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Clin Exp Immunol. Nov 2004; 138(2): 342–347.
PMCID: PMC1809206

Increased CCR4 expression on circulating CD4+ T cells in ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematosus

Abstract

Previous studies have suggested that CCR4 is particularly important in the selective recruitment of various subsets of leucocytes in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this study, we examined the percentage of CD4+/CCR4+ T cells within circulating lymphocytes in active ankylosing spondylitis (AS), RA and SLE patients. The clinical significance of CCR4 expression as well as possible associations between the expression and serum levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 were also examined. Our results showed that the percentage of CD4+/CCR4+ T cells was significantly elevated in AS and RA patients as compared with normal controls. The percentage was also significantly higher in SLE patients who had received no treatment with glucocorticoids or cytotoxic drugs (untreated SLE) than that in controls. In addition, the percentage of CD4+/CCR4+ T cells showed significant positive correlations with the Bath ankylosing spondylitis disease activity index (BASDAI) in AS and with the SLE disease activity index (SLEDAI) in untreated SLE. Of all the cytokines examined, the elevated serum IL-10 level was closely correlated with the percentage of CD4+/CCR4+ T cells in AS, RA and untreated SLE. These results suggest that CCR4 may be crucial in the pathogenesis of AS, RA and SLE. The percentage of CD4+/CCR4+ T cells can serve as a useful marker for the activity of AS and untreated SLE.

Keywords: CD4+ T cell, chemokine receptor, disease activity index, IL-10

INTRODUCTION

Ankylosing spondylitis (AS) is a common rheumatic disorder affecting the spine, sacroiliac and peripheral joints, in which inflammatory infiltration of CD4+ T cells, CD8+ T cells and macrophages may be particularly important in the structural lesions [1]. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown aetiology characterized by destruction of joints, in which the infiltrating CD4+ T cell-directed macrophage activity plays a central role in synovitis. Systemic lupus erythematosus (SLE) is the most representative autoimmune disease characterized by a wide range of autoantibodies and immune complexes, in which pathological infiltration of lymphocytes in target organs, especially the kidneys, is critical to the development of organ dysfunction [2].

Selective recruitment of various subsets of lymphocytes plays a prominent role in the pathogenesis in all the above diseases. Recently, several studies have indicated that CCR4, a receptor for thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), may be particularly important for CD4+ T cells migration to synovium in RA and renal tissues in SLE [36]. Whereas, to our knowledge, there have been no previous studies of the role of CCR4 in AS. In addition, there have been very few studies of the clinical significance of CCR4 expression and the association between the expression and serum levels of important cytokines in AS, RA and SLE.

In the present study, we investigated CCR4 expression on circulating CD4+ T cells in active AS, RA and SLE patients. The possible associations between the expression and disease activity variables as well as the serum levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 were also examined.

MATERIALS AND METHODS

Patients and normal controls

Eleven active AS patients as defined by the 1966 New York criteria [7], 11 active RA patients meeting the 1987 American College of Rheumatology criteria [8] and 16 active SLE patients based on the American College of Rheumatism criteria [9] were recruited from in-patients or out-patients at the Department of Rheumatology and Immunology of the First Affiliated Hospital of China Medical University. Samples of heparinized peripheral blood (PB) and serum were obtained from all patients. Ten healthy volunteers with no history of inflammatory joint disease, osteoarthritis or allergic diseases were examined as controls. Informed consent from each subject was obtained before enrolment into this study, which was conducted according to the ethical standards of China Medical University and University of Yamanashi.

Active AS was defined as a Bath ankylosing spondylitis disease activity index (BASDAI) of 3 or above [10]. Active RA was defined according to the method of Weinbaltt et al. [11]. Active SLE was defined as a SLE disease activity index (SLEDAI) of 6 or more or an increase of 3 or more points [12]. With the exception of non-steroidal anti-inflammatory drugs (NSAIDs), no other drugs had been administered to the patients with AS or RA or to nine of the SLE patients (untreated SLE). The remaining seven SLE patients had been treated with glucocorticoids alone or together with cytotoxic drugs (treated SLE). None of the patients had any other autoimmune or infectious diseases as confirmed at the time of the study.

Fluorescein activated cell sorter (FACS) analysis

Fresh heparinized blood were incubated directly with fluorescein isothiocyanate (FITC)-labelled antihuman CD4 mouse monoclonal antibody and phycoerythrin (PE)-labelled antihuman CCR4 mouse MoAb (BD Biosciences Pharmigen, San Diego, CA, USA) for 20 min followed by lysis of red blood cells. The stained cells were analysed using a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA). Appropriate control antibodies (BD Biosciences PharMingen) were also incubated to monitor non-specific binding.

Clinical and laboratory assessments

All the patients’ conditions were evaluated by the same physician throughout the study. For all the patients, clinical and laboratory variables assessed included sex, age, disease duration, history of drug use, current therapy, erythrocyte sendimentation rate (ESR in mm/h), C-reactive protein (CRP in mg/l), complete blood cell count, routine urinalysis, serum complement (C3, C4 in g/l), immunoglobulin level (IgA, IgG and IgM in g/l), serum determination of liver enzyme and renal function. For each AS patient, the following information was recorded: the BASDAI, Schober's test (cm), extra-articular manifestations (uveitis, cardiac involvement), radiological changes (sacroiliitis, scored from 1 to 4 on the New York criteria [13] and postero-anterior and lateral plain radiographs of the thoracic and lumbar spine) and presence or absence of HLA-B27. For RA patients, we recorded modified disease activity scores (DAS) [14], morning stiffness (min), 10 cm visual analogue pain scale (VAP), mean grip strength for both hands (mmHg), extra-articular manifestations (subcutaneous nodules, vasculitis, pleuropulmonary or cardiac manifestations) and IgM-rheumatoid factor (RF) (IU/ml). Plain radiographs of the hands of RA patients were graded from stages I–IV according to the method of Steinbrocker et al. [15]. For SLE patients, the SLE disease activity index (SLEDAI), serum levels of antibodies to double-stranded DNA (anti-dsDNA, IU/ml) and urinary protein excretion measured by 24 h (24 h proteinuria, g/24 h) were determined.

Cytokine and chemokine measurement

Serum levels of TNF-α, IL-10, IFN-γ and TARC were measured with specific sandwich enzyme-linked immunosorbent assay (ELISA) kits. Sensitivities of the various assays were as follows: TNF-α, 5 pg/ml (Beckman, Immunotech, Marseille, France); IL-10, 5 pg/ml (R&D Systems, Minneapolis, MN, USA); IFN-γ, 1 pg/ml (BD Biosciences Pharmingen); and TARC, 7 pg/ml (R&D Systems, Minneapolis, MN, USA).

Statistical analysis

anova was used to compare age and serum level of TARC. The Kruskal–Wallis test was used to compare disease duration, ESR, CRP, percentage of CD4+/CCR4+ T cells within circulating lymphocytes (percentage of CD4+/CCR4+ T cells) and the serum levels of cytokines. When a significant difference was found, the exact P-values were calculated using the Mann–Whitney U-test followed by Bonferroni's correction. Student's t-test was used for comparisons between two groups. Sex was analysed using the χ2 test. Spearman's r-test was used to assess the correlations between two parameters. In all instances, P < 0·05 was considered significant.

RESULTS

Demographic and clinical characteristics of patient and control groups

As shown in Table 1, there were no significant differences in age among the four groups. The proportion of males was significantly higher in AS than in RA, SLE and controls (all P < 0·05), whereas the sex ratio was not significantly different between RA, SLE and controls. There was a borderline non-significant difference for ESR and no significant difference for CRP among the three patient groups. RA and AS patients had longer disease duration than SLE patients, and there was no difference between RA and AS patients. Extra-articular manifestations were present in 27% of AS and 45% of RA patients. HLA-B27 antigen was detected in 91% of AS patients, and IgM-RF was positive in 82% of RA patients and 31% of SLE patients.

Table 1
Clinical and laboratory characteristics in patients and controls

CCR4 expression on circulating CD4+ T cells

Figure 1 shows representative flow cytometric dot plots of CCR4 expression on circulating CD4+ T cells in all groups. A gate was drawn around the lymphocyte population identified by characteristic forward angle and side-scatter profiles, and the percentage of CD4+/CCR4+ T cells was investigated based on this cell population. Based on the results of two-colour flow cytometry, the five groups differed in the percentage of CD4+/CCR4+ T cells (P = 0·0001). Significant increases in the percentage were found in AS (16·2 ± 7·3%, P = 0·02) and RA patients (22·3 ± 9·7%, P = 0·002) compared with controls (9·0 ± 1·6%). The percentage was significantly elevated in untreated SLE patients as compared with treated SLE patients and controls (19·7 ± 6·8 versus 11·2 ± 3·6%, 9·0 ± 1·6%, respectively; P = 0·04, P = 0·002, respectively). No significant difference was found in the percentage between treated SLE patients and controls (Fig. 2a).

Fig. 1
CCR4 expression on circulating CD4+ T cells from the peripheral blood of normal controls and patients with AS, RA, untreated SLE (SLE0) and treated SLE (SLE1). A gate was drawn around lymphocytes defined by characteristic forward-angle and side-scatter ...
Fig. 2
(a) Percentage of CD4+/CCR4+ T cells within circulating lymphocytes (% CD4+/CCR4+ T cells) in controls, AS, RA, untreated SLE (SLE0) and treated SLE (SLE1). For each group, the single symbol on the right represents the median. The vertical thin bars indicate ...

Considering that the significantly increased percentages of CD4+/CCR4+ T cells in the blood could be explained in two ways: either the increase in the absolute number of CD4+/CCR4+ T cells due to disease activity or the decrease in the absolute number of non-CCR4+ lymphocytes due to preferentially migrating to inflammatory sites, we then calculated the absolute numbers of CD4+/CCR4+ T cells based on the absolute numbers of lymphocytes in PB (Fig. 2b).

As shown in Fig. 2b, the absolute number of lymphocyte was not significantly different between AS and controls (2218·2 ± 616·1/µl versus 2090·1 ± 424·8/µl, P > 0·05) or between RA and controls (1945·5 ± 504·4/µl versus 2090·1 ± 424·8/µl, P > 0·05), while the absolute numbers of CD4+/CCR4+ T cells in AS and RA (344 ± 143·1/µl, 456·2 ± 314·7/µl, respectively) were significantly increased (both P < 0·01) compared with controls (187·3 ± 30·1/µl). In untreated SLE patients, the absolute number of lymphocytes was significantly less (1266·7 ± 500, P < 0·01) than controls, whereas the absolute number of CD4+/CCR4+ T cells (252·5 ± 139·5/µl, P > 0·05) was more than controls. These data demonstrated clearly that the increases in the percentages of CD4+/CCR4+ T cells were due to the increased absolute number of circulating CD4+/CCR4+ T cells in AS, RA and untreated SLE. In treated SLE patients, the absolute number of CD4+/CCR4+ T cells (139·3 ± 53·6/µl) was decreased correspondingly with the decreased lymphocytes (1371·4 ± 793·2/µl).

In addition, based on our results, there were no significant correlations between the percentage of CD4+/CCR4+ T cells and age or disease duration in all patient groups. There was no significant difference in the percentage between the patients with and without extra articular manifestions in AS [16·8 ± 8·2% (n = 3) versus 14·5 ± 5·2% (n = 8), P > 0·05] or in RA patients [24·4 ± 13·2% (n = 5) versus 19·9 ± 5·4% (n = 6), P > 0·05]. Because of the limited number of cases, this result should be regarded with caution. Omitting the treated SLE patients, no significant difference was found in the percentage of CD4+/CCR4+ T cells between the NSAIDs-taking group and the non-taking group [19·3 ± 10·2% (n = 10) versus 19·5 ± 7·8% (n = 21), P > 0·05].

Correlations between CCR4 expression and disease activity variables

The correlations between the percentage of CD4+/CCR4+ T cells and disease activity variables are summarized in Table 2. As shown in Table 2, the percentage showed a strong positive correlation with BASDAI in AS patients (P < 0·05) and SLEDAI (P < 0·01) and antibodies to ds-DNA (P < 0·05) in untreated SLE patients, whereas no significant correlation was found between the percentage and disease activity variables in RA or treated SLE patients. Figure 3 shows the correlations between the percentage of CD4+/CCR4+ T cells and BASDAI in AS and SLEDAI in untreated SLE patients.

Fig. 3
(a) Correlation between the Bath ankylosing spondylitis disease activity index (BASDAI) and the percentage of CD4+/CCR4+ T cells in the AS group (P < 0·05). (b) Correlation between the systemic lupus erythematosus disease activity index ...
Table 2
The correlation coefficients between the percentage of CD4+/CCR4+ T cells and disease activity variables

Serum cytokine levels

To investigate the associations between CCR4 expression and important cytokines in AS, RA and SLE patients, the serum levels of TNF-α, IL-10 and IFN-γ were measured. As shown in Table 3, all the patient groups showed significantly higher serum levels of IL-10 and IFN-γ than controls (all P < 0·05). Significantly increased serum levels of TNF-α were found in RA patients compared with controls. No significant correlations were found between the serum levels of cytokines and age or disease duration in any of the groups.

Table 3
Serum levels of cytokines in patients and controls

Correlation between CCR4 expression and cytokine serum levels

As shown in Table 4, the percentage of CD4+/CCR4+ T cells showed a strong positive correlation with serum levels of IL-10 in AS, RA and untreated SLE patients (all P < 0·01), while no significant correlations were found between the percentage and the serum levels of TNF-α or IFN-γ in any group.

Table 4
The correlation coefficients between the percentage of CD4+/CCR4+ T cells and serum levels of cytokines

Serum levels of TARC

Finally, we measured the serum levels of TARC, which was known to be one of CCR4 ligands. anova showed that there was no significant difference in serum levels of TARC among AS, RA, untreated SLE, treated SLE patient groups and controls (178·2 ± 109·1, 251·3 ± 131·1, 191·4 ± 171·6, 172·3 ± 70·7, 201·5 ± 133·4 pg/ml, respectively, P > 0·05).

DISCUSSION

In the present study, we have demonstrated for the first time that the percentage of CD4+/CCR4+ T cells was increased in active AS patients. The elevated percentage was also found in active RA and untreated SLE patients, while treatment with glucocorticoids either alone or together with cytotoxic drugs in the SLE patients decreased the CCR4 expression significantly. We also confirmed that the elevated CCR4 expression was correlated closely with BASDAI in AS and SLEDAI in untreated SLE. Moreover, we were able to show that CCR4 expression had a closely positive correlation with the serum level of IL-10 in active AS, RA and untreated SLE patients.

Previous studies have demonstrated the accumulation of CCR4+ T cells in RA synovial tissue and SLE renal tissue [3,6]. The increased percentages of CD4+/CCR4+ T cells in the current data suggest that circulating CD4+/CCR4+ T cells might be recruited preferentially to the inflammatory sites in AS, RA and SLE patients. Given that CCR4 is one of the major chemokine receptor of T helper 2 (Th2) cells, the up-regulation of CCR4 on CD4+ T cells indicates that Th2 responses might be enhanced in all the above diseases. Such a result is not surprising in the case of SLE, which is known as a Th2 disease. The consistent result was also found in RA (Th1 polarized disease) and AS (less cytokine deviation towards the impaired Th1 pattern than that in RA), indicating that Th2 responses might be enhanced as well as Th1 responses, although the immunoregulatory role of Th2 cells may be insufficient to control enhanced Th1 responses in them. Our data, together with previous studies that have shown increased production of Th1 and Th2 cytokines in both RA [16,17] and SLE [18,19], support the hypothesis that a balance of Th1 and Th2 is critical for an effective immune response and the outcome of autoimmune diseases [20]. On the other hand, consistent results from the blood also suggest the importance of studying CCR4 expression in inflammatory sites of the diseases.

Regarding the clinical significance of CCR4 expression, one of the most interesting findings of the present study was that there was a significant positive correlation between the percentage of CD4+/CCR4+ T cells and BASDAI, a comprehensive clinical index for AS activity. It was not surprising that the percentage showed a positive correlation with CRP and a negative correlation with ESR, because CRP could serve as a better laboratory marker than ESR for AS activity [21].

In RA, the percentage showed borderline non-significant positive correlations with disease activity index, morning stiffness, CRP and PLT, all four of which are good variables reflecting disease activity. The lack of significance of these correlations in RA might have been due to the limited number of RA patients examined in this study.

In untreated SLE, the percentage of CD4+/CCR4+ T cells showed strong correlations with SLEDAI and the serum levels of antibodies to ds-DNA, while treatment with glucocorticoids alone or together with cytotoxic drugs significantly altered the correlation spectrum in active SLE patients.

Furthermore, as distinct profiles of chemokine receptors on T cells are modulated by cytokines [22], we studied the association between the expression of CCR4 and serum levels of TNF-α, IFN-γ and IL-10. These three cytokines were chosen because of their importance in AS, RA and SLE [2326]. Our results showed that the elevated serum levels of IL-10 had the strongest correlation with the percentage of CD4+/CCR4+ T cells of all the cytokines in AS, RA and untreated SLE patients. It has been reported that IL-10 enhances CCR5 expression by human monocytes [27]. In this study, we examined the effect of IL-10 (0, 10 and 100 ng/ml) on peripheral blood mononuclear cells (PBMC) from healthy controls in vitro. However, the results showed that IL-10 did not affect the percentage of CD4+/CCR4+ T cells [IL-10 (0 ng/ml): 0 h, 8·8 ± 0·3%, 24 h, 8·5 ± 0·2%, 48 h, 7·9 ± 0·2%; IL-10 (10 ng/ml): 0 h, 8·6 ± 0·2%, 24 h, 8·7 ± 0·4%, 48 h, 8·0 ± 0·3%; IL-10 (100 ng/ml): 0 h, 8·6 ± 0·4%, 24 h, 8·4 ± 0·3%, 48 h, 7·6 ± 0·2%]. We also investigated whether stimulating CCR4 with TARC could promote IL-10 production from anti-CD3-activated (500 ng/ml) peripheral blood CD4+ T cells (2 × 106 cells/ml, purity of CD4+ T cells was more than 95%) of healthy controls. The result showed that TARC (0, 10, 100 ng/ml) did not promote IL-10 production [TARC (0 ng/ml): 48 h, 32·8 ± 1·1 pg/ml; TARC (10 ng/ml): 48 h, 30·2 ± 1·3 pg/ml; TARC (100 ng/ml): 48 h, 34·5 ± 2·9 pg/ml). These results indicate that the correlation between CCR4 and IL-10 cannot be explained by their mutual stimulation. Considering that CCR4 is expressed predominately on Th2 cells and IL-10 can be produced from Th2 cells, the correlation might be explained by the enhanced Th2 responses in all the above diseases. The question of whether the cells capable of producing IL-10 are abundant in CCR4-expressing CD4+ T cells needs to be investigated further.

Finally, we measured the serum level of TARC. A recent study indicated significantly elevated plasma level of TARC in patients with untreated SLE [28]. Our results showed that there were no significant differences in TARC between any patient group and healthy controls. Examination of the expression of TARC and MDC in disease sites, e.g. sacroiliac joints in AS, involved peripheral joints in RA and skin lesions or renal tissues in SLE should be more meaningful.

In conclusion, the significantly increased CCR4 expression on circulating CD4+ T cells in our study supports a crucial role for CCR4 in CD4+ T cell migration in AS, RA and SLE patients. Also, the proportion of CD4+/CCR4+ T cells with circulating lymphocytes may facilitate assessment of the disease activity in AS and SLE. As the number of patients included in the present study was limited, further studies in larger numbers of cases are required.

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