Systemic chemokine and chemokine receptor responses are divergent in allergic versus non-allergic humans
J. Darren Campbell1,
Monique J. Stinson1,
F. Estelle R. Simons1,2 and
Kent T. HayGlass1,2
Departments of 1 Immunology, and 2 Paediatrics and Child Health, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Manitoba R3E 0W3, Canada
Correspondence to: K. T. HayGlass; E-mail: HayGlass{at}ms.umanitoba.ca
Transmitting editor: S. Galli
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Abstract
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Th1- and Th2-polarized human T cell clones display distinct patterns of chemokine receptor expression and selective chemokine responsiveness in vitro. We hypothesized that natural exposure to environmental grass pollen would induce differential systemic chemokine and chemokine receptor expression patterns in individuals with allergic rhinitis compared to healthy controls with type 2- and type 1-dominated responses to allergen respectively. To this end, we compared chemokine receptor expression on peripheral blood T cells directly ex vivo and plasma chemokine levels between these two groups of study participants prior to and during the grass pollen season. Th1-associated CXC chemokine receptor (CXCR) 3 was strongly expressed on >50% CD4+/CD45RO+ cells of all subjects. When examined longitudinally, CXCR3 expression increased over the grass pollen season (P < 0.0001), solely in non-allergic subjects. In contrast, for both allergic and non-allergic subjects, CC chemokine receptor (CCR) 5 (Th1-associated) and CCR3 (Th2-associated) were weakly expressed on <10% of CD4+/CD45RO+ cells both prior to and during the grass pollen season. Type 1 chemokines CXC chemokine ligand (CXCL) 9 and CXCL10 (monokine induced by IFN-
and IFN-
-inducible protein of 10 kDa: CXCR3 ligands), and type 2 chemokines CC chemokine ligand (CCL) 11 (eotaxin: CCR3 ligand), CCL17 (thymus and activation-regulated chemokine: CCR4 ligand) and CCL22 (monocyte-derived chemokine: CCR4 ligand) were readily detectable in the plasma of most participants. Systemic CXCL9 levels decreased from pre- to grass pollen season in allergics (P < 0.05), whereas CCL17 decreased in non-allergics (P < 0.05) over the same period. Taken together, these longitudinal data suggest a systemic shift to more intensely type 1-dominated responses in non-allergic individuals and, conversely, to more type 2-dominated responses in allergic individuals upon natural re-exposure to grass pollen.
Keywords: allergic rhinitis, CCR5, CCL11, CCL17, CXCL9, CXCL10, CXCR3, ELISA, flow cytometry, grass pollen
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Introduction
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The chemokine family and their receptors regulate diverse aspects of immune homeostasis and inflammation. Chemokines direct cell trafficking and recruitment, have anti-tumor effects, activate inflammatory cells, and regulate Th1 and Th2 development and function (1). In vitro analysis of human T cell lines and clones demonstrates an association between Th1 phenotype and expression of the chemokine receptors CXC chemokine receptor (CXCR) 3 and CC chemokine receptor (CCR) 5. Conversely, CCR4, CCR8 and, initially, CCR3 expression has been associated with the Th2 phenotype of T cell clones in vitro (2,3). The extent to which this polarized pattern of chemokine receptor expression is seen in vivo among antigen-experienced T cells during type 1- or type 2-associated disease remains to be determined. T cell CXCR3 and CCR5 and their respective ligands CXC chemokine ligand (CXCL) 10 [IFN-
-inducible protein of 10 kDa (IP-10)] and CC chemokine ligand (CCL) 3 (MIP-1
) appear to be highly expressed at sites of inflammation and systemically in diseases of type 1-associated pathology such as multiple sclerosis (4). In contrast, in atopic dermatitis, an allergic disease with clear type 2-associated pathology, studies show both local and systemic up-regulation of T cell CCR3 and CCR4, as well as increases in their respective ligands CCL11 (eotaxin) and CCL17 [thymus and activation-regulated chemokine (TARC)] (510).
The type 2 immunity-associated chemokines CCL11 and CCL17 are highly expressed in the nasal mucosa of allergic rhinitis patients (11,12) as is CCL5 (RANTES) (13), a chemokine associated with type 1 immunity (14). However, the extent to which systemic chemokine and chemokine receptor expression is altered in response to natural exposure to grass pollen in allergic rhinitis patients and healthy individuals has not been determined. While type 2 immune responses clearly orchestrate the pathological manifestations of allergy such as the symptoms of allergic rhinitis, resistance to allergy development is associated with moderate type 1 responses to allergens (1517). Hence, we hypothesized that non-allergic individuals would respond to natural grass pollen exposure with type 1-dominated chemokine and chemokine receptor expression, while allergics would display enhanced type 2 expression patterns under these conditions. To test this hypothesis, we examined representative Th1 (CXCR3 and CCR5)- and Th2 (CCR3)-associated chemokine receptor expression on CD4+/CD45RO+ T cells longitudinally prior to and during the grass pollen season in grass-allergic and non-allergic individuals. In parallel, plasma levels of representative type 1 [CXCL9 (monokine induced by IFN-
; Mig) and CXCL10] and type 2 immunity-associated chemokines [CCL11, CCL17 and CCL22 (monocyte-derived chemokine; MDC)] were determined.
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Methods
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Human subjects
This study was approved by the University of Manitoba Research Ethics Boards and written informed consent was obtained from each participant. Twenty-seven subjects ranging from 18 to 35 years of age were included in the study. Grass-allergic individuals (n = 13) were identified on the basis of (i) a positive epicutaneous test (wheal diameter >4 mm that of the negative control) to grass pollen mix (grass mix 1649: Kentucky blue, orchard, redtop and timothy grass; Hollister-Stier, Spokane, WA) and (ii) a history of seasonal allergic rhinitis of at least 2 years duration. Allergic individuals had not previously received immunotherapy. Healthy participants (n = 14) had no history of allergic rhinitis or asthma, and exhibited negative epicutaneous tests to grass pollen and 14 other common environmental antigens. All of the subjects were free from known concurrent infections or conditions that might influence the parameters measured in the study. Blood was obtained from all participants prior to (preseason) and during (seasonal) the grass pollen season in Winnipeg, Canada. Peak atmospheric grass pollen levels (2070 grains/m3) were recorded from 6 June to 12 July (18).
Blood collection and plasma isolation
Peripheral blood (5 ml) was collected by venepuncture into 0.25 ml of 2.7% EDTA. A 0.5-ml aliquot of each sample was used for flow cytometry and the remaining blood was centrifuged at 200 g for 8 min to obtain platelet-poor plasma. Plasma was separated from cells within 30 min of blood collection, treated with NP-40 (0.5% final; Sigma, Oakville, Ontario, Canada) or left untreated and stored at 20°C until analysis of plasma chemokine levels. NP-40 treatment or freezing did not affect plasma chemokine levels observed (data not shown).
Flow cytometry
Chemokine receptor expression on CD4+ antigen-experienced (CD45RO+) peripheral blood mononuclear cells (PBMC) was quantified by three-color flow cytometry. CyChrome-labeled anti-human CD4 (clone RPA-T4) and phycoerythrin-labeled anti-human CD45RO (clone UCHL1; PharMingen, Mississauga, Ontario, Canada) were used to identify CD4+/CD45RO+ cells. FITC-labeled mouse IgG1 anti-human CXCR3 (clone 49801.111; R & D Systems, Minneapolis, MN), mouse IgG2b anti-human CCR5 (clone 45531.111; R & D Systems) and rat IgG2a anti-human CCR3 (clone 61828.111; R & D Systems) were used to determine chemokine receptor expression levels. FITC-labeled control mAb (R & D Systems), isotype-matched to the anti-chemokine receptor mAb, were used with each blood sample to determine background fluorescence and set quadrant markers for scatter plots. For each sample, 50 µl whole blood was stained with combinations of mAb for 15 min at room temperature and red blood cells lysed with FACS lysing solution (Becton Dickinson, San Jose, CA). Cells were then resuspended in 0.5ml 2% paraformaldehyde in PBS prior to analysis on a FACSCalibur flow cytometer (Becton Dickinson) calibrated daily with CaliBRITE beads. For each blood sample, lymphocytes (1 x 104 events) were gated based on forward and side scatter parameters. A secondary gate was drawn around the CD4+ population to allow analysis of chemokine receptor expression on the CD45RO+ (antigen-experienced) and CD45RO (naive) subsets of CD4+ cells. Data were analyzed using CellQuest software (Becton Dickinson).
Chemokine assays
Plasma chemokine levels were determined using specific sandwich ELISAs we developed for CXCL9, CXCL10, CCL11, CCL17 and CCL22 using chemokines, anti-chemokine capture mAb and biotinylated anti-chemokine detection mAb from R & D Systems and Peprotech (Rocky Hill, NJ). Chemokine levels were quantified in reference to serial dilutions of recombinant standards falling within the linear part of the standard curve. Sensitivities of the CXCL9, CXCL10, CCL11, CCL17 and CCL22 assays were 31, 7.8, 7.8, 3.9 and 17.2 pg/ml respectively. Each data point represents readings from a minimum of two independent assays performed in triplicate.
Statistical analysis
Plasma chemokine values were converted to base-10 logarithms to satisfy normality assumptions for statistical analysis using paired Students t-test (SPSS version 9.0; SPSS, Chicago, IL). Chemokine receptor expression was analyzed using Repeated Measures ANOVA (SAS version 8.0; SAS Institute, Cary, NC). All P values shown are two-tailed.
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Results
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CD4+/CD45RO+ T cell chemokine receptor expression prior to and during environmental exposure to grass pollen
Representative expression of chemokine receptors CXCR3, CCR3 and CCR5 on CD4+/CD45RO+ T cells is shown in Fig. 1. The Th1/0-associated receptor CXCR3 was strongly expressed on >50% CD4+/CD45RO+ cells for all subjects. In contrast, Th1-associated CCR5 and Th2-associated CCR3 were weakly expressed on <10% of CD4+/CD45RO+ cells prior to and during the grass pollen season for both grass-allergic and non-allergic individuals. All three chemokine receptors were predominantly expressed on the antigen-experienced (CD45RO+) subset of CD4+ cells (data not shown).

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Fig. 1. Representative flow cytometric analysis of chemokine receptor expression on human CD4+/CD45RO+ T cells. Fresh whole blood was stained directly ex vivo with CyChrome-labeled anti-CD4, phycoerythrin-labeled anti-CD45R0 and FITC-labeled anti-CXCR3, anti-CCR5 or anti-CCR3 as described in Methods. The figure shows surface chemokine receptor staining (solid lines) and staining with isotype-matched control antibodies (dotted lines). Following primary gating on lymphocytes by forward and side scatter, secondary gates were used to identify the CD4+/CD45RO+ population.
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In the absence of environmental antigenic stimulation, in vivo chemokine and chemokine receptor expression is longitudinally stable in healthy individuals (19). To determine if seasonal grass pollen exposure had differential effects on systemic Th1- and Th2-associated chemokine receptor expression in grass-allergic versus non-allergic populations, CXCR3, CCR5 and CCR3 expression on circulating T cells was quantified longitudinally: prior to and during the grass pollen season. Exposure to environmental grass pollen coincided with a highly significant increase in Th1/0-associated CXCR3 expression on CD4+/CD45RO+ cells of non-allergic individuals (P < 0.0001) (Fig. 2a). CXCR3 expression of grass-allergic participants was unchanged by seasonal allergen exposure. In contrast, Th1-associated CCR5 levels remained low from preseason to mid grass pollen season (Fig. 2b). Fewer than 5% of peripheral blood CD4+/CD45RO+ cells stained (weakly) positive for CCR5.

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Fig. 2. Preseason and seasonal type 1 chemokine receptor expression on CD4+/CD45RO+ T cells. CXCR3 (A) and CCR5 (B) expression on PBMC of grass-allergic (n = 13) and grass-non-allergic subjects (n = 14) was measured by three-color flow cytometry as described in Methods. CXCR3 and CCR5 levels were quantified as a percentage of CD4+/CD45RO+ T cells. CXCR3 expression significantly increased on cells of non-atopic individuals (P < 0.0001; repeated measures ANOVA), whereas CCR5 expression remained at low levels (<5% CD4+/CD45RO+ cells) from preseason to grass pollen season.
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Chemokine receptors CCR3, CCR4 and CCR8 are preferentially expressed on human Th2 cell lines and clones in vitro (2,3). However, at the time of this study, mAb to CCR4 and CCR8 were not commercially available. CCR3 has been reported on CD4+ T cells in allergic conditions (20,21) and its ligand eotaxin is highly expressed in response to allergen challenge in the nasal mucosa of subjects with allergic rhinitis (11,22). Hence, we examined Th2-associated systemic CCR3 expression prior to and during grass pollen season in allergic and non-allergic study participants. CCR3 expression was slightly higher than that of CCR5 on CD4+/CD45RO+ cells of both grass-allergic and non-allergic subjects, but did not differ between groups and remained at low levels (<10% cells) from pre- to mid-grass pollen season in both subject populations (Fig. 3).

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Fig. 3. Preseason and seasonal type 2 chemokine receptor expression on CD4+/CD45RO+ T cells. CCR3 expression on peripheral blood T cells of grass-allergic (n = 13) and grass-non-allergic subjects (n = 14) was measured by three-color flow cytometry as described in Methods. CCR3 levels were quantified as a percentage of CD4+/CD45RO+ T cells. CCR3 expression remained at low levels (<10% CD4+/CD45RO+ cells) from preseason to grass pollen season.
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Type 1- and type 2-associated plasma chemokine levels prior to and during environmental exposure to grass pollen
While most chemokines are promiscuous in receptor binding, CXCL9 and CXCL10 both bind exclusively to the Th1-associated receptor CXCR3. CCL11 binds only CCR3 (Th2 associated), while CCL17 and CCL22 bind exclusively to CCR4 (Th2 associated). Thus, through selective binding, these chemokines tend to participate selectively in type 1 or type 2 immune responses. As allergic and non-allergic individuals respond to the sensitizing environmental allergens with respective type 2- and type 1-dominated responses, we determined whether differential type 1 (CXCL9 and CXCL10) or type 2 (CCL11, CCL17 and CCL22) systemic chemokine responses were evident in our grass-allergic and grass-non-allergic subjects, and whether these responses were altered longitudinally in response to natural grass pollen exposure.
All five chemokines were readily detectable in the plasma of both grass-allergic and healthy individuals (Figs 4 and 5). Cross-sectional analysis of the data demonstrated no significant differences in plasma chemokine levels between the two groups at either time point. In contrast, longitudinal analysis of plasma levels of the type 1 chemokine CXCL9 were decreased upon natural allergen re-exposure, but, interestingly, only in the allergic group (P < 0.05), with no changes evident in non-sensitized individuals (Fig. 4). Conversely, levels of the type 2 chemokine CCL17 were reduced in non-allergic participants (P < 0.05), but not in grass-allergics, over the same time period (Fig. 5). There were no longitudinal changes in CCL11 or CXCL10 levels. Collectively, these data on chemokine and chemokine receptor expression patterns suggest that seasonal exposure to grass pollen promotes a subtle shift to a more type 1-dominated response in non-allergic individuals, but a shift to an increasingly type 2-dominated chemokine response in grass pollen-sensitized individuals.

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Fig. 4. Effect of natural grass pollen challenge on systemic type 1 chemokine levels in vivo. CXCL9 (A; Mig) and CXCL10 (B; IP-10) protein in plasma of grass-allergic (n = 13) and grass-non-allergic subjects (n = 14) was quantified by ELISA as described in Methods. Chemokine values were converted to base-10 logarithms to satisfy normality assumptions and analyzed using paired Students t-test. Plasma CXCL9 levels significantly decreased from preseason (PS) to grass pollen season (S), solely in allergic individuals (P < 0.05). There were no significant longitudinal changes in CXCL10 protein or between allergic and non-allergics for either type 1 chemokine.
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Fig. 5. Effect of natural grass pollen challenge on type 2 chemokine levels in plasma. CCL11 (A; eotaxin), CCL17 (B; TARC) and CCL22 (C; MDC) protein in plasma of grass-allergic (n = 13) and grass-non-allergic subjects (n = 14) was quantified by ELISA as described in Methods. Chemokine values were converted to base-10 logarithms to satisfy normality assumptions and analyzed using paired Students t-test. Plasma CCL17 levels significantly decreased from preseason (PS) to grass pollen season (S), solely in non-allergic individuals (P < 0.05). There were no significant longitudinal changes in either allergic or non-allergics for either of the other type 2 chemokines examined.
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Discussion
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In this report, we demonstrate differential longitudinal changes in peripheral blood chemokine levels and chemokine receptor expression in mildly grass pollen-allergic versus non-allergic individuals in response to seasonal allergen exposure. Seasonal grass pollen challenge resulted in elevated CXCR3 expression, a chemokine receptor associated with Th1 clones, on peripheral blood T cells of non-allergic subjects only. In contrast, CCR3 and CCR5 levels remained low prior to and during the grass pollen season. Concomitantly, plasma CXCL9 levels (an IFN-
-regulated chemokine) significantly decreased longitudinally in the allergic group, while CCL17 levels (a type 2 immunity-associated chemokine) significantly decreased in the non-allergic group over the same time period. Collectively, these data demonstrate: (i) the existence of systemic expression of type 1 and type 2 chemokines both in allergic individuals and in individuals not clinically allergic or sensitized, and (ii) differential chemokine/chemokine receptor recall responses in these populations as a consequence of natural allergen re-exposure. Elevated CXCR3 expression and reduced CCL17 levels from pre- to mid-grass pollen season are indicative of an increased type 1-dominated response in non-allergic individuals, whereas decreased plasma CXCL9 levels in grass pollen-allergic subjects suggest a shift to a more type 2-dominated response in vivo in sensitized individuals exposed to similar environmental stimuli. While such changes may be even more pronounced in severely atopic individuals, this study was restricted to mildly allergic subjects because analysis of severely asthmatic populations would likely be confounded by the effects of medications used for clinical management of disease (i.e. corticosteroids).
How the Th1- and Th2 polarized patterns of chemokine receptor expression seen with human T cell lines and clones in vitro relates to the maintenance of allergy in vivo is unclear. Panina-Bordignon et al. (23), using endobronchial biopsies from atopic asthmatics, observed that virtually all T cells were CCR4+ and that CCR8 was co-expressed on
28% of the CCR4+ cells. In contrast, T cells from lung biopsies of patients with chronic obstructive pulmonary disease expressed CXCR3, but not CCR4 or CCR8. However, a separate study of T cell chemokine receptor expression in atopic asthma revealed preferential expression of CXCR3 and CCR5 on lung T cells, and no difference between asthmatics and control subjects (24).
T cell expression of CCR3 is somewhat controversial. Neither of the above studies detected CCR3 expression on lung T cells of asthmatics (23,24). However, double-stained CD3+/CCR3+ cells were identified in nasal polyp tissue (21) and CD4+/CCR3+ cells have been identified in atopic dermatitis skin biopsies by serial staining (5). In our study, CCR3 expression was at very low intensity and on a low percentage of peripheral blood cells. It is likely that, at most, only a small proportion of Th2 cells express CCR3 in contrast to its high expression on eosinophils (25).
In contrast to CXCR3, the other Th1 clone-associated receptor CCR5 was expressed at weak intensity on few CD4+/CD45RO+ T cells. While systemic T cell CCR5 is strongly up-regulated in highly polarized type 1 inflammatory diseases such as multiple sclerosis (4), our data suggest that it may be of less value than CXCR3 as a marker of moderate type 1 responses to environmental allergens (i.e. in healthy subjects). Kim et al. (29) recently demonstrated that
88% of Th1 phenotype cells in blood are CXCR3+ and that other chemokine receptors such as CCR5 do not show preferential Th1-association unless co-expressed with CXCR3.
We were unable to measure expression of the putative Th2-associated chemokine receptor CCR4 because of lack of suitable commercial reagents at the time of this study. Recent studies demonstrate that CCR4 is highly expressed on almost all skin (but not intestinal)-homing memory T cells expressing the cutaneous lymphocyte antigen (2627). This may explain the high systemic and local levels of T cell CCR4 expression recently reported in atopic dermatitis (28). Interestingly, atopic dermatitis is also associated with a decreased frequency of CXCR3 expression on circulating T cells (28).
We emphasize that cross-sectional analysis was much less powerful in revealing differences in chemokine or chemokine receptor expression between atopic and control subjects than was the longitudinal analysis performed here. Grass pollen exposure increased T cell CXCR3 expression in non-allergics, whereas allergic subjects showed no change, emphasizing the importance of comparing CXCR3 expression of allergic and non-allergic subjects longitudinally to identify differential effects of natural allergen challenge. Similar improvements in sensitivity were evident upon longitudinal analysis of plasma chemokine levels. This is particularly important in examining systemic responses directly ex vivo (i.e. in plasma), as chemokine levels will reflect consequences of all environmental stimuli, not solely the allergens of interest. Despite the fact that these subjects were exposed to a great number of immunologic stimuli over the course of this study, seasonal allergen exposure resulted in a clearly observed shift towards expression of more type 1-dominated immunity in healthy subjects and more type 2-dominated in atopics. At the same time, multi-year studies will be required for dissection of the mechanisms underlying these differential immunoregulatory responses. Collectively, the data suggest that this approach will provide a much more sensitive strategy for identifying in vivo regulatory events associated with maintenance and exacerbation of immediate hypersensitivity than cross-sectional studies. The data also suggest that it will prove a useful approach for evaluation of therapeutic candidates that aim to re-orient ongoing maladaptive immune responses in vivo.
Finally, the utility of examination of plasma chemokine levels deserves comment. Multiple studies have examined local chemokine expression/production in allergic rhinitis patients. Collectively, they demonstrated up-regulation of nasal CCL11, CCL17, CCL5, CCL7 [monocyte chemotactic protein (MCP)-3] and CCL13 (MCP-4) in response to acute experimental allergen challenge (12,13,30,31). However, how systemic chemokine levels compare between healthy controls and subjects with allergic rhinitis has not been determined. Here, our cross-sectional and longitudinal analyses evaluated the effects of chronic natural allergen exposure on type 1 versus type 2 chemokines in allergic and non-allergic subjects by quantifying plasma levels of CXCL9 and CXCL10 (both type 1 associated) and circulatory levels of CCL11, CCL17, and CCL22 (type 2 associated). These chemokines were chosen based on their exclusivity in binding putative Th1- and Th2-associated receptors. Moreover, CXCL9 and CXCL10 are induced by IFN-
(32), whereas CCL11 and CCL17 production can be stimulated by type 2 cytokines such as IL-4 (12,33). We excluded CCR5 ligands from the study because of their promiscuous receptor binding. CCL5, for example, binds CCR3 as well as CCR5. Interestingly, while significant longitudinal changes in CXCL9 (in allergics only) and CCL17 (in non-allergics) were evident, there were no significant differences in chemokine expression between the allergic and non-allergic groups, and no longitudinal changes in CCL11 or CXCL10 levels. This may reflect the diverse sources and stimuli of chemokine production. Plasma levels comprise chemokine produced locally (e.g. by epithelial cells) as well as that secreted by circulating cells. Natural grass pollen exposure reduced CXCL9 levels in the plasma of allergic subjects and CCL17 levels in the plasma of non-allergic subjects, suggesting enhanced skewing to pathogenic type 2 and putatively protective type 1 responses respectively. The longitudinal reduction in CXCL9 levels within the grass-allergic group may be particularly indicative of a declining type 1 response as CXCL9 production has been suggested as a surrogate marker for IFN-
-producing PBMC (34). The extent to which such changes reflect a cause or an effect of ongoing immune processes remains to be determined. However, while much research focuses on the capacity of Th1 and Th2 cytokines to shape chemokine responses, we, and others, have demonstrated that this communication is two way. Chemokines can act as potent stimuli for initiation (35) or amplification (36) of allergen-specific type 1 versus type 2 immunity.
In conclusion, this is the first report to examine both systemic Th1- and Th2-associated chemokine and chemokine receptor responses in allergic rhinitis. The data indicate that exposure to allergen in the airways translates to distinct systemic patterns of chemokine and chemokine receptor expression depending on atopic status, and that longitudinal analysis provides markedly enhanced sensitivity for characterizing the nature and intensity of these changes. Specifically, longitudinal changes in CXCR3 expression as well as CXCL9 and CCL17 levels suggest a shift to a more type 1-dominated response in non-allergic individuals while eliciting a shift to more intensely type 2-dominated chemokine responses in grass-allergic individuals following natural exposure to grass pollen.
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Acknowledgements
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Supported by grants from the Canadian Institutes of Health Research (CIHR). K. T. H. holds the Canada Research Chair in Immune Regulation, F. E. R. S. holds the Bruce Chown Professorship, and J. D. C. holds the Canadian Allergy, Asthma and Immunology Foundation/GlaxoSmithKline/CIHR-Rx & D Fellowship in Allergy and Clinical Immunology.
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Abbreviations
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CCLCC chemokine ligand
CXCLCXC chemokine ligand
CCRCC chemokine receptor
CXCRCXC chemokine receptor
IP-10 (CXCL10)IFN-
-inducible protein of 10 kDa
MCPmonocyte chemotactic protein
MDC (CCL22)monocyte-derived chemokine
Mig (CXCL9)monokine induced by IFN-
PBMCperipheral blood mononuclear cells
TARC (CCL17)thymus and activation-regulated chemokine
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References
|
---|
- Rossi, D. and Zlotnik, A. 2000. The biology of chemokines and their receptors. Annu. Rev. Immunol. 18:217.[ISI][Medline]
- Sallusto, F., Lenig, D., Mackay, C. R. and Lanzavecchia, A. 1998. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187:875.[Abstract/Free Full Text]
- D Ambrosio, D., Iellem, A., Bonecchi, R., Mazzeo, D., Sozzani, S., Mantovani A. and Sinigaglia, F. 1998. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J. Immunol. 161:5111.[Abstract/Free Full Text]
- Balashov, K. E., Rottman, J. B., Weiner, H. L. and Hancock, W. W. 1999. CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1
and IP-10 are expressed in demyelinating brain lesions. Proc. Natl Acad. Sci. USA 96:6873.[Abstract/Free Full Text]
- Yawalkar, N., Uguccioni, M., Scharer, J., Braunwalder, J., Karlen, S., Dewald, B., Braathen, L. R. and Baggiolini, M. 1999. Enhanced expression of eotaxin and CCR3 in atopic dermatitis. J. Invest. Dermatol. 113:43.[Abstract/Free Full Text]
- Kakinuma, T., Nakamura, K., Wakugawa, M., Mitsui, H., Tada, Y., Saeki, H., Komine, M., Asahina, A. and Tamaki, K. 2002. Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin. Exp. Immunol. 127:270.[ISI][Medline]
- Wakugawa, M., Nakamura, T., Onai, N., Matsushima, K. and Tamaki, K. 2001. CC chemokine receptor 4 expression on peripheral blood CD4+ T cells reflects disease activity of atopic dermatitis. J. Invest. Dermatol. 117:188.[Abstract/Free Full Text]
- Kakinuma, T., Nakamura, K., Wakugawa, M., Mitsui, H., Tada, Y., Saeki, H., Torii, H., Asahina, A., Onai, N., Matsushima, K. and Tamaki, K. 2001. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. J. Allergy Clin. Immunol. 107:535.[ISI][Medline]
- Hossny, E., Aboul-Magd, M. and Bakr, S. 2001. Increased plasma eotaxin in atopic dermatitis and acute urticaria in infants and children. Allergy 56:996.[ISI][Medline]
- Taha, R. A., Minshall, E. M., Leung, D. Y., Boguniewicz, M., Luster, A., Muro, S., Toda, M. and Hamid, Q. 2000. Evidence for increased expression of eotaxin and moncyte chemotactic protein-4 in atopic dermatitis. J. Allergy Clin. Immunol. 105:1002.[ISI][Medline]
- Pullerits, T., Linden, A., Praks, L., Cardell, O. and Lotvall, J. 2000. Upregulation of nasal mucosal eotaxin in patients with allergic rhinitis during grass pollen season: effect of a local glucocorticoid. Clin. Exp. Allergy 30:1469[ISI][Medline]
- Terada, N., Nomura, T., Kim, W. J., Otsuka, Y., Takahashi, R., Kishi, H., Yamashita, T., Sugawara, N., Fukuda, S., Ikeda-Ito, T. and Konno, A. 2001. Expression of CC chemokine TARC in human nasal mucosa and its regulation by cytokines. Clin. Exp. Allergy 31:1923.[ISI][Medline]
- Rajakulasingham, K., Hamid, Q., OBrien, F., Shotman, E., Jose, P. J., Williams, T. J., Jacobson, M., Narkans, J. and Durham, S. R. 1997. RANTES in human allergen-induced rhinitis. Am. J. Respir. Crit. Care Med. 155:696.[Abstract]
- Schrum, S., Probst, P., Fleischer, B. and Zipfel, P. F. 1996. Synthesis of the CC chemokines MIP-1
, MIP-1ß, and RANTES is associated with a type 1 immune response. J. Immunol. 157:3598.[Abstract]
- Wierenga, E. A., Snoek, M., De Groot, C., Chretien, I., Bos, J. D., Jansen, H. M. and Kapsenberg, M. L. 1990. Evidence for compartmentalization of functional subsets of CD4+ T lymphocytes in atopic patients. J. Immunol. 144:4651.[Abstract/Free Full Text]
- Imada, M., Simons, F. E. R., Jay, F. T. and HayGlass, K. T. 1995. Allergen-stimulated interleukin-4 and interferon-
production in primary culture: responses of subjects with allergic rhinitis and normal controls. Immunology 85:373.[ISI][Medline]
- Holt, P. G. 1996. Primary allergic sensitization to environmental antigens: perinatal T cell priming as a determinant of responder phenotype in adulthood. J. Exp. Med. 183:1297.[ISI][Medline]
- Aerobiology Research Laboratories. 1999. Pollen and Spore Report. Aerobiology Research Laboratories, Nepean, Ontario, Canada.
- Campbell, J. D., Stinson, M. J., Simons, F. E. R., Rector, E. S. and HayGlass, K. T. 2001. In vivo stability of human chemokine and chemokine receptor expression. Hum. Immunol. 62:668.[ISI][Medline]
- Annunziato, F., Cosmi, L., Galli, G., Beltrame, C., Romagnani, P., Manetti, R., Romagnani, S. and Maggi, E. 1999. Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro and in vivo. J. Leukoc. Biol. 65:691.[Abstract]
- Gerber, B. O., Zanni, M. P., Uguccioni, M., Loetscher, M., Mackay, C. R., Pichler, W. J., Yawalkar, N., Baggiolini, M. and Moser, B. 1997. Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils. Curr. Biol. 7:836.[ISI][Medline]
- Minshall, E. M., Cameron, L., Lavigne, F., Leung, D. Y. M., Hamilos, D., Garcia-Zepada, E. A., Rothenberg, M., Luster, A. D. and Hamid, Q. 1997. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 17:683.[Abstract/Free Full Text]
- Panina-Bordignon, P., Papi, A., Mariani, M., Di Lucia, P., Casoni, G., Bellettato, C., Buonsanti, C., Miotto, D., Mapp, C., Villa, A., Arrigoni, G., Fabbri, L. M. and Sinigaglia, F. 2001. The CC chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. J. Clin. Invest. 107:1357.[Abstract/Free Full Text]
- Campbell, J. J., Brightling, C. E., Symon, F. A., Qin, S., Murphy, K. E., Hodge, M., Andrew, D. P., Wu, L., Butcher, E. C. and Wardlaw, A. J. 2001. Expression of chemokine receptors by lung T cells from normal and asthmatic subjects. J. Immunol. 166:2848.
- Heath, H., Qin, S., Rao, P., Wu, L., LaRosa, G., Kassam, N., Ponath, P. D. and Mackay, C. R. 1997. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest. 99:178.[Abstract/Free Full Text]
- Campbell, J. J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D. P., Warnke, R., Ruffing, N., Kassam, N., Wu, L. and Butcher, E. C. 1999. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400:776.[ISI][Medline]
- Andrew, D. P., Ruffing, N., Kim, C. H., Miao, W., Heath, H., Li, Y., Murphy, K., Campbell, J. J., Butcher, E. C. and Wu, L. 2001. CC chemokine receptor 4 expression defines a major subset of circulating nonintestinal memory T cells of both Th1 and Th2 potential. J. Immunol. 166:103.[Abstract/Free Full Text]
- Nakatani, T., Kaburagi, Y., Shimada, Y., Inaoki, M., Takehara, K., Mukaida, N. and Sato, S. 2001. CCR4+ memory CD4+ T lymphocytes are increased in peripheral blood and lesional skin from patients with atopic dermatitis. J. Allergy Clin. Immunol. 107:353.[ISI][Medline]
- Kim, C. H., Rott, L., Kunkel, E. J., Genovese, M. C., Andrew, D. P., Wu, L. and Butcher, E. C. 2001. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108:1331.[Abstract/Free Full Text]
- Terada, N., Hamano, N., Kim, W. J., Hirai, K., Nakajima, T., Yamada, H., Kawasaki, H., Yamashita, T., Nomura, T., Yoshie, O. and Konno, A. 2001. The kinetics of allergen-induced eotaxin level in nasal lavage fluid: its key role in eosinophil recruitment in nasal mucosa. Am. J. Respir. Crit. Care Med. 164:575.[Abstract/Free Full Text]
- Christodoulopoulos, P., Wright, E., Frenkiel, S., Luster, A. and Hamid, Q. 1999. Monocyte chemotactic proteins in allergen-induced inflammation in the nasal mucosa: effect of topical corticosteroids. J. Allergy Clin. Immunol. 103:1036.[ISI][Medline]
- Farber, J. M. 1997. Mig and IP-10: CXC chemokines that target lymphocytes. J. Leukoc. Biol. 61:246.[Abstract]
- Mochizuki, M., Bartels, J., Mallet, A. I., Christophers, E. and Schroder, J. M. 1998. IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy. J. Immunol. 160:60.[Abstract/Free Full Text]
- Brice, G. T., Graber, N. L., Hoffman, S. L. and Doolan, D. L. 2001. Expression of the chemokine MIG is a sensitive and predictive marker for antigen-specific, genetically restricted IFN
production and IFN
-secreting cells. J. Immunol. Methods 257:55.[ISI][Medline]
- Gu, L., Tseng, S., Horner, R. M., Tam, C., Loda, M. and Rollins, B. J. 2000. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404:407.[ISI][Medline]
- Gangur, V., Simons, F. E. R. and HayGlass, K. T. 1998. Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN
over IL-4 responses. FASEB J. 12:705.[Abstract/Free Full Text]