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Rheumatology 2008 47(1):45-49; doi:10.1093/rheumatology/kem313
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CXCL10 ({alpha}) and CCL2 (β) chemokines in systemic sclerosis—a longitudinal study

A. Antonelli1, C. Ferri2, P. Fallahi1, S. M. Ferrari1, D. Giuggioli2, M. Colaci2, A. Manfredi2, S. Frascerra1, F. Franzoni1, F. Galetta1 and E. Ferrannini1

1Department of Internal Medicine, University of Pisa School of Medicine, Pisa and 2Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.

Correspondence to: A. Antonelli, Department of Internal Medicine, University of Pisa School of Medicine, Via Roma, 67, I-56100, Pisa, Italy. E-mail: a.antonelli{at}med.unipi.it


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression.

Methods. Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later.

Results. SSc at onset showed significantly higher CXCL10 serum levels than controls (216 ± 126 vs 92 ± 53 pg/ml; P < 0.0001), as well as CCL2 (388 ± 172 vs 318 ± 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 ± 112 vs 270 ± 122 pg/ml, respectively; P < 0.0001), while no significant change was observed for CCL2 (418 ± 176 vs 405 ± 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 ± 0.8 vs 3.5 ± 2.5; P < 0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio.

Conclusions. Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.

KEY WORDS: CXCL10 (IP-10), CCL2 (MCP-1), Th1, Th2, Systemic sclerosis, Scleroderma


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Chemokines are a group of peptides with a low molecular weight that induce the chemotaxis of different leucocyte subtypes to inflammation sites [1, 2]. So far, only two of these families have been extensively studied and characterized: namely, the CC and CXC chemokines according to the organization of positionally conserved cysteine residues. Chemokines of the CC family are generally chemoattractant for T lymphocytes, monocytes and natural killer (NK) cells while CXC chemokines attract neutrophils and promote their adherence to endothelial cells [3, 4]. Monocyte chemoattractant protein 1 (MCP-1/CCL2) is a prototype CC chemokine, that plays an important role in innate immunity [5–7], and a crucial factor for the development of adaptive Th2 responses [8]. Among CXC chemokines, CXCL10 displays a strong chemoattractant activity for Th1 lymphocytes secreting interferon-{gamma} (INF-{gamma}), with several experimental data suggesting that CXCL10 measurement is a reliable marker of aggressive Th1-mediated autoimmune disease [9]. More recently, chemokines have been identified to play an important role in endocrine autoimmune disease and particular attention has been raised by studies demonstrating both CC and CXC chemokine overexpression in the early phases of Graves’ disease (GD) and Hashimoto thyroiditis (HT) [10–16].

Only a few studies have focused on the possible role of circulating {alpha}- and β-chemokines in SSc. In particular, regarding CXCL10, there is only one cross-sectional study showing high serum levels of the Th1 chemoattractant CXCL10 and Th2 chemoattractants, TARC and MDC, in patients with SSc [17].

Whereas Hasegawa et al. [18] first reported high levels of serum CCL2, in patients with SSc in association with lung fibrosis, this finding has been subsequently confirmed by other studies [19, 20].

In the study by Matsushita et al. [20], serum cytokine levels were longitudinally/retrospectively examined in 26 patients with early diffuse cutaneous SSc treated with immunomodulant drugs. Serum levels of Th2 cytokines (CCL2) were high at first evaluation, and decreased as skin sclerosis regressed. Conversely, levels of serum interleukin (IL)-12, a Th1-inducing cytokine, were low at first visit but became significantly higher after 6 yrs. These results suggested that Th2 to Th1 shifting correlates with skin sclerosis improvement in SSc.

More recently, the molecular mechanisms governing skin fibrosis in murine sclerodermatous graft-vs-host disease (Scl GVHD), a model for human scleroderma, has been investigated [21]. A novel finding previously unreported in sclerodermatous disease is the increased expression of IFN-{gamma}-inducible chemokines, most likely a response to the high IFN-{gamma} skin levels in the early stages of the disease. The Th1/Th2-like environment changes over time, from high (Th1-like) to low IFN-{gamma} and high IL-10 (Th2-like). This study suggests that the disease progresses from early inflammatory (Th1-like) to later non-inflammatory (Th2-like), much like scleroderma and localized scleroderma (morphoea) [21].

The patterns of cytokines secreted by Th1 and Th2 cells result in particular combinations that specifically drive particular types of immune response [22]. Therefore, the simultaneous assessment of different chemokines may potentially be of great interest, as demonstrated in multiple sclerosis (MS) (a Th1-mediated autoimmune disease) in which CXCL10 and CCL2 display different behaviour in relation to the acute or stable phase of the disease [23–25] and autoimmune thyroiditis [15, 16].

To our knowledge, no study has evaluated contemporarily and prospectively both {alpha}- and β-chemokines in the sera of patients with SSc. The aim of the present study was to measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclasses (CXC and CC) in patients with newly diagnosed SSc, and to relate the findings to clinical phenotypes and disease progression.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
SSc patients
The study included 72 SSc patients (65 females, 7 males; age 54 ± 13 yrs) referred to our Rheumatology Unit between 2001 and 2005 and 72 sex- and age-matched healthy controls. In all patients, SSc was classified according to the American College of Rheumatology 1980 preliminary criteria [26]; only untreated patients, consecutively recruited at the time of diagnosis (mean duration of SSc clinical symptoms, other than Raynaud's phenomenon, 2.5 ± 1.8 yrs) and without other autoimmune disorders, such as autoimmune thyroiditis, were investigated. Standardized criteria were followed for the evaluation of SSc clinico-serological features as previously described [27–29]. Skin sclerosis was observed in all patients (diffuse 10%, intermediate 19% and limited 71%). At the first evaluation, the presence of peripheral vascular manifestations (Raynaud's phenomenon with digital pitting scars and/or ulcerations or gangrene) was recorded in 84% of the patients; joint/tendon (polyarthralgias or arthritis when inflammatory changes were observed in more than two joints) in 11%; oesophageal (dysphagia and or oesophageal radiographic dysmotility) and/or gastrointestinal in 43%; cardiac (pericarditis and/or congestive heart failure and/or severe arrhythmias and/or atrio-ventricular conduction defects) in 22%; kidney (mild–moderate renal failure) in 6%; and interstitial lung involvement (ground glass and/or interstitial fibrosis detected by high-resolution computed tomography) in 43% [27–29]. Autoantibody evaluation was carried out according to standard methodologies [27]; namely, anti-nuclear antibodies (ANA) were found in 89%, anti-centromere in 31% and anti-Scl70 in 35% of the cases, respectively (the titres of anti-Scl70, ANA and ACA were constantly ≥1:160).

After 5 yrs from the initial assessment, 37 SSc patients without corticosteroid and/or immunosuppressive treatments for at least 2 months were re-evaluated. At the initial evaluation, their clinico-serological phenotype was comparable with that observed in the whole series. After the 5-yr follow-up, visceral organ involvement showed a variable worsening as follows: peripheral vascular system, 93%; gastrointestinal system, 56%; lung, 62%; joints/tendons, 18%; heart, 31%; and kidney 10%.

The control group consisted of 72 healthy subjects (65 females, 7 males; age, 53 ± 14 yrs), extracted from a random sample of the general population within the same geographic area [14], coupled with SSc patients by sex and age (±5 yrs), which is a well-known confounding factor [12]. Moreover, a complete clinical work-up excluded the presence of autoimmune diseases, particularly thyroid disorders that are a well-known cause of abnormally high levels of CXCL10 [15, 16]. Among the above controls, 35 subjects were also re-evaluated 5 yrs after the initial study; after the exclusion of possible autoimmune diseases, they were coupled according to age and sex with the 35 revisited SSc patients.

In all patients and controls, a blood sample was collected in the morning, after overnight fasting, and serum was kept frozen until CXCL10 and CCL2 measurement.

All subjects gave their informed consent to enter the study. The study was approved by the local ethical committee.

Chemokine assay
Serum CXCL10 levels were assayed by a quantitative sandwich immunoassay using a commercially available kit (R&D Systems, Minneapolis, MN, USA), with a sensitivity ranging from 0.41–4.46 pg/ml. The intra- and inter-assay coefficients of variation were 3.0 and 6.9%, respectively. Serum CCL2 levels were assayed by a quantitative sandwich immunoassay using a commercially available kit (R&D Systems), with a sensitivity of <5.0 pg/ml. The intra- and inter-assay coefficients of variation were 4.7 and 5.8%, respectively.

Data analysis
Values are given as mean ± S.D. for normally distributed variables. Mean group values were compared by using one-way analysis of variance (ANOVA) for normally distributed variables. Proportions were compared by the chi-square test. Post hoc comparisons on normally distributed variables were carried out using the Bonferroni–Dunn test. Paired data were compared by Wilcoxon signed-rank test and univariate analysis was performed by simple regression.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Transverse evaluation
Patients with SSc at diagnosis showed significantly higher mean CXCL10 serum levels than controls (216 ± 126 vs 92 ± 53 pg/ml, respectively; P < 0.0001) (Fig. 1a), also serum CCL2 levels were higher in SSc patients (388 ± 172 vs 318 ± 120 pg/ml, respectively; P = 0.01) (Fig. 1b).


Figure 1
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  		FIG. 1. (a) CXCL10 serum levels were significantly higher in scleroderma patients at first evaluation than in controls (P < 0.001; ANOVA). (b) CCL2 serum levels were significantly higher in scleroderma patients at first evaluation than in controls (P < 0.01; ANOVA). The box indicates the lower and upper quartiles and the central line is the median value; the horizontal lines at the end of the vertical lines are the 2.5 and 97.5% values.

 
In order to better define the role of increased serum chemokines in SSc, CXCL10 and CCL2 were correlated to the extent of skin sclerosis and the presence/absence of main clinico-serological features of SSc patients. Interestingly, CXCL10 levels were significantly increased in SSc patients with interstitial lung involvement and in those with kidney involvement (P = 0.01 and P = 0.02, respectively), while nearly significant differences (P = 0.06) were observed in relation to anti-topoisomerase I (anti-Scl-70) positivity (Table 1). On the contrary, serum CCL2 levels were not significantly changed in relation to the clinical features of SSc patients (data not shown). Moreover, no correlation (simple regression) between CXCL10 and CCL2 serum levels could be demonstrated in SSc patients; finally, mean levels of both CXCL10 and CCL2 did not differ among various SSc cutaneous subsets.


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  		TABLE 1. Relationship between CXCL10 levels and main clinico-serological features of SSc

 
By defining a high CXCL10 level as a value of at least 2 S.D. above the mean value of the control group (>198 pg/ml), 46% (33/70) of SSc patients and only 5% (4/70) of the control subjects had high CXCL10 (P < 0.0001; chi-square). Instead, high CCL2 levels, defined as above, characterized a comparably small percentage of patients and controls, 16 and 11% (P = NS), respectively.

Longitudinal evaluation
A significant decrease of CXCL10 serum levels was observed after 5 yrs from the initial evaluation in SSc (137 ± 112 vs 270 ± 122 pg/ml; respectively; P < 0.0001) (Fig. 2a), while no significant changes were observed for CCL2 (418 ± 176 vs 405 ± 164 pg/ml; P = NS) (Fig. 2b). The CCL2/CXCL10 ratio, an expression of the Th2/Th1 balance, significantly increases from first to fifth year evaluation (1.7 ± 0.8 vs 3.5 ± 2.5; P < 0.0001) (Fig. 2c). The changes of CXCL10 and CCL2 serum levels, and CCL2/CXCL10 ratio were not associated with the variations of any SSc clinical features.


Figure 2
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  		FIG. 2. (a) CXCL10 serum levels were significantly higher in scleroderma patients at SSc diagnosis (onset) than after 5 yrs (P < 0.001; by Wilcoxon signed-rank test). (b) CCL2 serum levels were not significantly different in scleroderma patients at SSc diagnosis (onset) than after 5 yrs. (c) The CCL2/CXCL10 ratio significantly increased in scleroderma after 5 yrs (P < 0.0001; by Wilcoxon signed-rank test). Data are displayed as box-and-whisker plots.

 
Finally, no significant changes were observed in control subjects from the basal to the 5-yr evaluation with regards to CXCL10 (from 71 ± 45 to 73 ± 34, pg/ml; P = NS), CCL2 (from 296 ± 121 to 300 ± 148 pg/ml; P = NS), or CCL2/CXCL10 ratio (from 4.4 ± 8.9 to 2.9 ± 6.6; P = NS).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our study demonstrates high serum levels of both CXCL10 (Th1) and CCL2 (Th2) chemokines in untreated SSc patients with relatively short disease duration. High values of CXCL10 seem to be associated with more severe clinical phenotype, namely with the presence of lung fibrosis and/or kidney involvement. After the 5-yr follow-up, CXCL10 serum levels decreased, while circulating CCL2 was unchanged. The different behaviour of these chemokines is responsible for a significant increase of CCL2/CXCL10 ratio, suggesting a shift from Th1 to Th2 dominant immune response in the course of the disease.

The aetiology of SSc is probably multifactorial; it may be correlated to different triggering agents—infectious/environmental—and predisposing genetic co-factors; the consequence is a combination of diffuse microvascular damage, fibroblast dysfunction with collagen overproduction and immune system alterations [30–33].

A large body of clinical and laboratory studies suggests a crucial role of the immune system in the pathogenesis of SSc, which may involve both T- and B-lymphocytes, as well as some ‘pathogenetic’ auto-antibodies [30, 31]. A variable combination of the aforementioned alterations of the immune system may explain the appearance of different SSc clinico-serological phenotypes. Moreover, the natural history of the disease, often characterized by unpredictable progression and outcome, suggests a multistep pathogenetic process. In this scenario, it is supposable that the immune system modulation, due to different pathogenetic factors and possibly to therapeutic interventions, is responsible for markedly variable disease expression. Altogether, the above considerations may explain the contrasting data present in the literature, particularly on the possible role of Th1/Th2 balance [31, 34, 35]: a variable polarization of T lymphocytes with different cytokine/chemokine repertoires might be present during the SSc progression, varying from prevalent vascular to fibrotic alterations [30, 31, 34, 35]. On the other hand, variable composition of the patient series and/or employed methodologies in different studies should also be taken into account.

CXCL10 serum levels in SSc patients have been evaluated in another study [17] showing that serum levels of Th1 chemoattractant CXCL10/IP-10 and Th2 chemoattractants, TARC and MDC, were elevated in patients with SSc. The study evaluated patients with mean SSc duration of about 7 ± 10 yrs, therefore the reported findings are only partially comparable with those observed in the present study.

With regards to CCL2, Hasegawa et al. [18] first reported high levels of this chemokine in patients with SSc complicated by lung fibrosis; mean SSc duration in these patients was about 5.5 ± 6 yrs. These data have subsequently been confirmed by Peterlana et al. [19] in patients with longer disease duration.

In the study by Matsushita et al. [20], serum cytokine levels were longitudinally/retrospectively examined in 26 patients with early diffuse cutaneous SSc treated with corticosteroid and D-penicillamine. Serum levels of the Th2 cytokines and CCL2 were higher at first evaluation compared with healthy controls, and decreased as skin sclerosis regressed. Conversely, levels of serum IL-12, a Th1-inducing cytokine, were lower at first visit compared with controls, but increased significantly after 6 yrs. Surviving patients with diffuse cutaneous SSc exhibited elevated IL-12 levels compared with deceased patients. These results suggested that a shift from Th2 to Th1 response correlates with the improvement of skin fibrosis and better SSc prognosis. In the same study, high CCL2 serum levels were present at the start of the study and remained stable during the 6-yr follow-up; this observation is in agreement with our finding of high serum CCL2 before/after the 5-yr follow-up. However, our data of Th1 (CXCL10) immune response in recently diagnosed SSc patients and its decline with the follow-up contrast with the above observations. This discrepancy may be explained by many considerations: CXCL10, the prototype of IFN-{gamma}-dependent chemokines, has not been evaluated in Matsushita's retrospective study; at first evaluation, some SSc patients were treated with corticosteroid, while only 12 patients, all under corticosteroids and/or D-penicillamine, were re-evaluated (on the contrary, our 37 patients were not taking any immunomodulant treatment for at least 2 months before chemokine re-evaluation). Other relevant differences between the two SSc series should be taken into account, mainly their racial and clinico-epidemiological peculiarities such as a different selection of patients: the Japanese study did not exclude other autoimmune disorders such as autoimmune thyroiditis, frequently found in SSc patients [10–16], and was responsible per se for important immune system alterations [36].

More recently, the molecular mechanisms governing skin fibrosis in murine sclerodermatous graft-vs-host disease (Scl GVHD), a model for human scleroderma, have been investigated [21]. The temporal histopathological development of murine cutaneous Scl GVHD is accompanied by the up-regulated expression of many chemokines and their receptors (Th1-like: IFN-{gamma}, CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC; and Th2-like: IL-6, Il-10 and IL-13). A novel finding not reported previously in sclerodermatous disease is the increased expression of IFN-{gamma}-inducible chemokines, most likely a response to high IFN-{gamma} levels in the skin in the early stages of the disease. The Th1/Th2-like environment changes over time, from high IFN-{gamma} (Th1-like) to low IFN-{gamma}–high IL10 (Th2-like). This study suggests that the disease progresses from early inflammatory (Th1-like) to later non-inflammatory (Th2-like), much like scleroderma and localized scleroderma (morphoea) [21].

Our findings are fully consistent with the aforementioned model of murine Scl GVHD mentioned earlier in this article. In the early phases of SSc, high serum levels of both CXCL10 (Th1) and CCL2 (Th2) were found; successively, serum CXCL10 declines, while CCL2 levels remain unmodified, as a consequence the Th2/Th1 balance (roughly evaluated through the CCL2/CXCL10 ratio) significantly increases, suggesting that the disease progresses from early inflammatory (Th1-like) to later non-inflammatory (Th2-like) stages, when the fibrosis prevails on inflammation. Furthermore, our finding of higher CXCL10 in SSc patients with lung fibrosis is in keeping with the results of other studies that have demonstrated the importance of CXC chemokines in other types of pulmonary fibrosis [37].

Future studies will be needed to evaluate the source (immune cells [16], fibroblasts [14], endothelial cells [38]), of the circulating chemokines in SSc patients. This model is consistent with other studies that showed CCL2 profibrotic effects in SSc [39–44].

The patterns of chemokines secreted by Th1 and Th2 cells constitute paradigmatic combinations that specifically drive particular types of immune response, but other such combinations are probably yet to be unveiled [45]. Therefore, the simultaneous assessment of different chemokines may potentially be of great interest, as shown in other Th1-mediated autoimmune disorders such as MS and neuropsychiatric lupus [46]. In this view, relevant findings arise from two previous reports in which CXCL10 and CCL2 have been contemporarily assessed in the serum and cerebrospinal fluid (CSF) of MS patients, showing no correlation between the two chemokines but their different behaviour in relation to the phase of the disease. In detail, CXCL10 was higher in acute MS and lower in stable disease while the opposite profile characterized CCL2 secretion, demonstrating a pathogenetic role for both chemokines with reciprocal changes according to the clinical phase of MS [47–49]. A significant imbalance of CCL2/CXCL10 ratio in CSF has also been proposed as a useful clinical tool in other conditions such as the neuropsychiatric lupus [50]. Our findings about significant changes in CCL2/CXCL10 ratio in sera of SSc patients are in keeping with the observation mentioned earlier in this article, and suggest that this ratio might be usefully employed in pathogenetic and clinico-therapeutical studies.

In conclusion, our study demonstrates high serum levels of both CXCL10 (Th1) and CCL2 (Th2) chemokines at the time of SSc diagnosis; high CXCL10 values could be associated with more severe clinical phenotypes. Different serological behaviour of these two chemokines—CXCL10 decreases while CCL2 remains high—suggests that the disease progresses from early inflammatory (Th1-like) to a later non-inflammatory, fibrotic (Th2-like) stage. Future studies in larger SSc series should better evaluate the potential usefulness of serum chemokines as inflammation/fibrosis and/or outcome markers in SSc patients.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity (2000) 12:121–7.[CrossRef][Web of Science][Medline]
  2. Arenberg DA, Polverini PJ, Kunkel SL, et al. The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer. J Leukoc Biol (1997) 62:554–62.[Abstract]
  3. Luster AD. Chemokines–chemotactic cytokines that mediate inflammation. N Engl J Med (1998) 338:436–45.[Free Full Text]
  4. Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clin Endocrinol (2003) 59:207–13.[CrossRef][Medline]
  5. Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med (1998) 187:601–8.[Abstract/Free Full Text]
  6. Maghazachi AA, Al-Aoukaty A, Schall TJ. CC chemokines induce the generation of killer cells from cd56+ cells. Eur J Immunol (1996) 26:315–9.[Web of Science][Medline]
  7. Taub DD, Sayers TJ, Carter CR, Ortaldo JR. Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol (1995) 155:3877–88.[Abstract]
  8. Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD, Barrett TA. Differential CC chemokine-induced enhancement of t helper cell cytokine production. J Immunol (1997) 158:4129–36.[Abstract]
  9. Rotondi M, Rosati A, Buonamano A, et al. High pretransplant serum levels of cxcl10/ip-10 are related to increased risk of renal allograft failure. Am J Transplant (2004) 4:1466–74.[CrossRef][Web of Science][Medline]
  10. Antonelli A, Rotondi M, Fallahi P, et al. Iodine-131 given for therapeutic purposes modulates differently interferon-{gamma}-inducible {alpha}-chemokine CXCL10 serum levels in patients with active Graves’ disease or toxic nodular goiter. J Clin Endocrinol Metab (2007) 92:1485–90.[Abstract/Free Full Text]
  11. Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Serio M, Miccoli P. Serum levels of the interferon-gamma-inducible alpha chemokine CXCL10 in patients with active Graves' disease, and modulation by methimazole therapy and thyroidectomy. Br J Surg (2006) 93:1226–31.[CrossRef][Web of Science][Medline]
  12. Antonelli A, Fallahi P, Rotondi M, et al. Increased serum CXCL10 in Graves’ disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process. Eur J Endocrinol (2006) 154:651–8.[Abstract/Free Full Text]
  13. Antonelli A, Rotondi M, Fallahi P, et al. Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy. Clin Endocrinol (2006) 64:189–95.[CrossRef][Medline]
  14. Antonelli A, Rotondi M, Ferrari SM, et al. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab (2006) 91:614–20.[Abstract/Free Full Text]
  15. Antonelli A, Rotondi M, Fallahi P, et al. Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis. Eur J Endocrinol (2005) 152:171–7.[Abstract/Free Full Text]
  16. Antonelli A, Rotondi M, Fallahi P, et al. High levels of circulating CXC chemokine ligand 10 are associated with chronic autoimmune thyroiditis and hypothyroidism. J Clin Endocrinol Metab (2004) 89:5496–9.[Abstract/Free Full Text]
  17. Fujii H, Shimada Y, Hasegawa M, Takehara K, Sato S. Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis. J Dermatol Sci (2004) 35:43–51.[CrossRef][Web of Science][Medline]
  18. Hasegawa M, Sato S, Takehara K. Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis. Clin Exp Immunol (1999) 117:159–65.[CrossRef][Web of Science][Medline]
  19. Peterlana D, Puccetti A, Caramaschi P, et al. Endothelin-1 serum levels correlate with MCP-1 but not with homocysteine plasma concentration in patients with systemic sclerosis. Scand J Rheumatol (2006) 35:133–7.[CrossRef][Web of Science][Medline]
  20. Matsushita T, Hasegawa M, Hamaguchi Y, Takehara K, Sato S. Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. J Rheumatol (2006) 33:275–84.[Abstract/Free Full Text]
  21. Zhou L, Askew D, Wu C, Gilliam AC. Cutaneous gene expression by DNA microarray in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol (2007) 127:281–92.[CrossRef][Web of Science][Medline]
  22. Ashhab Y, Dominguez O, Sospedra M, Roura-Mir C, Lucas-Martin A, Pujol-Borrell R. A one-tube polymerase chain reaction protocol demonstrates CC chemokine overexpression in Graves’ disease glands. J Clin Endocrinol Metab (1999) 84:2873–82.[Abstract/Free Full Text]
  23. Sorensen TL, Tani M, Jensen J, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest (1999) 103:807–15.[Web of Science][Medline]
  24. Sorensen TL, Sellebjerg F, Jensen CV, Strieter RM, Ransohoff RM. Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis. Eur J Neurol (2001) 8:665–72.[CrossRef][Web of Science][Medline]
  25. Franciotta D, Martino G, Zardini E, et al. Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies. J Neuroimmunol (2001) 115:192–8.[CrossRef][Web of Science][Medline]
  26. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum (1980) 23:581–90.[Web of Science][Medline]
  27. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (2002) 81:139–53.[CrossRef][Medline]
  28. Ferri C, Cazzato M, Giuggioli D, Sebastiani M, Magro C. Systemic sclerosis following human cytomegalovirus infection. Ann Rheum Dis (2002) 61:937–8.[Free Full Text]
  29. Ferri C, Colaci M, Battolla L, Giuggioli D, Sebastiani M. Thymus alterations and systemic sclerosis. Rheumatology (2006) 45:72–5.[Abstract/Free Full Text]
  30. Arnett FC. Is scleroderma an autoantibody mediated disease? Curr Opin Rheumatol (2006) 18:579–81.[Web of Science][Medline]
  31. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest (2007) 117:557–67.[CrossRef][Web of Science][Medline]
  32. Medsger TJ. Systemic sclerosis (scleroderma): clinical aspects. In: Arthritis and allied conditions—Koopman WJE, ed. (2001) Philadelphia: Lippincott Williams & Wilkins. 1590–624.
  33. Black C, Denton C. Scleroderma and related disorders in adults and children. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC, eds. In: Oxford textbook of rheumatology (2004) 2. Oxford: Oxford Writing Press. 872–95.
  34. Giacomelli R, Cipriani P, Fulminis A, et al. Circulating gamma/delta T lymphocytes from systemic sclerosis (SSC) patients display a T helper (Th) 1 polarization. Clin Exp Immunol (2001) 125:310–5.[CrossRef][Web of Science][Medline]
  35. Valentini G, Baroni A, Esposito K, et al. Peripheral blood T lymphocytes from systemic sclerosis patients show both Th1 and Th2 activation. J Clin Immunol (2001) 21:210–7.[CrossRef][Web of Science][Medline]
  36. Antonelli A, Ferri C, Fallahi P, et al. Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis. Eur J Endocrinol (2007) 156:431–7.[Abstract/Free Full Text]
  37. Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest (2007) 117:549–56.[CrossRef][Web of Science][Medline]
  38. Marx N, Mach F, Sauty A, et al. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, MIG, and I-TAC in human endothelial cells. J Immunol (2000) 164:6503–8.[Abstract/Free Full Text]
  39. Distler JH, Jungel A, Caretto D, et al. Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. Arthritis Rheum (2006) 54:214–25.[CrossRef][Web of Science][Medline]
  40. Karrer S, Bosserhoff AK, Weiderer P, et al. The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis. J Invest Dermatol (2005) 124:92–8.[CrossRef][Web of Science][Medline]
  41. Distler O, Pap T, Kowal-Bielecka O, et al. Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum (2001) 44:2665–78.[CrossRef][Web of Science][Medline]
  42. Yamamoto T, Eckes B, Krieg T. High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol (2001) 31:2936–41.[CrossRef][Web of Science][Medline]
  43. Galindo M, Santiago B, Rivero M, Rullas J, Alcami J, Pablos JL. Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum (2001) 44:1382–6.[CrossRef][Web of Science][Medline]
  44. Yamamoto T, Hartmann K, Eckes B, Krieg T. Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. J Dermatol Sci (2001) 26:106–11.[CrossRef][Web of Science][Medline]
  45. Lakatos P, Foldes J, Horvath C, et al. Serum interleukin-6 and bone metabolism in patients with thyroid function disorders. J Clin Endocrinol Metab (1997) 82:78–81.[Abstract/Free Full Text]
  46. Romagnani S. The Th1/Th2 paradigm. Immunol Today (1997) 18:263–6.[Web of Science][Medline]
  47. Cooper DS. Antithyroid drugs. N Engl J Med (1984) 311:1353–62.[Abstract]
  48. Weetman AP, McGregor AM, Hall R. Evidence for an effect of antithyroid drugs on the natural history of Graves’ disease. Clin Endocrinol (1984) 21:163–72.[Medline]
  49. Weetman AP, Tandon N, Morgan BP. Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells. Lancet (1992) 340:633–6.[CrossRef][Web of Science][Medline]
  50. Okamoto H, Iikuni N, Kamitsuji S, Yoshio T, Minota S, Kamatani N. IP-10/MCP-1 ratio in CSF is an useful diagnostic marker of neuropsychiatric lupus patients. Rheumatology (2006) 45:232–4.[Free Full Text]
Submitted 7 May 2007; revised version accepted 29 October 2007.
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J. H. W. Distler, A. Akhmetshina, G. Schett, and O. Distler
Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis
Rheumatology, February 1, 2009; 48(2): 98 - 103.
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