Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients
- Qiong Fu†1, 2,
- Xiaoqing Chen†1, 2,
- Huijuan Cui1, 2,
- Yanzhi Guo1,
- Jing Chen1,
- Nan Shen†1, 2Email author and
- Chunde Bao†1Email author
© Fu et al.; licensee BioMed Central Ltd. 2008
Received: 28 February 2008
Accepted: 15 September 2008
Published: 15 September 2008
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with a heterogeneous course and varying degrees of severity and organ damage; thus, there is increasing interest in identifying biomarkers for SLE. In this study we correlated the combined expression level of multiple interferon-inducible chemokines with disease activity, degree of organ damage and clinical features in SLE, and we investigated their roles as biomarkers.
Peripheral blood cells obtained from 67 patients with SLE patients, 20 patients with rheumatoid arthritis (RA) and 23 healthy donors were subjected to real-time PCR in order to measure the transcriptional levels of seven interferon-inducible chemokines (RANTES, MCP-1, CCL19, MIG, IP-10, CXCL11, and IL-8). The data were used to calculate a chemokine score for each participant, after which comparisons were performed between various groups of SLE patients and control individuals.
Chemokine scores were significantly elevated in SLE patients versus RA patients and healthy donors (P = 0.012 and P = 0.002, respectively). Chemokine scores were correlated positively with SLE Disease Activity Index 2000 scores (P = 0.005) and negatively with C3 levels (P < 0.001). Compared with patients without lupus nephritis and those with inactive lupus nephritis, chemokine scores were elevated in patients with active lupus nephritis, especially when their daily prednisone dosage was under 30 mg (P = 0.002 and P = 0.014, respectively). Elevated chemokine scores were also associated with the presence of cumulative organ damage (Systemic Lupus International Collaborating Clinics/American Society of Rheumatology Damage Index ≥ 1; P = 0.010) and the occurrence of anti-Sm or anti-RNP autoantibodies (both P = 0.021).
The combined transcription level of interferon-inducible chemokines in peripheral blood leucocytes is closely associated with disease activity, degree of organ damage, and specific autoantibody patterns in SLE. The chemokine score may serve as a new biomarker for active and severe disease in SLE.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by immune dysregulation that results in the production of antinuclear and other autoantibodies, as well as immune complex deposition in the kidneys and other organs. The disease course of SLE is heterogeneous and characterized by unpredictable flares and remissions. Thus, there is a pressing need to identify biomarkers that will facilitate better assessment of disease activity and organ involvement, and provide insight into the relationships between pathogenesis and clinical manifestations.
Recently, we and others have used gene expression microarrays to identify a group of type I IFN-inducible genes (IFIGs) that are significantly upregulated in peripheral blood cells from SLE patients [1–4]. The expression of these IFIGs, often referred to as IFN signatures, was later found to be closely associated with increased disease activity, specific autoantibody profiles and significant organ damage in SLE patients [5, 6]. In addition to carrying markers of the IFN signature, peripheral blood cells from SLE patients are also elevated in a variety of chemokines . Chemokines are a group of small molecules with the ability to recruit specific leucocytes to target tissue sites, thereby contributing to the organ damage seen in SLE. Other functions of chemokines include their ability to influence dendritic cell maturation, induction of B-cell and T-cell development, determination of peripheral cell localization, and involvement in T-helper-1 and T-helper-2 polarization .
A number of studies have identified increased plasma concentrations of chemokines, including 'regulated upon activation normal T-cell expressed and secreted' (RANTES), monocyte chemotactic protein (MCP)-1, IL-8, IFN-inducible protein 10 (IP-10), and monokine induced by IFN-γ (MIG), in patients with active SLE [9–12]. In addition, the ex vivo production of chemokines by peripheral blood cells from SLE patients appears to be significantly higher than that of cells from normal control individuals, after stimulation by lipopolysaccharide or phytohaemagglutinin , which suggests that the elevated expression of chemokines is involved in the immune dysregulation seen in this disorder.
Although the contributions made by chemokines in the pathogenesis of SLE have been studied extensively, the mechanisms that give rise to the increased chemokine responses in peripheral blood cells from SLE patients remain unclear. It has been reported that certain chemokine responses are strongly dependent upon IL-2 . Another study  revealed that the plasma concentrations of IP-10 and MIG are significantly correlated with that of IL-18. A recent study  found that several serum chemokines were significantly elevated in SLE patients with increased expression of IFIGs, implying that the production of certain chemokines may be regulated by the type I IFN pathway. It is also interesting that IFN-inducible chemokines are significantly elevated in active SLE patients, a fact that raises the possibility that they might serve as novel biomarkers for SLE disease activity, and which adds a new link between these two essential aspects of SLE pathogenesis. However, the associations between the IFN-inducible chemokines and the clinical features of SLE have not been fully studied. Moreover, the finding that IFN-inducible chemokines may serve as a biomarker in active SLE requires verification in a larger cohort of patients, as well as in patients from different races and backgrounds.
In the present study we measured the transcription levels of seven IFN-inducible chemokines, as well as those of five classical IFIGs, in peripheral blood cells drawn from 67 patients with SLE, 20 with rheumatoid arthritis (RA), and 23 healthy donors, and calculated a chemokine score and an IFN score for each participant. We found that the transcriptional levels of IFN-inducible chemokines in peripheral blood cells were closely associated with disease activity and organ damage in SLE, and may be useful in disease monitoring and prognostication.
Materials and methods
Patients and control individuals
Demographics of SLE and RA patients and healthy donors
SLE patients (n = 67)
RA patients (n = 20)
Healthy donors (n = 23)
35.43 ± 1.85 (14–60)
37.2 ± 1.68 (17–61)
32.21 ± 2 (16–58)
Disease duration (years)
5.58 ± 0.75 (0.04–24)
5.93 ± 1.3 (1.2–21)
8.06 ± 0.68 (0–25)
0.82 ± 0.17 (0–6)
The lupus patients were all receiving steroid therapy at the time of the study, with an average prednisone (or equivalent) dosage of 40 mg/day. In addition, 28 patients were taking immunosuppressive therapy and 28 were receiving an antimalarial drug (hydrochloroquine 200 to 400 mg/day). For each patient, disease activity and disease-related damage were assessed at the time of blood donation using the SLE Disease Activity Index 2000 (SLEDAI-2K)  and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) .
Sample handling and RNA processing
Peripheral blood samples donated by each participant were collected in tubes containing anticoagulant-citrate-dextrose solution A. After plasma was collected, erythrocytes were lysed immediately and total RNA extracted from leucocytes using Trizol Reagent (Invitrogen, Carlsbad, CA, USA). Traces of DNA contamination were routinely removed by On-column DNase treatment using RNeasy Mini Kit (Qiagen, Hamburg, Germany). The integrity of RNA was assessed using capillary gel electrophoresis, and the quality and quantity of RNA were measured using NanoDrop™ 1000 Spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA) with 260 nm/280 nm ratio above 1.8. About 1 μg total RNA was then reverse transcribed into cDNA using SuperScript II Reverse Transcriptase (Invitrogen). All plasma, RNA and cDNA samples were stored at -70°C before use.
Primers used to amplify transcripts of chemokines and IFIGs
Calculation of chemokine scores and IFN scores
IFN scores were calculated as described in previous studies [5, 6]. The mean and standard deviation (SD) for the expression level of each IFIG in the healthy donor group (meanHD and SDHD, respectively) were used to obtain a standardized expression level (S) of each gene for each SLE patient, as follows: S = (GeneSLE - GeneHD)/SD (GeneHD). In this equation, GeneSLE is the expression level of a particular gene in a given SLE patient and GeneHD is the mean level of this gene in healthy donors. All of the standardized expression level values were summed to calculate a total IFN expression score for each participant . A chemokine score for each participant was calculated in a similar manner.
Data were analyzed using the SPSS software for Windows (Version 11.0; SPSS Inc., Chicago, IL, USA). The continuous variable data were not normally distributed because of the extremely elevated expression of IFIGs and chemokines in particular patients; consequently, all values were expressed as medians with 25th and 75th percentiles and interquartile ranges (IQRs), and comparisons were conducted using the nonparametric Mann-Whitney test. Correlations between groups were evaluated using the Spearman test. P values under 0.05 were considered statistically significant.
Increased average chemokine score in SLE patients
Correlation of chemokine score with disease activity, as assessed using SLEDAI-2K and hypocomplementaemia
Chemokine scores by presence or absence of SLE clinical features
SLE clinical features present
SLE clinical features absent
Median (interquartile range)
Median (interquartile range)
8.32 (1.43 to 19.41)
3.39 (-1.43 to +12.48)
1.27 (-0.65 to +4.17)
6.23 (-0.42 to +15.60)
5.09 (-2.48 to +13.98)
5.93 (0.12 to 14.01)
5.47 (0.67 to 38.08)
5.32 (-0.93 to +13.96)
2.37 (-2.27 to +13.96)
7.39 (0.89 to 15.634)
4.21 (1.95 to 14.33)
5.93 (-4.46 to +14.01)
7.39 (-2.77 to +13.91)
5.09 (0.59 to 14.81)
8.511 (2.01 to 23.25)
3.39 (-1.56 to +12.56)
5.47 (-0.32 to +14.17)
5.72 (-0.44 to +14.81)
6.05 (1.85 to 13.96)
5.47 (-1.76 to +15.69)
11.56 (3.89 to 23.82)
3.56 (-1.72 to +12.66)
10.28 (3.08 to 18.97)
2.95 (-1.72 to +12.56)
7.50 (1.63 to 15.69)
3.73 (-0.46 to +13.91)
Predisone dose >30 mg/day
4.76 (-1.56 to +12.66)
7.72 (2.12 to 19.89)
9.98 (0.53 to 17.33)
3.08 (-1.43 to +12.65)
2.15 (-1.72 to +12.11)
8.92 (2.34 to 18.97)
Elevated chemokine scores in SLE patients with organ damage
Because prednisone may impair the expression of IFIGs by peripheral blood cells, medication used by patients at the time of blood donation could interfere with current results. Consequently, in order to limit the potential influence of high-dose prednisone on chemokine expression, we then selected SLE patients taking daily prednisone doses less than 30 mg to examine further the association between chemokine scores and renal manifestations. As shown in Figure 3b, in these subgroups of patients chemokine scores were significantly higher in patients with active LN than in those with inactive LN or without LN (P = 0.014 and P = 0.002, respectively; Figure 3b), indicating that chemokine scores are associated with ongoing renal inflammation.
We also investigated the association between chemokine scores and both chronic and irreversible tissue damage in SLE, comparing scores between SLE patients with different levels of chronic damage, as assessed using SDI. Results revealed significantly elevated chemokine scores in SLE patients with SDI scores of 1 to 2 and those with scores above 2 versus those without tissue damage (P = 0.010 and P < 0.05, respectively; Figure 3c). When patients with a prednisone dose under 30 mg/day were selected, those with an SDI score of 1 to 2 had significantly higher chemokine scores than did those with no damage (P = 0.039). Although there was only one patient in this lower dose prednisone analysis with SDI above 2 (which therefore prevented statistical analysis), the chemokine score of this single patient (SDI score = 6) did appear inordinately high relative to all others (Figure 3d). These data suggest that chemokine scores are associated with cumulative organ damage in SLE, and that such a score might be useful in predicting long-term outcomes in SLE patients.
In order to investigate whether the chemokine score is responsive to treatment and changes over time in conjunction with disease activity, we selected four SLE patients who had initial onset of biopsy-proved type IV LN and collected peripheral blood samples at the beginning of treatment and after 3 months of treatment. Three of the patients (patient 1, 3 and 4) used high-dose predisone(1 mg/kg per day) plus monthly pulse of cyclophosphamide (0.8 g/month), whereas the other (patient 2) used predisone plus mycophenolate mofetil (1.5 g/day). After 12 weeks of treatment, two patients (patients 1 and 2) achieved clinical renal remission, with the urinary protein level dropping to less than 0.5 g/24 hour and their daily dosage of predisone tapering to 35 mg. Patient 3 also had great improvement in LN, with dramatic decreases in her urinary protein level (from 6.5 g/24 hours to 0.8 g/24 hours). In concordance with the clinical improvement in nephritis, chemokine scores in these three patients also significantly lowered. In contrast, patient 4 did not respond to therapy and progressed rapidly to renal failure despite aggressive treatment, including repeated pulses of glucocorticoid (500 mg intravenous methylprednisolone) and cyclophosphamide therapies. Three months after the first blood draw, the patient was suffering from severe oedema and ascites, as well as aggravated renal and heart failure. In parallel, the chemokine score in her peripheral blood leucocytes was dramatically elevated compared with baseline (Figure 3e). The patient's condition worsened rapidly and she died a month later. This result, although preliminary, suggests that escalation in chemokine score may predict an unfavourable outcome.
Although chemokine scores and IFN scores appear to be linked, we did not find significant differences in the mean value of IFN scores between patients with various levels of SDI (P = 0.27; data not shown). This finding added additional credence to the use of chemokine scores as a novel biomarker for SLE.
Association of chemokine scores with clinical features in SLE
To assess associations between chemokine scores and clinical manifestations, autoantibody profiles and medication use, the chemokine scores were compared between patients with versus those without certain clinical features. We identified no significant differences in chemokine scores between patients with versus those without rash, mucosal ulcer, arthritis, serositis, and either neurological or haematological manifestations of SLE (Table 3). However, chemokine scores did appear to be associated with autoantibody production, being elevated in patients with anti-Sm antibodies (median = 11.56, IQR = 3.89 to 23.82;P = 0.021) or anti-RNP antibodies (median = 10.28, IQR = 3.08 to 18.97; P = 0.021; Table 3). In contrast to these results, the presence of anti-dsDNA or anti-Ro antibodies was not significantly associated with chemokine score (Table 3).
When medical therapies were considered, chemokine scores were significantly decreased in patients on antimalarial drugs at the time of blood donation (median = 2.15, IQR = -1.72 to +12.11; P = 0.048; Table 3). Chemokine scores also exhibited a trend toward being lower in patients receiving medium to high doses of prednisone (>30 mg/daay; median = 4.76, IQR = -1.56 to +12.66; P > 0.05). Treatment with immunosuppressive agents was not associated with elevated or depressed chemokine scores (Table 3).
In the present study, we selected seven IFN-inducible chemokines (RANTES, MCP-1, CCL19, MIG, IP-10, CXCL11 and IL-8), and we investigated the associations between their combined expression level and specific clinical features of SLE. Of these seven chemokines, MCP-1, RANTES and CCL19 are members of the CC family, and preferably recruit monocytes, macrophages, T cells and dendritic cells. In contrast, MIG, IP-10, CXCL11 and IL-8 are from the CXCL family, the first three of which are chemoattractants of activated T cells, whereas IL-8 is chemotactic for neutrophils . All of these chemokines have been reported to have consensus sequences for IFN-responsive elements, including ISRE (IFN-stimulated responsive element), GAS (IFN-γ activation site) and IRF (interferon regulatory factor), within their gene promoter regions [19–22]. Consequently, the expression levels of these chemokines can be regulated by the IFN pathway, making them IFN inducible. These chemokines have been studied extensively, and their contributions to SLE have been confirmed by several different investigative teams [23–26].
Rather than focusing on individual chemokines, as most previous investigators have done, we investigated the expression of multiple chemokines and assessed the impact that overall chemokine expression has on SLE disease features. We measured the transcription levels of these chemokines in peripheral leucocytes and calculated a chemokine score by combining their expression levels. Given that there are various sources of serum chemokines, other than those produced by peripheral blood leucocytes, measurement of the mRNA levels of these chemokines in peripheral blood cells is possibly a direct indicator of the dysregulation of chemokine expression that exists in peripheral immune cells in patients with SLE. Moreover, the method is simple, inexpensive and has high throughput, making it a suitable approach to gaining an overview of the expression of multiple chemokines.
In the SLE patients included in the study, IFN score was significantly correlated with chemokine scores (Figure 1c), implying that expression levels of the IFN-inducible chemokines are associated with those of classical IFIGs in SLE. This result, however, was difficult to interpret because we did find elevated chemokine scores in some SLE patients with a low IFN score (IFN-low) and low chemokine scores in patients with a high IFN score (IFN-hi). In addition, we found that the overall chemokine score was significantly higher in SLE patients than in RA patients or healthy donors (Figure 1a), whereas IFN score was elevated in both of the disease groups compared to healthy donors. This result verifies previous reports that IFIGs are notably elevated in a subgroup of RA patients  but fails to identify any increase in the expression of IFN-inducible chemokines in RA, indicating that an elevated chemokine score might be more specific for SLE than for RA.
One of the potential explanations for the discrepancy between the expression of IFIGs and IFN-inducible chemokines is the highly complicated regulation of chemokine expression that exists in various diseases. Stimuli other than type I IFNs, such as IL-18 or IL-2, as suggested by previous studies [10, 13], may be playing a role in driving the expression of chemokines in SLE. Moreover, medication used by the patients at the time of blood donation may elicit different responses in the expression of chemokines or IFIGs. The use of multiple drugs (and probably different drugs) by patients in the two patient groups might also complicate data interpretation. Nevertheless, regardless of the precise mechanism, these data suggest that the chemokine score we present here, although closely linked to IFN score, is an independent index for research and has novel and specific clinical significance.
In the present study we found that chemokine scores were associated with disease activity, as assessed using the SLEDAI-2K score and C3 level, and with ongoing or cumulative organ damage, as assessed based on the presence of active LN or SDI score in SLE patients. An elevated chemokine score may thus be helpful to identify SLE patient with active and severe disease. The preliminary longitudinal data also show that these chemokine scores are responsive to treatment and may change in conjunction with disease activity and severity, suggesting that chemokine score might be used to monitor disease progression and guide therapy. One of the weaknesses of the SLEDAI-2K score is its insensitivity in detecting improvement or worsening in a manifestation, because this can only be recorded as absent or present. For example, although patient 3 (see Figure 3e) had a dramatic decrease in urinary protein level from 6.5 g/24 hours to 0.8 g/24 hours, the SLEDAI-2K score failed to capture the improvement because she was still scored as positive in the proteinuria category. Her chemokine score, however, exhibited a significant decrease in concordance with the clinical improvement. This result, although limited and preliminary, lent further support to the chemokine score as a new and valuable marker of SLE disease activity and severity. However, prospective longitudinal studies with a larger sample size and more visits are needed to assess the role of chemokine score as a reliable biomarker in SLE.
Our conclusion that increased overall production of IFN-inducible chemokines by peripheral blood cells is important in the pathogenesis of SLE is supported by a number of published papers. Chemokines may contribute to SLE by recruiting immune and inflammatory cells to target tissues and by altering the normal trafficking and localization of certain populations of immune cells in the body; hence, they may impair the normal function of such cells. In cutaneous lupus erythematosus, MIG and IP-10 have been found to be significantly upregulated in inflamed skin and to help in the recruitment of plasmacytoid dendritic cells (pDCs), the major producers of type I IFN, to the skin . This result could explain, at least in part, the observation that the number of pDCs is reduced in the peripheral blood of SLE patients , and that pDCs are recruited into and enriched within inflamed target tissues [30, 31]. Moreover, ectopic expression of CCL19 can retain dendritic cells in target tissue and prevent their normal homing and migration to lymph nodes . Previous investigators have reported that systemic over-expression of MCP-1 in mice can impair the homing and migration of monocytes to a localized MCP-1 gradient , and that MCP-1 may inhibit the normal differentiation of monocytes, which is possibly one of the mechanisms that is involved in autoimmunity . In confirmation of these reports, our current data demonstrate that the overall production of IFN-inducible chemokines, as measured using a chemokine score, may serve as a useful indicator of the ongoing state of immune dysregulation in SLE.
In addition, in a small-scale study we also observed that the expression levels of those IFN-inducible chemokines were notably elevated in CD14+ monocytes compared with T and B lymphocytes from SLE patients, indicating that monocytes might be more important contributors to the chemokine score than lymphocytes (data not shown). Therefore, the number as well as the activation state of the circulating monocytes might be a valuable clinical marker in SLE. In accordance with this assumption, it was recently reported  that activated renal macrophages are markers of disease onset and remission in LN, adding the possibility that active circulating monocytes might also be useful in disease monitoring in SLE. However, additional studies are needed in this area.
The patients with anti-Sm or anti-RNP autoantibodies had higher chemokine scores than did SLE patients without these two autoantibodies. An association of chemokine score with anti-Sm and anti-RNP antibodies is, to our knowledge, reported here for the first time. The underlying pathophysiological mechanism for this remains unknown. One possible explanation, however, is that the expression of IFN-inducible chemokines is somewhat linked to the IFN signature. The association between the IFN signature and anti-RNP autoantibodies was reported in earlier studies [5, 6, 36]. Although the mechanisms are unclear, it has been proposed that activation of pDCs by single-stranded or double-stranded RNA, through Toll-like receptors, might lead to the induction of type I IFN production and enhanced presentation of RNA-associated materials to autoreactive T and B cells. This, in turn, has the potential to cause upregulation of IFIGs and the appearance of anti-RNA-associated protein autoantibodies. Given that patients who are positive for anti-Sm or anti-RNP antibodies exhibit increased IFN scores, it is not surprising that such patients also have higher expressions of IFN-inducible chemokines and exhibit higher chemokine scores.
The present study provides new evidence that IFN-inducible chemokine gene transcript levels in peripheral blood leucocytes may act as a new and reliable marker for disease activity and organ damage in human SLE. The data also suggest that the type I IFN system may contribute to SLE by modulating the expression of chemokines, linking these two networks in the pathogenesis of SLE. Additional studies are required to elucidate the highly complex interactions between IFIGs and chemokines, especially within the context of specific autoimmune diseases. The findings of such studies will shed new light on the dysregulation of the immune system and the involvement of inflammation in the initiation and perpetuation of autoimmunity.
C-C chemokine ligand
C-X-C chemokine ligand
interferon-induced protein with tetratricopeptide repeats
IFN-inducible protein 10
lymphocyte antigen 6 complex, locus E
monocyte chemotactic protein
monokine induced by IFN-γ
myxovirus resistance 1
polymerase chain reactions
plasmacytoid dendritic cell
regulated upon activation normal T-cell expressed and secreted
Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index
systemic lupus erythematosus
SLE Disease Activity Index 2000.
Dr Bao's work was supported by grants from the Chinese Natural Science Foundation (No. 30571737 and 30471582). Dr Shen's work was supported by the National High Technology Research and Development Program of China (Program 863; No. 2007AA02Z123), the Key Basic Program of the Shanghai Commission of Science and Technology (No. 06JC14050), and the Program of Shanghai Subject Chief Scientist (No. 07XD14021). Dr Fu's work was supported by the Doctorate Foundation of the Shanghai Jiao Tong University School of Medicine (No. BXJ0717). We thank the patients, healthy donors and rheumatologists in the Department of Rheumatology of Renji Hospital, who participated in this study.
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