Eur J Endocrinol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1530/eje.1.01847
European Journal of Endocrinology, Vol 152, Issue 2, 171-177
Copyright © 2005 by European Society of Endocrinology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Antonelli, A.
Right arrow Articles by Serio, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Antonelli, A.
Right arrow Articles by Serio, M.
CLINICAL STUDY

Increase of interferon-{gamma} inducible {alpha} chemokine CXCL10 but not ß chemokine CCL2 serum levels in chronic autoimmune thyroiditis

Alessandro Antonelli1, Mario Rotondi2, Poupak Fallahi1, Paola Romagnani3, Silvia Martina Ferrari1, Aldo Paolicchi4, Ele Ferrannini1 and Mario Serio3

1 Metabolism Unit, Department of Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy, 2 Department of Clinical and Experimental Medicine and Surgery ‘F. Magrassi-A. Lanzara,’ Second University of Naples, Naples, Italy, 3 Department of Clinical Pathophysiology, Endocrinology Unit, University of Florence, Florence, Italy and 4 Department of Experimental Pathology, University of Pisa School of Medicine, Pisa, Italy

(Correspondence should be addressed to A Antonelli; Email: a.antonelli{at}med.unipi.it)


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective: To measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclass (CXC and CC) in patients with newly diagnosed chronic autoimmune thyroiditis (AT), and relate the findings to the clinical phenotype.

Design and methods: Serum CXCL10 and CCL2 were assayed in 70 consecutive patients with newly diagnosed chronic AT, in sex- and age-matched healthy volunteers (n = 37) and in 20 patients with non-toxic multinodular goiter, extracted from a random sample of the general population from the same geographic area.

Results: CXCL10 serum levels were significantly higher in patients with thyroiditis than in controls or multinodular goiter patients, while comparable CCL2 levels were found between groups. CXCL10 levels were significantly increased in hypothyroid patients and in those with an hypoechoic pattern (P = 0.0004 and P = 0.0001, respectively) while serum CCL2 levels were significantly increased in patients older than 50 years and in those with hypothyroidism (P = 0.0001 and P = 0.03, respectively). No correlation between CXCL10 and CCL2 serum levels could be demonstrated. CXCL10 and CCL2 were studied separately in relation to clinical features of AT patients. Two separate multiple linear regression models for CXCL10 and CCL2 were performed, including age, thyroid volume, thyroid stimulating hormone (TSH), FT4, anti-thyroid peroxidase (AbTPO), hypoechoic pattern, and the presence of hypervascularity, demonstrating that ln of serum CXCL10 levels was associated with TSH independently of other possible confounders levels [regression coefficient (R.C.) 0.143 confidence interval (C.I.) (0.042–0.245); P = 0.0059], while serum CCL2 were significantly associated only with age [R.C. 5.412 C.I. (3.838–6.986); P < 0.0001].

Conclusion: Our results, obtained in a large cohort of newly diagnosed AT patients demonstrate increased CXCL10 especially in hypothyroid patients with a more aggressive disorder, and normal CCL2 serum levels in AT.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Chemokines are a group of peptides of low molecular weight that induce the chemotaxis of different leukocyte subtypes (1). The major function of chemokines is the recruitment of leukocytes to inflammation sites, but they also play a role in tumoral growth, angiogenesis, and organ sclerosis (2, 3). At present, more than 50 chemokines have been described, which have been classified into four major families (1). 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 generally are chemoattractant for T lymphocytes, monocytes, and natural killer (NK) cells while CXC chemokines attract neutrophils and promote their adherence to endothelial cells (4–6). Monocyte chemoattractant protein 1 (MCP-1) is a prototype CC chemokine, playing an important role in innate immunity (7–10). Moreover, CCL2 is also a crucial factor for the development of adaptive T-helper (Th)2 responses by directing the differentiation of Th0 cells to Th2 in vitro (11). Among CXC chemokines, CXCL10 similarly to other non-ELR (glutamic acid-leucine-arginine negative) chemokines, is a poor neutrophil chemoattractant and activator. However, it displays a strong chemoattractant activity for Th1 lymphocytes secreting INF-{gamma}, with several experimental data suggesting that CXCL10 measurement is a reliable marker of aggressive Th1-mediated autoimmune disease (12).

Autoimmune thyroid disease (AITD) with Hashimoto’s thyroiditis (HT) and Graves’disease (GD) are the most frequent endocrine autoimmune conditions, both being characterized by diffuse lymphocytic infiltration which is predominant in HT and varies with the type and stage of AITD (13). Cytokine production during autoimmune thyroid disease shows the expression of interleukin (IL)-1, IL-2, IL-6, IL-10, interferon (IFN)-{gamma} and tumour necrosis factor (TNF)-{alpha} by infiltrating T cells and macrophages (14–17). In addition, thyroid follicular cells (TFC) themselves produce many cytokines (18–21). 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 HT and in early phases of GD (22–23).

Subsequent studies have shown that expression of CXCL10 and CCL2 is also stimulated by different proinflammatory cytokines in thyroid follicular cells (TFC) (24, 22) and that both {alpha} and ß chemokines are overexpressed in GD thyroid tissue (25).

In addition, by immunohistochemistry an increase in CXCL10/IP-10 and CXCL9/Mig was found in thyroid tissue specimens obtained from subjects affected by HT (22).

The possible role of circulating {alpha} and ß chemokines in AITD has been less extensively studied, with only one previous observation regarding increased serum CCL2 levels in chronic autoimmune thyroiditis (AT) and increased serum CXCL10 in GD patients (23, 26, 27).

Besides their chemotactic activity, chemokines modulate the immune responses through the recruitment of specific T helper subsets and cytokine production. The patterns of cytokines secreted by Th1 and Th2 cells result in particular combinations that specifically drive particular types of immune response (25). Therefore the simultaneous assessment of different chemokines may be potentially 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 disease (28–30).

To our knowledge, no study has evaluated contemporarily serum {alpha} and ß chemokines in patients with AT. The aim of the present study therefore was to measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclass (CXC and CC) in patients with newly diagnosed chronic AT, and relate the findings to the clinical phenotype.


   Patients and methods
Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients

From the outpatient clinic, we selected 70 consecutive Caucasian patients with newly diagnosed chronic AT (Table 1Go). The patients were referred to us by general practitioners or other hospitals because of the presence of circulating thyroid autoantibodies or hypothyroidism, or clinical suspicion of a thyroid disorder. The diagnosis of AT (31, 32) was established from the clinical presentation (presence of a firm goiter, varying in size from small to very large, with a lobulated surface), thyroid hormones and thyroid autoantibody measurements, and/or thyroid ultrasonography (decreased, dyshomogeneous echogenicity). The majority of these patients had a normal thyroid volume, some showed goiter (13%) or atrophic thyroiditis (8%). A minority of patients (4%) were submitted to fine-needle aspiration to exclude the presence of thyroid cancer or lymphoma; in these cases, cytology confirmed the presence of a lymphocytic infiltration.


View this table:
[in this window]
[in a new window]
  		Table 1 Thyroid status of control subjects and patients with thyroditis or multinodular goiter. Values are means±S.D. for normally distributed variables.
 
Controls

Two age- and sex-matched controls groups were used. The first control group (control I, n = 37) consisted of 37 subjects, extracted from a random sample of the general population from the same geographic area (33) in whom a complete thyroid work-up (history, physical examination, thyroid-stimulating hormone (TSH), FT3, FT4, anti-thyroglobulin (AbTg) and anti-thyroid peroxidase (AbTPO) antibody measurements, and ultrasonography) was available, and excluded the presence of thyroid disorders. A second control group comprised 20 patients with non-toxic multinodular goiter extracted from the same random sample of the general population. The majority of these patients had a normal thyroid volume, some showed goiter (30%). All these patients were submitted to fine-needle aspiration to exclude the presence of thyroid cancer; cytology confirmed the absence of a malignancy. In all patients and controls, a blood sample was collected in the morning, after overnight fasting, and serum was kept frozen until thyroid hormone, thyroid autoantibody, CXCL10 and CCL2 measurement.

All study subjects gave their informed consent to the study, which was approved by the local Ethical Committee.

Ultrasonography of the neck and fine-needle aspiration (FNA)

Neck ultrasonography was performed by the same operator, who was unaware of the results of thyroid hormone, autoantibody, CXCL10 and CCL2 measurements, using a probe (Esaote, Florence, Italy; AU5 with a sectorial 7.5 MHz transducer). Thyroid volume was calculated using the ellipsoid formula, as described (31, 34). The presence of hypoechoic and dyshomogeneous echogenicity was arbitrarily rated at three levels (0 = normal echogenicity; 1 = slight hypoechoic and dyshomogeneous; 2 = severely hypoechoic and dyshomogeneous) in order to evaluate structural abnormalities of thyroid tissue associated with thyroid autoimmunity (32, 34). The presence of thyroid nodules was recorded, and nodules with a diameter > 10 mm were submitted to ultrasonography-guided FNA, which was performed by the same operator, using a free-hand method as already described (33, 34).

Thyroid blood flow

Thyroid blood flow (TBF) by color-flow doppler (CFD) was studied in all patients (35). The CFD pattern was defined as normal (or type 0): TBF limited to peripheral thyroid arteries; type I: TBF mildly increased; type II: TBF clearly increased; type III: TBF markedly increased (35). In AT patients TBF bore no relation to the thyroid status, and was type 0 in 63%, type I in 31%, type II in 6% of patients, while none had type III CFD pattern.

Laboratory evaluation

Thyroid function and thyroid autoantibodies were measured as previously described (31). Circulating FT3 and FT4 were measured by commercial RIA kits (AMERLEX-MAB FT3/FT4 Kit; Amersham Biosciences, Little Chalfont, UK). Serum TSH (DiaSorin, Saluggia, Italy), AbTPO and AbTg (ICN Pharmaceuticals, Costa Mesa, CA, USA) were evaluated by IRMA methods. For AbTg and AbTPO, positivity was set at > 50, and > 10 UI/ml, respectively.

Chemokines 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 interassay coefficients of variation were 3.0% and 6.9% respectively. Serum CCL2 levels were also assayed by a quantitative sandwich immunoassay using a commercially available kit (R&D Systems), with a sensitivity of less than 5.0 pg/ml. The intra- and interassay coefficients of variation were 4.7% and 5.8% respectively.

Data analysis

Values are given as means±S.D. for normally distributed variables. Mean group values were compared by using one-way analysis of variance (ANOVA) for normally distributed variables, otherwise by the Mann–Whitney U test. Proportions were compared by the {chi}2 test. Post-hoc comparisons on normally distributed variables were carried out using the Bonferroni–Dunn test. Univariate analysis was performed by simple regression and multivariate analysis was performed by multiple linear regression analysis using CXCL10 or CCL2 as dependent variables and age, thyroid volume, TSH, FT4, AbTPO, hypoechoic pattern, and the presence of hypervascularity as covariates.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
The demographic and clinical features of patients and controls are reported in Table 1Go.

As expected, patients with AT showed significantly higher serum TSH and thyroid autoantibody levels, as well as hypoechogenicity and hypervascularity of the thyroid gland in comparison to both control groups. Interestingly, mean CXCL10 serum level was significantly higher in patients with thyroiditis than in controls or multinodular goiter patients, while serum CCL2 levels were found comparable between groups (Table 1Go). The assignement of AT patients to two groups on the basis of their normal or impaired thyroid function demonstrated significantly older age, lower FT4 and higher CXCL10 and CCL2 in AT patients with hypothyroidism (Table 2Go).


View this table:
[in this window]
[in a new window]
  		Table 2 Clinical and biochemical features of patients with chronic autoimmune thyroiditis with or without hypothyroidism. Values are means±S.D. for normally distributed variables.
 
In order to better define the role of increased serum chemokines in AT, CXCL10 and CCL2 were studied separately in relation to clinical features of AT patients. As shown in Table 3Go, serum CXCL10 levels were significantly increased in hypothyroid patients and in those with an hypoechoic pattern (P = 0.0004 and P = 0.0001, respectively). Nearly significant differences (P = 0.06) were observed in relation to AbTPO positivity and age.


View this table:
[in this window]
[in a new window]
  		Table 3 CXCL10 levels in relating to clinical features of chronic autoimmune thyroiditis subjects. Values are means±S.D.
 
By contrast, serum CCL2 levels (Table 4Go) were significantly increased in patients older than 50 years and to a lesser degree of significance in those with hypothyroidism (P = 0.0001 and P = 0.03, respectively). Finally, no correlation between CXCL10 and CCL2 serum levels could be demonstrated.


View this table:
[in this window]
[in a new window]
  		Table 4 CCL2 levels in relation to clinical features of chronic autoimmune thyroiditis subjects. Values are means±S.D.
 
In a multiple linear regression model including age, thyroid volume, TSH, FT4, Ab TPO, hypoechoic pattern, and the presence of hypervascularity, only TSH was significantly related to ln of serum CXCL10 levels [R.C. 0.143 C.I. (0.042–0.245); P = 0.0059] (Fig. 1Go). A similar regression model performed with CCL2 as dependent variable showed that only age was significantly related to the circulating chemokine level [R.C. 5.412 C.I. (3.838–6.986); P < 0.0001] (Fig. 2Go).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1 In a multiple regression model including age, thyroid volume, TSH, FT4, AbTPO, hypoechoic pattern and hypervascularity, only TSH was significantly related to serum CXCL10 levels.

 


View larger version (20K):
[in this window]
[in a new window]
  		Figure 2 In a multiple regression model including age, thyroid volume, TSH, FT4, AbTPO, hypoechoic pattern and hypervascularity, only age was significantly related to serum CCL2 levels.

 
By defining a high CXCL10 level as a value at least 2 S.D. above the mean value of the control group, 26% of patients with AT, 5% of multinodular goiter patients and none of the control subjects had high CXCL10 (P < 0.0001). Instead, high CCL2 levels defined as above characterized 1% of patients with AT, none of the multinodular goiter patients and 3% of controls.


   Discussion
Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The AT patients in the present study were typical with respect to clinical phenotype and pattern of autoimmune markers, furthermore all patients were newly diagnosed with AT. Thyroid volume was significantly larger in patients with multinodular goiter and comparable between AT patients and controls. Circulating CXCL10 levels were clearly elevated in AT patients as compared with normal controls or patients with multinodular goiter, while comparable serum CCL2 were found between groups. In patients with AT, multivariate analysis shows that serum CXCL10 levels were associated with TSH independently from other possible confounders, while serum CCL2 were significantly associated only with age.

Within the AT group, higher CXCL10 levels were associated with a hypoechoic gland, and hypothyroidism, while in hypothyroid patients with AT, CXCL10 levels were more strongly associated with the hypothyroidism itself than with thyroid autoantibody levels or thyroid volume. Furthermore, the significantly higher CXCL10 levels in patients with an hypoechoic thyroid gland at ultrasound, a reliable sign of lymphocytic infiltration, is in line with previous reports showing that CXCL10 plays a role in massive inflammatory infiltrates in the liver (36). Such results suggest that raised CXCL10 is not only associated with the autoimmune process itself, but may be a marker of an aggressive thyroditic process. The role of CXCL10 in autoimmune process-dependent thyroid destruction, can be reasonably assumed in view of its chemoattractant activity for Th1 lymphocytes secreting IFN-{gamma} whose intraglandular production results in thyrocyte apoptosis (37) and severe hypothyroidism (38). CXCL10-induced recruitment of Th1 lymphocytes, which secrete interferon-{gamma}, in turn stimulates chemokine production by follicular cells, thus maintaining the autoimmune process (6, 27).

Previous studies evaluating intraglandular mRNA expression of CC chemokines reported comparable CCL2 levels between patients with AT and multinodular goiter, in agreement with our results (6, 25). However, comparisons between data obtained by tissutal quantification of chemokine expression and assessment of circulating levels must be always careful.

A previous paper has reported increased serum CCL2 levels in AT with respect to normal controls or patients with cold nodules, with a weak but significant association between circulating chemokine level and AbTg and AbTPO in AT patients (26). In our experience, neither finding could be confirmed.

Several factors may help to explain such discrepancy. Mainly the fact that in the previous reports (26), AT patients were significantly older than controls and several reports have demonstrated that serum CCL2 levels increase with age even in normal subjects (39, 40). Differences may also reflect the fact that some patients in the study by Kokkotou et al. (26) were under L-T4 therapy that potentially may affect chemokine secretion; owing to the levothyroxine substitutive treatment, any comparison between euthyroid and hypothyroid AT patients could not be performed. In our serie, despite comparable CCL2 levels between HT patients and controls, significantly higher CCL2 levels were observed in hypothyroid with respect to euthyroid HT patients. However, multivariate regression analysis clearly showed that such relation was mainly due to older age of such patients, identifying age as the only factor among those taken into account being closely linked to CCL2. Furthermore, while CXCL10 was higher in patients with hypothyroidism and those with an hypoechogenic pattern, CCL2 showed no variation with respect to thyroid gland echogenicity, thus supporting the concept of a minor role played by CCL2. In addition, all of our patients were newly diagnosed AT, while in the Kokkotu et al. study, no information was given with regards to onset of disease, such a variable seems crucial as different time points in the disease process and is surely an important factor in determinining serum concentration of markers of autoimmunity (28–30).

Besides their chemotactic activity, chemokines modulate the immune responses through the recruitment of specific T helper subsets and cytokine production. Several experimental evidences have demonstrated that in vivo, cytokines act in distinct combinations that determine the final effect on the target cells. 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 (25). Therefore the simultaneous assessment of different chemokines may be potentially of great interest.

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 disease. In details, CXCL10 was higher in acute MS and lower in stable disease while the contrary characterized CCL2 secretion profile, demonstrating a pathogenetic role for both chemokines with reciprocal changes according to the clinical phase of MS (28–30). However, no correlation between serum CXCL10 and CCL2 levels in AT patients was found in our study group. Increased CXCL10 and normal CCL2 levels in AT are consistent with the recently proposed immunoregulatory characteristics of AT. In fact, CXCL10 is clearly a Th1 oriented chemokine while CCL2 is regulated by IL-4, the cardinal Th2 cytokine, and influences T cells toward Th2 commitment. It has been proposed that an environment strongly enriched in Th1 (CXCL10) accompanied by inadequate Th2 response (CCL2) would lead to very severe non-remitting disease, as previously suggested by reports demonstrating the association of increased serum CXCL10 levels with more severe course and aggressiveness of Th1 mediated autoimmune reactions (12).

Experiments performed in vitro have demonstrated a differential role for RANTES (known to favour the attraction of Th1 cells) and CCL2 (preferentially active on Th2 cells) in murine experimental AT, with distinct secretion profiles for the two chemokines during the onset, the course, and the remission of disease. This demonstrates that CCL2 attracts specific immune regulatory cells that down-regulate the autoimmune reaction as shown by a decrease in murine thyreoglobulin proliferative response and in a lesser degree of thyroid infiltration (41).

The study design (only patients with newly diagnosed AT) does not permit to draw conclusion regarding the pathogenetic role of CCL2 in long standing AT, as it is possible that circulating chemokine levels at other stages of disease may be substantially different as a result of the shift in the Th1/Th2 balance during later stages of disease, acting as a feed-back mechanism widely described with disease progression in several human autoimmune conditions.

In conclusion, our results, obtained in a large cohort of newly diagnosed AT patients showed increased CXCL10 which was more evident in hypothyroid patients with a more aggressive disorder and normal CCL2 serum levels in AT. Prospective clinical trials performed in large patient cohorts will be required to evaluate the differential impact of autoimmunity and hypothyroidism ‘per se’, on CXCL10 serum levels, and the utility for the clinical management in AT patients.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A Antonelli and M Rotondi have contributed equally to this work


   References
Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

    1. Zlotnik A & Yoshle O. Chemokines: a new classification system and their role in immunity. Immunity 2000 12 121–127.[CrossRef][ISI][Medline]

    2. Arenberg DA, Polverini PJ, Kunkel SL, Shanafelt A, Hesselgesser J, Horuk R & Strieter RM. The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer. Journal of Leukocyte Biology 1997 62 554–562.[Abstract]

    3. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E & Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001 410 50–56.[CrossRef][Medline]

    4. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998 39 565–568.

    5. Luster AD. Chemokines – chemotactic cytokines that mediate inflammation. The New England Journal of Medicine 2001 338 436–445.

    6. Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF & Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clinical Endocrinology 2003 59 207–213.[CrossRef][Medline]

    7. Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North R, Gerard C & Rollins BJ. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. Journal of Experimental Medicine 1998 187 601–608.[Abstract/Free Full Text]

    8. Maghazachi AA, Al-Aoukaty A & Schall TJ. C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells. Role for G proteins. Journal of Immunology 1994 153 4969–4977.[Abstract]

    9. Maghazachi AA, Al-Aoukaty A & Schall TJ. CC chemokines induce the generation of killer cells from CD56+ cells. European Journal of Immunology 1996 26 315–319.[ISI][Medline]

    10. Taub DD, Sayers TJ, Carter CR & Ortaldo JR. Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. Journal of Immunology 1995 155 3877–3888.[Abstract]

    11. Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD & Barrett TA. Differential CC chemokine-induced enhancement of T helper cell cytokine production. Journal of Immunology 1997 158 4129–4136.[Abstract]

    12. Rotondi M, Rosati A, Buonamano A, Lasagni L, Lazzeri E, Pradella F, Fossombroni V, La Villa G, Serio M, Bretoni E, Salvatori M & Romagnani P. High pretransplant serum levels of CXCL10/IP-10 are related to increased risk of allograft failure. American Journal of Transplantation 2004 4 1466–1474.

    13. Weetman AP & McGregor AM. Autoimmune thyroid disease: further developments in our understanding. Endocrine Reviews 1994 15 788–830.[Abstract]

    14. Paschke R, Schuppert F, Taton M & Velu T. Intrathyroidal cytokine expression profiles in autoimmune thyroiditis. Journal of Immunology 1994 141 309–315.

    15. Watson PF, Pickerill AP, Davies R & Weetman AP. Analysis of cytokine gene expression in Graves’ disease and multinodular goitre. Journal of Clinical Endocrinology and Metabolism 1994 79 355–360.[Abstract]

    16. Ajjan RA, Watson PF, McIntosh RS & Weetman AP. Intra-thyroidal cytokine gene expression in Hashimoto’s thyroiditis. Clinical and Experimental Immunology 1996 105 523–528.[CrossRef][ISI][Medline]

    17. Roura-Mir C, Catalfamo M, Sospedra M, Alcalde L, Pujol-Borrell R & Jaraquemada D. Single cell analysis of intra-thyroidal lymphocytes shows differential cytokine expression in Hashimoto’s and Graves’ disease. European Journal of Immunology 1997 27 3290–3302.[ISI][Medline]

    18. Grubeck-Lobenstein B, Buchan G, Chantry D, Kassal H, Londei K, Pirich K, Barrett K, Turner M, Waldhausl W & Feldmann M. Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: thyroid follicular cells produce interleukin-1{alpha} and interleukin-6. Clinical and Experimental Immunology 1989 77 324–330.[ISI][Medline]

    19. Zheng RQH, Abney E, Chu CQ, Field M, Grubeck-Lobenstein B, Maini RN & Feldmann M. Detection of interleukin-6 and interleukin-1 production in human thyroid epithelial cells by non-radioactive in situ hybridization and immunohistochemical methods. Clinical and Experimental Immunology 1991 83 314–319.[ISI][Medline]

    20. Kayser L, Broholm H, Francis D, Perrild H, Engelbrecht-Olsen B, Bendtzen K & Hoyer PE. Immunocytochemical localisation of interleukin-1{alpha} and interleukin-6 in thyroid tissues from patients with neoplastic or autoimmune thyroid disorders. Autoimmunity 1995 20 75–82.[ISI][Medline]

    21. Watson PF, Pickerill AP, Davies R & Weetman AP. Semi-quantitative analysis of interleukin-1{alpha}, interleukin-6 and interleukin-8 mRNA expression by human thyrocytes. Journal of Molecular Endocrinology 1995 15 11–21.[Abstract]

    22. Garcià-Lòpez MA, Sancho D, Sànchez-Madrid F & Marazuela M. Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3 + lymphocytes. Journal of Clinical Endocrinology and Metabolism 2001 86 5008–5016.[Abstract/Free Full Text]

    23. Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, Buonamano A, Milani S, Vitti P, Chiovato L, Tonacchera M & Bellastella A. Serio M Expression of IP-10/CXCL10 and Mig/CXCL9 in the thyroid and increased serum levels of IP-10/CXCL10 in the serum of subjects with recent onset Graves’ disease. American Journal of Pathology 2002 161 195–206.[Abstract/Free Full Text]

    24. Kasai K, Banba N, Motohashi S, Hattori Y, Manaka K & Shimoda S. Expression of monocyte chemoattractant protein-1 in cultured human thyrocytes. FEBS Letters 1996 394 137–140.[CrossRef][ISI][Medline]

    25. 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. Journal of Clinical Endocrinology and Metabolism 1999 84 2873–2882.[Abstract/Free Full Text]

    26. Kokkotou E, Marafelia P, Mantzos EI & Tritos NA. Serum monocyte chemoattractant protein-1 is increased in chronic autoimmune thyroiditis. Metabolism 2002 51 1489–1493.[CrossRef][ISI][Medline]

    27. Rotondi M, Lazzeri E, Romagnani P & Serio M. Role for interferon-{gamma} inducile chemokines in endocrine autoimmunity: an expanding field. Journal of Endocrinological Investigation 2003 26 177–180.[ISI][Medline]

    28. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL & Ransohoff RM. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. Journal of Clinical Investigation 1999 103 807–815.[ISI][Medline]

    29. Sorensen TL, Sellebjerg F, Jensen CV, Strieter RM & Ransohoff RM. Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis. European Journal of Neurology 2001 8 665–672.[CrossRef][ISI][Medline]

    30. Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L & Cosi V. Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies. Journal of Neuroimmunology 2001 115 192–198.[CrossRef][ISI][Medline]

    31. Antonelli A, Fallahi P, Nesti C, Pupilli C, Marchetti P, Takasawa S, Okamoto H & Ferrannini E. Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves’ disease. Clinical and Experimental Immunology 2001 126 426–431.[CrossRef][ISI][Medline]

    32. Antonelli A, Saracino A, Alberti B, Canapicchi R, Cartei F, Lepri A, Laddaga M & Baschieri L. High-dose intravenous immunoglobulin treatment in Graves’ Ophthalmopathy. Acta Endocrinologica 1992 126 13–23.[Medline]

    33. Antonelli A, Ferri C & Fallahi P. Thyroid cancer in patients with hepatitis C infection. JAMA 1999 281 1588.[Free Full Text]

    34. Antonelli A, Miccoli P, Fallahi P, Grosso M, Nesti C, Spinelli C & Ferrannini E. Role of neck ultrasonography in the follow-up of children operated on for thyroid papillary cancer. Thyroid 2003 13 479–484.[CrossRef][ISI][Medline]

    35. Vitti P, Rago T, Mazzeo S, Brogioni S, Lampis M, De Liperi A, Bartolozzi C, Pinchera A & Martino E. Thyroid blood flow evaluation by color-flow Doppler sonography distinguishes Graves’ disease from Hashimoto’s thyroiditis. Journal of Endocrinological Invesigation 1995 18 857–861.

    36. Lalor PF, Shields P, Grant A & Adams DH. Recruitment of lymphocytes to the human liver. Immunology and Cell Biology 2002 80 52–64.[CrossRef][Medline]

    37. Wang SH, Bretz JD, Phelps E, Mezosi E, Arscott PL, Utsugi S & Baker JR Jr. A unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transformnon-destructive to destructive thyroiditis in experimental autoimmune thyroiditis. Journal of Immunology 2002 168 2470–2474.[Abstract/Free Full Text]

    38. Caturegli P, Hejazi M, Suzuki K, Dohan O, Carrasco N, Kohn LD & Rose NR. Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid. PNAS 2000 97 1719–1724.[Abstract/Free Full Text]

    39. Inadera H, Egashira K, Takemoto M, Ouchi Y & Matsushima K. Increase in circulating levels of monocyte chemoattractant protein-1 with aging. Journal of Interferon and Cytokine Research 1999 19 1179–1182.[CrossRef][ISI][Medline]

    40. Pulsatelli L, Meliconi R, Mazzetti I, Dolzani P, Meneghetti A, Neri S, Silvestri T, Ravaglia G, Forti P, Facchini A & Mariani E. Chemokine production by peripheral blood mononuclear cells in elderly subjects. Mechanisms of Ageing and Development 2000 121 89–100.[CrossRef][ISI][Medline]

    41. Goulvestre C, Batteux F & Charreire J. Chemokines modulate experimental autoimmune thyroiditis through attraction of auto-reactive or regulatory T cells. European Journal of Immunology 2002 32 3435–3442.[ISI][Medline]

Received 11 August 2004
Accepted 9 November 2004




This article has been cited by other articles:


Home page
 EndocrinologyHome page
E. Borgogni, E. Sarchielli, M. Sottili, V. Santarlasci, L. Cosmi, S. Gelmini, A. Lombardi, G. Cantini, G. Perigli, M. Luconi, et al.
Elocalcitol Inhibits Inflammatory Responses in Human Thyroid Cells and T Cells
Endocrinology, July 1, 2008; 149(7): 3626 - 3634.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
A. Antonelli, C. Ferri, P. Fallahi, S. M. Ferrari, D. Giuggioli, M. Colaci, A. Manfredi, S. Frascerra, F. Franzoni, F. Galetta, et al.
CXCL10 ({alpha}) and CCL2 ( ) chemokines in systemic sclerosis a longitudinal study
Rheumatology, January 1, 2008; 47(1): 45 - 49.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
C Crescioli, L Cosmi, E Borgogni, V Santarlasci, S Gelmini, M Sottili, E Sarchielli, B Mazzinghi, M Francalanci, A Pezzatini, et al.
Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes
J. Endocrinol., October 1, 2007; 195(1): 145 - 155.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
M. Rotondi, L. Chiovato, S. Romagnani, M. Serio, and P. Romagnani
Role of Chemokines in Endocrine Autoimmune Diseases
Endocr. Rev., August 1, 2007; 28(5): 492 - 520.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
A. Antonelli, C. Ferri, P. Fallahi, M. Cazzato, S. M. Ferrari, M. Sebastiani, and E. Ferrannini
Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis
Eur. J. Endocrinol., April 1, 2007; 156(4): 431 - 437.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Antonelli, M. Rotondi, P. Fallahi, M. Grosso, G. Boni, S. M. Ferrari, P. Romagnani, M. Serio, G. Mariani, and E. Ferrannini
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., April 1, 2007; 92(4): 1485 - 1490.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. Antonelli, P. Fazzi, P. Fallahi, S. M. Ferrari, and E. Ferrannini
Prevalence of hypothyroidism and graves disease in sarcoidosis.
Chest, August 1, 2006; 130(2): 526 - 532.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
A. Antonelli, P. Fallahi, M. Rotondi, S. M. Ferrari, P. Romagnani, M. Grosso, E. Ferrannini, and M. Serio
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., May 1, 2006; 154(5): 651 - 658.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Antonelli, M. Rotondi, S. M. Ferrari, P. Fallahi, P. Romagnani, S. S. Franceschini, M. Serio, and E. Ferrannini
Interferon-{gamma}-Inducible {alpha}-Chemokine CXCL10 Involvement in Graves' Ophthalmopathy: Modulation by Peroxisome Proliferator-Activated Receptor-{gamma} Agonists
J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 614 - 620.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Antonelli, A.
Right arrow Articles by Serio, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Antonelli, A.
Right arrow Articles by Serio, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS