of blood pDCs was significantly higher in the patients with asthma than in the normal subjects (5.8 ± 0.5 versus 3.0 ± 0.3/µl, p < 0.0001) (Figure 2). The patients with asthma had a significant decrease in the numeric ratio of blood mDCs to pDCs compared with that of the normal subjects (3.7 ± 0.4 versus 6.7 ± 0.5, p < 0.0001) (Figure 2).



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  		Figure 2. Numbers of DCs, mDCs, pDCs, and the ratio of mDCs to pDCs in the peripheral blood (PB) of patients with asthma and normal control subjects. Blood mDCs and pDCs were defined as shown in Figure 1. Absolute numbers of mDCs and pDCs, and the ratio of mDCs to pDCs, were determined as described in METHODS. Values represent means ± SEM from 44 patients with bronchial asthma (BA) and 38 normal subjects (NC); *p < 0.0001.

 
Several studies have reported that inhaled glucocorticoids decrease the number of airway DCs in animals as well as in patients with asthma (22, 23). Thus, it is possible that the doses of inhaled glucocorticoids affect the number and/or phenotypes of blood DCs in patients with asthma. To clarify this, we compared the numbers of blood DC subtypes in patients treated with low doses of inhaled glucocorticoids (BDP at less than or equal to 400 µg/day, or FP at 200 µg/day) with those of patients treated with high doses of inhaled glucocorticoids (BDP at more than 400 µg/day, or FP at more than 200 µg/day). Fifteen patients received low doses of glucocorticoids, with BDP (average) at 378 ± 22 µg/day, or FP at 200 ± 0 µg/day, whereas 29 received high doses of glucocorticoids, with BDP (average) at 800 ± 0 µg/day, or FP at 516 ± 41 µg/day. As shown in Figure 3 , the doses of inhaled glucocorticoids did not affect the number of blood DCs, mDCs, or pDCs in the patients with asthma (low dose versus high dose: PBDCs, 23.0 ± 2.5 versus 20.8 ± 1.4/µl; mDCs, 17.0 ± 2.0 versus 15.1 ± 1.0/µl; pDCs, 6.0 ± 0.8 versus 5.7 ± 0.6/µl, respectively).



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  		Figure 3. Numbers of DCs, mDCs, pDCs, and the ratio of mDCs to pDCs, in patients with asthma treated with low doses of inhaled glucocorticoids (LD) and high doses of inhaled glucocorticoids (HD). Blood mDCs and pDCs were defined as shown in Figure 1. Absolute numbers of mDCs and pDCs, and the ratio of mDCs to pDCs, were determined as described in METHODS. Values represent means ± SEM from 15 LDs and 29 HDs.

 
Numbers of Blood mDCs and pDCs in Patients with Atopic Asthma and in Patients with Nonatopic Asthma
No differences were found in the number of total PBDCs, mDCs, or pDCs between patients with atopic asthma and patients with nonatopic asthma (PBDCs, 22.3 ± 1.4 versus 20.0 ± 2.6/µl; mDCs, 16.2 ± 1.1 versus 14.9 ± 2.0/µl; pDCs, 6.1 ± 0.6 versus 5.2 ± 1.0/µl; respectively) (Figure 4) . The ratio of mDCs to pDCs tended to be lower in patients with atopic asthma than in patients with nonatopic asthma (mDC:pDC ratio, 3.3 ± 0.4 versus 4.6 ± 0.9, respectively), although the difference was not statistically significant (Figure 4).



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  		Figure 4. Numbers of DCs, mDCs, pDCs, and the ratio of mDCs to pDCs, in patients with atopic asthma (AA) and patients with nonatopic asthma (NAA). Blood mDCs and pDCs were defined as shown in Figure 1. Absolute numbers of mDCs and pDCs, and the ratio of mDCs to pDCs, were determined as described in METHODS. Values represent means ± SEM from 31 AA and 13 NAA.

 
Serum Levels of IL-3 and G-CSF
Because IL-3 and G-CSF have been reported to proliferate, differentiate, and mobilize the distinct subtypes of DCs (16, 18, 24), we measured the serum levels of these cytokines. Neither IL-3 nor G-CSF was detected in the sera of patients with asthma or in the sera of normal subjects (data not shown).

DISCUSSION

In the present study, we directly enumerated two distinct DC subsets, mDCs and pDCs, in the peripheral blood of patients with asthma, using three-color flow cytometry. We demonstrated that the patients with asthma had a significantly higher number of pDCs, leading to an apparent shift of the mDC:pDC balance toward pDCs.

During the primary immune responses, the DC subset involved is one of the critical determinants for polarizing naive T cells into Th1 or Th2 cells (14). In 1999, Rissoan and coworkers demonstrated for the first time that the distinct subsets of human DCs, DC1 and DC2, induce the different profiles of T cell responses (14). Consistent with this, reports have shown that mDCs produce a large amount of IL-12 and preferentially induce Th1 development, whereas pDCs secrete lower amounts of IL-12 and primarily elicit Th2 development (24–26). Contrary to these observations, several studies described a plasticity of the DC subsets in directing T cell responses (5, 27–29). For example, certain signals stimulate immature mDCs to induce Th2 differentiation; these include antiinflammatory molecules, such as IL-10, transforming growth factor-ß, and prostaglandin E2 (5, 8, 27, 30). This suggested that the functional differences between DCs in guiding T cell responses might depend on not only their lineage but also the microenvironment of cytokines and/or inflammatory mediators in the primary immune response. However, it is generally agreed that pDCs are one of the principal APCs inducing a Th2 response. Thus, the shift in mDC:pDC balance toward pDCs in the patients with asthma may be involved in Th2 polarization.

The mechanisms governing the blood mDC:pDC balance remain unknown. In asthma, it is also uncertain whether the alteration in blood mDC:pDC balance reflects an intrinsic aberrancy, or follows from commitment imposed by extrinsic factors inducing allergic inflammation. Two reports have shown that Flt3 ligand expanded both mDCs and pDCs (24), whereas G-CSF increased only pDCs, not mDCs, in human peripheral blood (25). Because G-CSF has a potent capacity to recruit granulocytes and CD34+ progenitor cells from the bone marrow into the circulation, it might also selectively mobilize pDCs or their precursor into the peripheral blood. We measured the serum levels of G-CSF as well as IL-3, but failed to detect them in the patients with asthma. Interestingly, the more recent study by Caron and coworkers (31) demonstrated that histamine, a mediator released by activated mast cells in allergic inflammatory sites, polarized human DCs to the pDC phenotype. It is likely that mediators produced in allergic inflammation, such as histamine, may contribute to a selective increase in pDCs in patients with asthma. Further studies will be required to clarify the precise mechanisms causing an increase in pDCs.

The distinct DC subsets in the peripheral blood have different migration properties. mDCs in the circulation populate the peripheral tissues or inflammatory sites through the blood stream (32). These mDCs capture foreign antigens and migrate into the regional lymph nodes through afferent lymphatics, where they present the antigens to T cells (13). Thus, mDCs are considered to be the primary Th1-inducing DCs responsible for the surveillance against pathogenic intruders in the periphery. By contrast, pDCs directly enter the T cell areas of the lymph nodes from the blood stream via high endothelial venules (15). pDCs express high levels of L-selectin, which mediates their extravasation by interaction with L-selectin ligand peripheral lymph node addressin, which in turn is exclusively expressed by high endothelial venules (15, 33). Interestingly, Jahnsen and coworkers demonstrated that pDCs dramatically accumulated in the nasal mucosa in response to topical allergic challenge in patients with allergic rhinitis (33). This study showed that the allergic inflammation elicited by allergen challenge induced the aberrant expression of peripheral lymph node addressin in the nasal mucosa, which in turn might facilitate the recruitment of pDCs. Likewise, in patients with asthma, increased pDCs in the circulation may be recruited to the airways, where they preferentially promote a Th2 response. More recently, the same authors have reported that mDCs, but not pDCs, rapidly accumulated in the bronchial mucosa of patients with asthma 4–5 hours after allergen challenge (34). In their previous study of allergic rhinitis, an increase in pDC number was found after daily provocation for 7 days. Thus, it is possible that the distinct subsets of DCs may be recruited at different time points to the effector sites of allergic inflammation. Further studies will be required to elucidate this.

In summary, the present data clearly indicate that in patients with asthma, the mDC:pDC balance polarizes toward pDCs in the peripheral blood, which may be associated with a Th2-biased phenotype of the immune responses in asthma and may possibly be involved in its pathogenesis.

FOOTNOTES

Supported by a grant-in-aid for scientific research (11670572) from the Japan Society for the Promotion of Science (to T.S.).

Received in original form October 16, 2001; accepted in final form July 10, 2002

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Higher Prostaglandin E2 Production by Dendritic Cells from Subjects with Asthma Compared with Normal Subjects
Am. J. Respir. Crit. Care Med., September 1, 2004; 170(5): 485 - 491.
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D.-J. Chiang, Y.-L. Ye, W.-L. Chen, Y.-L. Lee, N.-Y. Hsu, and B.-L. Chiang
Ribavirin or CpG DNA Sequence-Modulated Dendritic Cells Decrease the IgE Level and Airway Inflammation
Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 575 - 580.
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A. K. De, K. Laudanski, and C. L. Miller-Graziano
Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation
J. Immunol., June 15, 2003; 170(12): 6355 - 6362.
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M. J. Tobin
Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 319 - 332.
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