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(Investigative Ophthalmology and Visual Science. 2006;47:1063-1068.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0966
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Elevated Serum Levels of CXCL9/Monokine Induced by Interferon-{gamma} and CXCL10/Interferon-{gamma}-Inducible Protein-10 in Ocular Sarcoidosis

Masaru Takeuchi, Keiko Oh-i, Jun Suzuki, Takaaki Hattori, Aya Takeuchi, Yoko Okunuki, Yoshihiko Usui, and Masahiko Usui

From the Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. Sarcoidosis is a chronic multisystem granulomatous disorder characterized by an accumulation of activated CD4+ T cells and monocytes/macrophages in involved organs. Chemokines are required for the extravasation of leukocytes to the inflammation site. This study was undertaken to determine which chemokines are augmented in the serum of patients with active ocular sarcoidosis.

METHODS. Seventeen patients with diagnosed ocular sarcoidosis, 28 with suspected ocular sarcoidosis, 16 with Behçet’s disease, 17 with Vogt-Koyanagi-Harada disease, and 18 healthy subjects were studied. Serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were simultaneously measured by cytometric bead array using flow cytometer. In addition, serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis were compared with respect to ocular disease activity, the presence of bilateral hilar lymphadenopathy (BHL), and laboratory data.

RESULTS. Serum levels of both CXCL9 and CXCL10 were markedly elevated in the patients with diagnosed or suspected ocular sarcoidosis compared with patients with other types of uveitis and healthy subjects. Although CCL2 and CXCL8 were detected in the serum of all subjects, the levels were extremely low with no significant differences between groups. Elevation of serum CXCL9 and CXCL10 in ocular sarcoidosis correlated significantly with ocular disease activity and ACE (angiotensin converting enzyme) levels and was unrelated to the presence of BHL, erythrocyte sedimentation rate, white blood cell count, serum IgG, or serum lysozyme.

CONCLUSIONS. The results demonstrated that serum levels of CXCL9 and CXCL10 were elevated markedly in the patients with ocular sarcoidosis and correlated with ocular disease activity and ACE level.

Sarcoidosis is a chronic, multisystem, granulomatous disorder thought to result from an exaggerated cellular immune response to a variety of self antigens or non–self antigens.1 The etiology of sarcoidosis is unknown, perhaps in part because of the diverse manifestations of the disease and the absence of approved diagnostic criteria.

Ocular disease may be the initial manifestation of sarcoidosis and may progress to severe visual impairment or even blindness. No specific extraocular manifestations of sarcoidosis have been associated with the development of ocular involvement or uveitis.2 3

Chemokines are a family of cytokines involved in the extravasation of leukocytes to the site of inflammation.4 CCL2/monocyte chemoattractant protein-1 (MCP-1), which is chemotactic for monocytes,5 and CXCL8/IL-8, which chemoattracts neutrophils,6 have been reported to be elevated in the bronchoalveolar lavage fluid (BALF) or serum of patients with active pulmonary sarcoidosis.7 8 9 10 CCL3/macrophage inflammatory protein-1{alpha} (MIP-1{alpha}), CCL4/MIP-1ß, and CCL5/regulated on activation normal T-cell expressed and secreted (RANTES) also have been shown to be elevated in the BALF of patients with pulmonary sarcoidosis.11 12 13 As a result of the findings that CCL3 and CCL5 share the same CC chemokine receptor (CCR5) that is expressed abundantly on Th1-type cells and that CCR5 mRNA expression is upregulated in BALF of patients with pulmonary sarcoidosis, these chemokines have been suggested to be involved in the recruitment of Th1 cells14 from the circulation to the granulomas in pulmonary sarcoidosis.15 The CXCL9/monokine induced by IFN-{gamma} (MIG) and CXCL10/IFN-{gamma}-induced protein 10 (IP-10) are similar in structure and biological function16 17 and are involved in the selective recruitment of lymphocytes. The receptor of CXCL9 and CXCL10, CXC receptor 3 (CXCR3), is predominantly expressed on memory or activated T cells, especially Th1 cells.18 19 CXCL9 and CXCL10 have been reported to play an important role in the pathogenesis of inflammatory and autoimmune diseases by inducing the recruitment of activated Th1 cells.19 20 An increased number of CD4+ T cells expressing CCR5 and CXCR3 has been demonstrated in the BALF of patients with pulmonary sarcoidosis, and a positive correlation between the number of T cells expressing Th1 cytokines and CXCR3 or CXCL10 levels has been reported in the BALF of these patients.21 22

In this study, we sought to determine whether serum levels of chemokines including CCL5, CXCL9, and CXCL10 involved in the recruitment of Th1 cells are augmented in patients with active ocular sarcoidosis by comparing them with levels in healthy subjects or patients with other types of uveitis.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Study Population
The characteristics of the study population are summarized in Table 1 .


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  		TABLE 1. The Characteristics of the Study Population

 
The study group comprised 17 patients with diagnosed ocular sarcoidosis, 28 with suspected ocular sarcoidosis, 16 with Behçet’s disease, 17 with Vogt-Koyanagi-Harada (VKH) disease, and 18 healthy subjects. Ocular sarcoidosis was diagnosed by the criteria for systemic sarcoidosis established by the Japanese Committee for Diffuse Lung Diseases.23 The criteria require histologic or clinical diagnosis in addition to typical ocular manifestations of sarcoidosis, including a combination of granulomatous iritis with mutton-fat keratic precipitates or iris nodules, trabecular nodules, tent-like peripheral anterior synechiae, snowball or string-of-pearls vitreous opacities, retinal perivasculitis, and spotty retinochoroidal exudates. Histopathological findings are usually examined by conjunctival or transbronchial lung biopsy (TBLB). The clinical findings consist of five systemic tests: (1) tuberculin skin test, (2) serum IgG level, (3) serum angiotensin converting enzyme (ACE) level, (4) serum lysozyme level, and (5) 67Ga scintigraphy. Three positive findings including either (1) or (3) fulfill the clinical diagnosis. Patients with suspected ocular sarcoidosis had ocular manifestations typical of sarcoidosis, but did not fulfill the criteria.

Although all patients had ongoing ocular inflammation and were undergoing topical corticosteroid treatment, 3 of 17 patients with ocular sarcoidosis, 1 of 28 with suspected ocular sarcoidosis, 3 of 16 with Behçet’s disease, and 7 of 17 with VKH disease were treated with systemic corticosteroids. Immunosuppressive drugs, such as cyclosporine and methotrexate, were not used in any patient enrolled in the study, and patients with any systemic complication requiring medical treatment were excluded.

The protocol for this study adhered to the tenets of the Declaration of Helsinki, and the manuscript was approved by the Internal Review Board of Tokyo Medical University. Written informed consent was obtained from all participating patients and control subjects.

Cytokine Assay
One milliliter of peripheral blood was sampled, and serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were quantified with the cytometric bead array (CBA) kits and CBA software supplied by BD Pharmingen (San Diego, CA). These assay kits contained a mixture of five types of microbeads with distinct fluorescent intensities (FL-3) and were precoated with capture antibodies specific for each cytokine. Fifty microliters of serum or cytokine standard was added to the premixed microbeads in 12 x 75 mm Falcon tubes (BD Biosciences, Carlsbad, CA). After the addition of 50 µL of a mixture of phycoerythrin (PE)-conjugated antibodies against the cytokines, the mixture was incubated for 3 hours in the dark at room temperature (the method varied slightly for the CBA kit for inflammation). This mixture was washed and centrifuged at 500g for 5 minutes and the pellet resuspended in 300 µL of wash buffer. A flow cytometer (FACSCalibur; BD Pharmingen) was calibrated with setup beads, and 3000 events were acquired for each sample. Individual cytokine concentrations were determined by measuring individual fluorescence intensities (Fl-2) and computing with the standard reference curve of the software (Cellquest and CBA software; BD Pharmingen).

Statistical Analysis
Data were analyzed on computer (JMP ver. 5; Business Unit of SAS, Cary, NC). Group comparisons were made with the nonparametric Mann-Whitney test, and individual data were compared with normal reference ranges using Student’s t-test for independent samples at a 95% confidence level. Pearson’s rank correlation and ANOVA were used for data comparison. Correlation of continuous variables was analyzed by the Spearman correlation coefficient.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Serum CCL2, CXCL8, CXCL9, and CXCL10 Levels
Serum CCL2, CCL5, CXCL8, CXCL9, and CXCL10 levels in the patients with ocular sarcoidosis, suspected ocular sarcoidosis, Behçet’s disease, or VKH disease were compared with those in healthy subjects. Figure 1 displays the mean serum levels of CCL2, CXCL8, CXCL9, and CXCL10 in the five groups.


Figure 1
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  		FIGURE 1. Serum CCL2, CXCL8, CXCL9, and CXCL10 levels in the patients with ocular sarcoidosis. Serum samples were obtained from healthy subjects (group A, n = 18) and from patients with diagnosed ocular sarcoidosis (group B, n = 17), suspected ocular sarcoidosis (group C, n = 28), with Behçet’s disease (group D, n = 16), or VKH disease (group E, n = 17). CCL2, CXCL8, CXCL9, and CXCL10 concentrations were measured with CBA kits. *Statistically significant difference (P < 0.05) when compared with group A.

 
CCL5 was undetectable in all the serum samples examined by the CBA method. Serum CXCL9 levels were highest in the patients with ocular sarcoidosis, then in those with suspected ocular sarcoidosis, and then in those with Behçet’s (mean ± SD: 2461 ± 1489, 1357 ± 1538, and 1143 ± 1627 pg/mL, respectively), but a significant difference was observed only between the patients with ocular sarcoidosis and healthy subjects (568.2 ± 586.1 pg/mL). Serum CXCL10 levels were also significantly higher (P < 0.05) in the patients with ocular sarcoidosis, suspected ocular sarcoidosis, or Behçet’s disease (1708 ± 769, 1162 ± 702, and 954 ± 534 pg/mL, respectively) compared with healthy subjects (328.1 ± 273 pg/mL). In addition, the mean serum CXCL10 level in the patients with ocular sarcoidosis was significantly higher than in those with Behçet’s disease (P < 0.05). Although CCL2 and CXCL8 were detected in serum samples of all subjects, the levels were extremely low, and statistically significant differences were not observed between groups or when compared with healthy subjects.

Relationship between Serum CXCL9 or CXCL10 Levels and BHL on Chest Radiographs
Although the presence of BHL on chest radiograph is not necessary for a diagnosis of ocular sarcoidosis according to the criteria used in this study, it is possible that the increases in serum CXCL9 and CXCL10 levels in ocular sarcoidosis observed in this study may depend on the involvement of pulmonary disease. Therefore, we compared the serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis who manifested BHL (n = 20) and in those without BHL (n = 25). The results are shown in Figure 2 .


Figure 2
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  		FIGURE 2. Serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis with or without bilateral hilar lymphadenopathy (BHL). Each dot indicates serum CXCL9 (A) or CXCL10 (B) of a patient with diagnosed or suspected ocular sarcoidosis. The data were compared between those with or without BHL. Horizontal lines: mean of each group.

 
The mean serum CXCL9 was slightly higher in the patients with ocular sarcoidosis with BHL than in those without BHL; however, no significant difference was observed. The mean serum CXCL10 in the patients with ocular sarcoidosis with BHL was almost the same as that in the patients without BHL, with no significant difference.

Serum CXCL9 and CXCL10 Levels in Active and Remission Periods of Patients with Ocular Sarcoidosis
Because the increases in serum CXCL9 and CXCL10 levels in the patients with ocular sarcoidosis were unrelated to the presence of BHL, we subsequently examined the relationship of serum CXCL9 and CXCL10 levels with activity of ocular sarcoidosis. Serum levels of CXCL9 and CXCL10 were measured in serial blood samples collected at the active and remission phases of ocular disorders in 14 patients with ocular sarcoidosis. The results are shown in Table 2 . The mean period from active phase sampling to remission phase sampling was 1136 days. As expected, serum levels of both CXCL9 and CXCL10 were significantly higher in the active phase of ocular disorder than in remission, indicating that CXCL9 and CXCL10 increases are related to ocular disease activity.


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  		TABLE 2. The Relationship of Serum CXCL9 and CXCL10 Levels with Activity of Ocular Sarcoidosis

 
Relationship between Serum CXCL9 or CXCL10 Level and Other Markers of Disease Activity
We also examined the relationship of serum CXCL9 and CXCL10 levels with other markers of disease activity: erythrocyte sedimentation rate (ESR); white blood cell (WBC) counts; and serum levels of IgG, angiotensin-converting enzyme (ACE), and lysozyme in the patients diagnosed with diagnosed or suspected ocular sarcoidosis (n = 45). The results are presented in Figure 3 .


Figure 3
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  		FIGURE 3. Relationship between serum levels of CXCL9, CXCL10, and markers of disease activity in the patients with diagnosed or suspected ocular sarcoidosis. Relations between serum levels of CXCL9, CXCL10, IgG, ACE, lysozyme, ESR, and WBC in the patients (n = 45) were analyzed by Spearman’s correlation coefficient by rank. *Significant and strong correlation.

 
Both serum CXCL9 and CXCL10 levels correlated significantly with ACE level (rs = 0.62, P = 0.0004; rs = 0.56, P = 0.0014, respectively), and serum CXCL9 also correlated with lysozyme level (rs = 0.82, P = 0.0000). No statistically significant and strong correlation (rs > 0.5, P < 0.05) was observed between serum CXCL9 or CXCL10 and the other markers of disease activity. As expected, statistically significant correlation was noted between serum CXCL9 and CXCL10 levels (rs = 0.70, P = 0.0000). Serum levels of lysozyme also correlated with IgG and ACE levels (rs = 0.64, P = 0.0034; rs = 0.71, P = 0.0006, respectively), but a significant correlation was not noted between the IgG and ACE levels (rs = 0.33, P = 0.08).

Characteristics of the Patients with Suspected Ocular Sarcoidosis with High Serum CXCL9 and CXCL10 Levels
Because some of the patients with suspected ocular sarcoidosis had a higher serum CXCL9 or CXCL10 level than the mean level in those with diagnosed ocular sarcoidosis, we subsequently examined the characteristics of those patients. The summary is displayed in Table 3 .


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  		TABLE 3. Laboratory Data of Patients with Suspected Ocular Sarcoidosis with Serum CXCL9 or CXCL10 Level Higher Than the Mean Level in Patients with Diagnosed Ocular Sarcoidosis

 
Six with suspected ocular sarcoidosis had serum CXCL10 higher than the mean level of the patients with ocular sarcoidosis, and among them two patients also had serum CXCL9 higher than the mean level of the patients with ocular sarcoidosis. All six patients manifested active granular uveitis typical of sarcoidosis (data not shown) and had negative results in a tuberculin skin test. In addition, as can be predicted from the results of correlation analysis in Figure 3 , serum CXCL9 and ACE levels were high in the patients with high serum CXCL10 levels.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study first demonstrated that serum CXCL9 and CXCL10 levels were markedly augmented in the patients with ocular sarcoidosis compared with healthy subjects or patients with other types of uveitis and that the augmented serum levels of CXCL9 and CXCL10 in the patients with ocular sarcoidosis were unrelated to the presence of BHL, but correlate with ocular disease activity and ACE level. These results also suggest a role for CXCL9 and CXCL10 in the mechanisms that account for migration of activated Th1 cells to the eye and the development of ocular sarcoid granuloma.

Recent studies have indicated important roles of CXCL9, CXCL10, and CXCR3 lymphocytes in the pathophysiology of inflammatory and autoimmune diseases20 such as rheumatoid arthritis, ulcerative colitis,24 autoimmune thyroid disorders,25 and multiple sclerosis.26 Increases of CXCL10 protein level and mRNA expression in BAL fluid and biopsy samples have been demonstrated in the patients with pulmonary sarcoidosis compared with healthy subjects.21 27 A positive correlation was also shown between CXCL10 level and the number of sarcoid CD45R0+/CD4+ cells in BAL. However, serum CXCL9 and CXCL10 levels in sarcoidosis have never been studied. This is the first report that demonstrates increased serum CXCL9 and CXCL10 levels in sarcoidosis.

In this study, the elevation of serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis was unrelated to the presence of BHL on chest radiographs. Considering the risk of traumatic stress to the subjects without pulmonary symptoms, we did not further examine whether pulmonary sarcoidosis lesions were present in these patients with BHL. It is possible that some of them would have pulmonary lesions and some would not. Therefore, we assume that serum CXCL9 and CXCL10 levels would be increased in the patients with at least concurrent active ocular lesions, unrelated to the pulmonary lesion without any symptoms.

Although all patients with ocular sarcoidosis were treated with topical steroids, three patients were also treated with systemic steroids at the time of blood sampling. Despite the systemic treatment, their serum CXCL9 levels were 1529, 1701, and 3884 pg/mL, and CXCL10 levels were 2227, 3151, and 1698 pg/mL, respectively, and those mean levels (CXCL9, 2371 pg/mL; CXCL10, 2356 pg/mL) were within the mean ± SD of all subjects (CXCL9, 2461 ± 1489 pg/mL, and CXCL10, 1708 ± 769 pg/mL). Because patients with sarcoidosis treated with systemic steroids presented more severe ocular inflammation, it is possible that the effect of steroids on serum levels of chemokines may be masked. However, their serum levels were dependent on ocular disease activity. In two patients who had serial samples, the CXCL9 level decreased from 1529 pg/mL in the acute phase to 643.8 pg/mL at remission in one and from 1701 pg/mL to 525 pg/mL in the other, while the CXCL10 level decreased from 2227 to 1112 pg/mL and from 3151 to 1144 pg/mL, respectively (Table 2) .

CXCL9 and CXCL10 are members of the C-X-C subfamily. They induce chemotaxis of stimulated human T lymphocytes and are believed to be more important in the Th1-type immune responses, which are stimulated by IFN-{gamma} and inhibited by IL-4. In this study, serum CXCL10 levels were augmented not only in the patients with diagnosed or suspected ocular sarcoidosis but also in those with Behçet’s disease. Although sarcoidosis is characterized by a persistent accumulation of macrophages and activated Th1-type cells, Behçet’s disease is also known to be a Th1-mediated disease.28 29 However, the findings that (1) serum CXCL10 levels were higher in ocular sarcoidosis than Behçet’s disease; and (2) serum levels of CXCL9 were augmented in ocular sarcoidosis, but not in Behçet’s disease suggest that Th1 cells expressing CXCR3, which is a receptor for CXCL9 and CXCL10, may be more important in sarcoidosis than in Behçet’s disease for the development of ocular lesion.

We also measured serum levels of IFN-{gamma} in these serum samples (data not shown). However, serum levels of IFN-{gamma} were detected in only three patients with ocular sarcoidosis, two with suspected ocular sarcoidosis, two with Behçet’s disease, and four with VKH disease, and were not detectable in other samples (<4 pg/mL). The levels ranged from 4.3 to 31.9 pg/mL, and statistical analysis could not be performed.

In this study, serum CCL5 levels were undetectable, and serum CCL2 and CXCL8 levels were measurable but were low, and no differences were observed between the tested subjects. CCL5 levels have been shown to be elevated in the BALF of patients with pulmonary sarcoidosis,12 but the serum levels have not been reported. CCL2 and CXCL8 have been reported to be elevated in BALF and also in the serum of patients with active pulmonary sarcoidosis.7 8 9 10 These discrepancies occasionally result from differences in the assay system and accuracy. In addition, it is possible that the differences in serum CCL2 and CXCL8 levels in pulmonary and ocular sarcoidosis may reflect the tissue specificity of the lesion, although the constituents of sarcoid granuloma are the same in the eye and in the lung.

Among the markers of sarcoidosis activity—ESR, WBC IgG, ACE, and lysozyme—only ACE correlated with both serum CXCL9 and CXCL10 levels (rs = 0.62, P = 0.0004; rs = 0.56, P = 0.0014, respectively). In addition, ACE was high in four of the six patients with suspected ocular sarcoidosis, with serum CXCL10 higher than the mean level in those with diagnosed ocular sarcoidosis; and among the four with suspected disease, two also had serum CXCL9 higher than the mean level in the patients with ocular sarcoidosis. A recent study has reported that the serum concentrations of IL-12 p40, an essential component of IL-12 which induces differentiation of naïve Th cells into Th1 cells,30 are significantly higher in pulmonary sarcoidosis than healthy subjects and correlate well with serum levels of ACE and lysozyme.31 Good correlation of both CXCL9 and CXCL10 with ACE at a highly significant level (CXCL9: rs = 0.62, P = 0.0004; CXCL10: rs = 0.56, P = 0.0014) may be related to the Th1 immune response induced in ocular sarcoidosis.

In conclusion, the results provide evidence of elevation of serum CXCL9 and CXCL10 levels in ocular sarcoidosis compared with patients with other forms of uveitis and healthy subjects, especially in the active phase, suggesting that serum CXCL9 and CXCL10 may be a useful marker for diagnosing ocular sarcoidosis.


   Footnotes
 
Supported by Grant-in-Aid 16591769 for Scientific Research from the Japan Society for the Promotion of Science.

Submitted for publication July 26, 2005; revised November 15, 2005; accepted January 23, 2006.

Disclosure: M. Takeuchi, None; K. Oh-i, None; J. Suzuki, None; T. Hattori, None; A. Takeuchi, None; Y. Okunuki, None; Y. Usui, None; M. Usui, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Masaru Takeuchi, Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; takeuchi{at}tokyo-med.ac.jp.


   References
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 Abstract
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 Discussion
 References
 

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