Abstract
MCP-1 and MIP-1α exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Up-regulated expression of MCP-1 and MIP-1α in the affected organ of sarcoidosis has been shown; however, the relationship between their plasma levels and the clinical course of this disease has not been determined. In the present study we measured plasma MCP-1 and MIP-1α levels in 26 patients with active sarcoidosis by ELISA in order to assess the state of MCP-1 and MIP-1α in this disease. Most patients in this study (21/26) had clinical evidence of extrathoracic disease in addition to pulmonary involvement. In addition, a high proportion of patients (n = 15) showed spontaneous remission of disease, whereas five patients showed no spontaneous remission and six patients were treated with corticosteroids over the 2-year period of study. At the time of diagnosis, both plasma MCP-1 and MIP-1α levels in patients with active sarcoidosis were significantly higher than in the normal controls. The levels of these cytokines in patients with extrathoracic disease were compatible with those in patients without extrathoracic disease. A longitudinal evaluation of plasma MCP-1 and MIP-1α levels showed that the changes in both cytokines were closely related to the clinical course of sarcoidosis. These results suggest that plasma MCP-1 and MIP-1α may be useful parameters for monitoring the clinical course of sarcoidosis. In addition, plasma MCP-1 and MIP-1α may reflect subclinical evidence of extrathoracic sarcoidosis and may play a role in initiating monocyte migration into the tissue.
Keywords: sarcoidosis, MCP-1, MIP-1α
INTRODUCTION
Sarcoidosis is a systemic granulomatous disorder of unknown origin, characterized by a chronic T lymphocyte macrophage inflammatory process, granuloma formation and distortion of normal architecture [1,2]. This chronic granulomatous disease is characterized, at least in part, by accumulation of T cells and macrophages in the affected organ [1,2]. Therefore, the recruitment of macrophages and T cells into the affected organ is thought to be an important step in the production and development of sarcoidosis.
MCP-1 and MIP-1α are members of the C-C chemokine supergene family [3,4]. Both cytokines exhibit chemotactic activity toward monocytes and induce the production of inflammatory cytokines, including IL-1, IL-6 and tumour necrosis factor-alpha (TNF-α) [3–11]. It has been described that MCP-1 and MIP-1α play an important role in the production and development of various inflammatory diseases [12–15]. In sarcoidosis, the elevation of MCP-1 and MIP-1α levels in bronchoalveolar lavage fluid (BALF) and the up-regulated expression of these chemokines in macrophages in the affected organ have been shown [16,17]. From this evidence, it has been proposed that MCP-1 and MIP-1α may be responsible for the recruitment of macrophages into the affected organ and the induction of inflammatory cytokines.
As mentioned, up-regulated expression of MCP-1 and MIP-1α in active sarcoidosis has already been demonstrated. However, there is no information about the relationship between the levels of MCP-1 and MIP-1α, and the clinical course of sarcoidosis. In this study, we have made serial measurements of plasma MCP-1 and MIP-1α levels in order to evaluate the relationship between plasma MCP-1 and MIP-1α levels and the clinical course of this disease. We determined the levels of these cytokines in plasma rather than those in BALF, since sarcoidosis is a systemic disease and we hypothesized that these chemokines may be involved in the mechanisms leading to monocyte extravasation into tissues. Most patients in this study had clinical evidence of extrathoracic disease in addition to pulmonary involvement, and a high proportion showed spontaneous remission without treatment over the 2-year period of study.
PATIENTS AND METHODS
Study population
The characteristics of the study population are summarized in Table 1. The study group comprised 26 patients with active sarcoidosis (13 women and 13 men) with a median age of 30.0 years (range 22–73 years). The diagnosis of sarcoidosis was established using defined criteria including transbronchial lung biopsy and biopsy of affected organs [1,2]. All 26 patients had pulmonary involvement proved by the histopathological findings of sarcoidosis. Active sarcoidosis at the time of diagnosis was determined based on clinical symptoms such as new or progressive dyspnoea (two out of 26 patients) and cough (seven out of 26 patients) or active uveitis (20 out of 26 patients); new radiographic abnormalities on chest radiograph (24 out of 26 patients); an increase in lymphocytes in BALF and an increased CD4/CD8 ratio of lymphocytes in BALF (all 26 patients); elevated levels of serum angiotensin converting enzyme (SACE) (22 out of 26 patients) [1,2,18–20]. Four patients who did not have elevated levels of SACE had uveitis and new radiographic abnormalities on chest radiography. From these clinical symptoms and laboratory data, all patients in this study were regarded as having active disease. At the time of diagnosis, two had no abnormalities on chest radiograph (radiographic stage 0). One case was diagnosed as sarcoidosis following tonsilar biopsy and another case was diagnosed as Heerfordt's syndrome following uveitis, swelling of parotid gland and facial nerve palsy. These two cases also had pulmonary involvement proved by transbronchial lung biopsy. Fifteen had bilateral hilar lymph node enlargement (BHL) (radiographic stage I); six had BHL and parenchymal shadowing (stage II); three had parenchymal shadowing without BHL (stage III). At the time of diagnosis, the patients had not been treated with corticosteroids. The patients were assessed clinically and radiographically, and the initial blood samples were taken at the time of diagnosis and follow-up blood samples were taken at about 3 or 6 months after diagnosis and then at 6 monthly intervals up to a total of 2 years.
Table 1.
The characteristics of patients
In all patients, a longitudinal evaluation of plasma MCP-1 and MIP-1α levels was carried out to evaluate the relationship between plasma MCP-1 and MIP-1α levels and the course of sarcoidosis, therapy and clinical measurements of disease activity (mean ± s.d. 21.2 ± 6.2 months; median (range) 21.8 (12–24 months)). To this end, patients with sarcoidosis were divided into three groups on the basis of clinical course: 15 untreated patients with disease of short duration (spontaneous remission of the disease); five untreated patients with more long-standing disease (no spontaneous remission of the disease); six other patients without spontaneous remission were treated with corticosteroids. In our study, the decision to start corticosteroid therapy was based on the clinical evaluation. In general, the criteria for institution of corticosteroid therapy included severe hypoxaemia, systemic symptoms and signs such as severe uveitis that did not respond to topical therapy and central nervous system (CNS) involvement. Of six treated patients, one had Heerfordt's syndrome, three cases had severe uveitis, and two other cases had advanced pulmonary parenchymal involvement with severe hypoxaemia, CNS involvement, and severe uveitis. Five untreated patients, who were also regarded as having active sarcoidosis at the time of diagnosis, with no spontaneous remission, were not treated with corticosteroids since they did not fulfil the criteria for institution of corticosteroid therapy over a period of study. Improvement or remission was defined by the improvement of abnormalities on chest radiograph, pulmonary function testing, accompanied by a comparable improvement in the patient's dyspnoea levels and other objective clinical symptoms such as uveitis, and a decrease in SACE levels. No improvement or remission of disease was defined by no change or improvement in abnormalities of chest radiograph, pulmonary function testing and skin involvement, continuous requirement for topical therapy of uveitis and no decrease in SACE levels.
Twenty-six age- and sex-matched normal subjects were recruited as normal control subjects. All patients and normal control subjects in this study had never smoked. Informed consent was obtained from all patients and normal control subjects.
Measurement of plasma MCP-1 and MIP-1α levels
Plasma MCP-1 and MIP-1α levels were measured by commercially available ELISA kits (Amersham International plc, Aylesbury, UK). ELISA was performed according to the manufacturer's instructions. All samples were assayed in duplicate. The sensitivity of MCP-1 and MIP-1α ELISA was 5 pg/ml and 3 pgml, respectively.
Statistical analysis
Statistical significance was analysed using the Mann–Whitney U-test. Spearman's test was used for correlation analysis. P < 0.05 was considered significant.
RESULTS
Plasma MCP-1 and MIP-1α levels
Plasma MCP-1 and MIP-1α levels from the initial samples in the patients with sarcoidosis at the time of diagnosis were compared with those in the normal controls. Plasma from patients with sarcoidosis contained more MCP-1 (n = 26; mean ± s.d. 385.0 ± 157.0 pg/ml; median (range) 324.0 (184.0–768.0 pg/ml)) than in normal controls (n = 26; 77.7 ± 25.5 pg/ml; 84.0 (5.0–104.0 pg/ml); P < 0.001) (Fig. 1a). Plasma from patients with sarcoidosis also contained more MIP-1α (n = 26; 482.0 ± 166.9 pg/ml; median (range) 411.0 (284.0–904.0 pg/ml)) than in the normal controls (n = 26; 75.4 ± 30.2 pg/ml; 80.0 (3.0–114.0 pg/ml); P < 0.001) (Fig. 1b). There was no overlap in plasma MCP-1 levels between patients with sarcoidosis and normal controls. There was also no overlap in plasma MIP-1α levels between the two groups. Plasma MCP-1 and MIP-1α levels from the initial samples in patients with sarcoidosis at the time of diagnosis were significantly correlated (rs = 0.974, P < 0.001) (Fig. 2).
Fig. 1.
Plasma MCP-1 and MIP-1α levels in patients with sarcoidosis. Plasma MCP-1 levels (a) and plasma MIP-1α levels (b) from the initial samples in 26 patients with sarcoidosis at the time of diagnosis were compared with normal controls. Horizontal short lines represent mean of each group. Plasma MCP-1 and MIP-1α levels were significantly higher in patients with sarcoidosis than normal controls (P < 0.001 and P < 0.001, respectively).
Fig. 2.
Correlation between plasma MCP-1 and MIP-1α levels in patients with sarcoidosis. Relationship between plasma MCP-1 levels and plasma MIP-1α levels from the initial samples in 26 patients with sarcoidosis at the time of diagnosis was analysed. Plasma MCP-1 levels were significantly correlated with plasma MIP-1α levels (rs = 0.974, P < 0.001).
Relationship between plasma MCP-1 or MIP-1α levels, and other markers of disease activity
Relationship between plasma MCP-1 and MIP-1α levels from the initial samples at the time of diagnosis and other markers of disease activity at the time of diagnosis was determined in 26 patients with sarcoidosis. Plasma MCP-1 and MIP-1α levels correlated with SACE levels (rs = 0.48, P < 0.05; rs = 0.48, P < 0.05, respectively), the percentage of lymphocytes in BALF (rs = 0.59, P < 0.05; rs = 0.56, P < 0.05, respectively), and the ratio of CD4/CD8 of lymphocytes in BALF (rs = 0.55, P < 0.05, rs = 0.51, P < 0.05, respectively). At the time of diagnosis, plasma MCP-1 levels in 21 patients with extrathoracic disease and five patients without extrathoracic disease were 391.8 ± 155.9 pg/ml (median (range) 364.0 (184.0–768.0 pg/ml)) and 356.6 ± 61.9 pg/ml (348.0 (270.0–442.0 pg/ml)), respectively. Plasma MIP-1α levels in 21 patients with extrathoracic disease and five patients without extrathoracic disease were 478.2 ± 155.9 pg/ml; 442.0 (284.0–904.0 pg/ml) and 415.6 ± 37.1 pg/ml; 402.0 (372.0–484.0 pg/ml), respectively. There was no significant difference in plasma MCP-1 or MIP-1α levels between the two groups. There was no significant difference in plasma MCP-1 and MIP-1α levels between 15 patients with radiographic stage I and six patients with radiographic stage II (data not shown).
Changes in plasms MCP-1 and MIP-1α levels during the course of disease
A longitudinal evaluation of plasma MCP-1 and MIP-1α levels was carried out to evaluate the relationship between plasma MCP-1 or MIP-1α levels and the course of sarcoidosis. The results of changes in plasma MCP-1 and MIP-1α levels from 20 untreated patients are shown in Fig. 3. At the time of diagnosis, plasma MCP-1 levels in 15 untreated patients with spontaneous remission and five patients with no spontaneous remission were 364.5 ± 120.2 pg/ml (median (range) 342.0 (246.0–621.0 pg/ml)) and 308.4 ± 89.0 pg/ml (304.0 (184.0–464.0 pg/ml)), respectively. Plasma MIP-1α levels in 15 patients with spontaneous remission and in five patients with no spontaneous remission were 455.5 ± 129.5 pg/ml (404.0 (291.0–724.0 pg/ml)) and 388.4 ± 97.8 pg/ml (382.0 (284.0–562.0 pg/ml)), respectively. No significant difference in plasma MCP-1 or MIP-1α levels was found between 15 untreated patients with spontaneous remission and five untreated patients with no spontaneous remission. A decrease in plasma MCP-1 and MIP-1α levels was observed in 15 untreated patients with spontaneous remission over the study period (Fig. 3a,b). On the other hand, in five untreated patients with no spontaneous remission over the study period, there was no significant decrease in plasma MCP-1 and MIP-1α levels (Fig. 3c,d). Of these five patients, four had radiographic stage I with uveitis, and one had radiographic stage II with uveitis and skin involvement. No resolution of abnormalities on chest radiograph and no improvement of skin involvement over the period of study were observed, and uveitis was under control with topical therapy but continuous topical therapy was required. In six patients treated with corticosteroids, five patients showed improvement of clinical symptoms and signs accompanied by a decrease in MCP-1 and MIP-1α levels over the study period (24 months).
Fig. 3.
Changes in plasma MCP-1 and MIP-1α levels during the course of disease. Changes in plasma MCP-1 levels (a) and plasma MIP-1α levels (b) in 15 untreated patients with spontaneous remission of disease over a period of study, and changes in plasma MCP-1 levels (c) and plasma MIP-1α levels (d) in five untreated patients with no spontaneous remission over a period of study.
A representative patient treated with corticosteroids who showed improvement of clinical symptoms and signs is shown in Fig. 5a. However, another case had relapse of disease accompanied by elevation of plasma MCP-1 and MIP-1α levels (Fig. 5b).
Fig. 5.
Case examples of the relationship between changes in plasma MCP-1 and MIP-1α levels, and clinical course of sarcoidosis in patients treated with corticosteroids. Changes in plasma MCP-1 (•) and MIP-1α (○) levels, serum angiotensin converting enzyme (SACE) (▪) and serum lysozyme levels (□) and chest radiographs in one patient with remission (a) and in one patient with relapse (b). Illustrated chest radiographs show diffuse bilateral coarse nodular densities with marked bilateral lymph node enlargement (BHL) at the time of diagnosis and complete resolution of abnormalities on chest radiographs after treatment with corticosteroids (a). An illustrated chest radiograph at the time of diagnosis shows bilateral diffuse coarse nodular densities. Corticosteroid therapy resulted in mild resolution of abnormalities on chest radiograph, but after 12 months reappearance of chest abnormalities evidenced radiographically was noted. Complete resolution of abnormalities on chest radiographs after treatment with 30 mg corticosteroids per day was noted (b).
Case examples of the relationship between plasma MCP-1 and MIP-1α levels and clinical course of sarcoidosis
Figures 4 and 5 show the results of a longitudinal evaluation of plasma MCP-1 and MIP-1α in representative patients with sarcoidosis from each group and the relationship with SACE and clinical indices of sarcoidosis. Figure 4a shows an untreated patient with spontaneous remission of the disease. This case was a 27-year-old male who presented with BHL on chest radiograph. Plasma MCP-1 and MIP-1α levels were significantly elevated at the time of diagnosis and decreased to normal levels accompanied by resolution of BHL. Figure 4b shows an untreated patient with no spontaneous remission of the disease. This case was a 35-year-old male who presented with BHL and uveitis. Plasma MCP-1 and MIP-1α levels were significantly elevated at the time of diagnosis and decreased at 4 months; however, thereafter, plasma MCP-1 and MIP-1α levels remained at approximately the same levels as those which were observed at 4 months over a period of 24 months. In this case, he had no resolution of BHL and continuous requirement of topical therapy of uveitis. Figure 5a,b shows two representative patients treated with corticosteroids. A 51-year-old female presented with neurological symptoms, severe uveitis, hypoxaemia and advanced parenchymal involvement on chest radiograph. Corticosteroid therapy was started. After 4 weeks of therapy with 30 mg of corticosteroids per day, plasma MCP-1 and MIP-1α levels decreased rapidly, accompanied by improvement in her symptoms, the resolution of abnormalities on chest radiograph and a decrease in SACE levels (Fig. 5a). The other case was a 66-year-old female who was treated with 30 mg of corticosteroids per day because of advanced pulmonary parenchymal involvement, advanced hepatic involvement and severe uveitis. After 4 weeks of therapy with 30 mg of corticosteroids, plasma MCP-1 and MIP-1α levels decreased rapidly, accompanied by improvement in her symptoms, resolution of abnormalities of chest radiograph and a decrease in SACE and lysozyme. Thereafter, the dose of corticosteroids was gradually reduced to a maintenance dose of 5 mg per day. After 12 months of therapy with corticosteroids, a marked elevation of plasma MCP-1 and MIP-1α levels accompanied by reappearance of pulmonary parenchymal shadows on chest radiograph and an increase in SACE levels and serum lysozyme levels was noted. Because of deterioration, 30 mg of corticosteroids per day was administered. Thereafter, plasma MCP-1 and MIP-1α levels decreased rapidly, accompanied by improvement of her symptoms and laboratory data (Fig. 5b).
Fig. 4.
Case examples of the relationship between changes in plasma MCP-1 and MIP-1α levels, and clinical course of sarcoidosis in untreated patients. Changes in plasma MCP-1 (•) and MIP-1α (○) levels, serum angiotensin converting enzyme (SACE) (□) and serum lysozyme (▪) levels and chest radiographs in one patient with spontaneous remission (a) and in one patient with no spontaneous remission (b). Illustrated chest radiographs show marked bilateral lymph node enlargement (BHL) at the time of diagnosis and complete resolution of BHL after 16 months (a). Illustrated chest radiographs at the time of diagnosis and during the course of disease show marked BHL and no resolution of BHL (b).
DISCUSSION
In the present study, we measured plasma MCP-1 and MIP-1α levels in patients with active sarcoidosis at the time of diagnosis and made serial measurements of plasma MCP-1 and MIP-1α levels in order to evaluate the relationship between plasma MCP-1 and MIP-1α levels and clinical course of this disease. Our results show that plasma MCP-1 and MIP-1α levels at the time of diagnosis were significantly higher in patients with active sarcoidosis than in normal controls. A longitudinal evaluation of plasma MCP-1 and MIP-1α levels shows that the changes in plasma MCP-1 and MIP-1α levels were closely related to clinical course of this disease.
Sarcoidosis is characterized, at least in part, by accumulation of T cells and macrophages in the affected organs [1,2]. MCP-1 and MIP-1α have been proposed to be responsible for the recruitment of macrophages into the affected organ and the induction of inflammatory cytokines affecting granuloma formation [3–11,16,17]. In this study, all patients had pulmonary involvement. Most patients (21/26) had clinical evidence of extrathoracic disease in addition to pulmonary involvement. Thus, 21 out of 26 patients appeared to have systemic disease, whereas five other patients had predominant pulmonary involvement without clinical evidence of extrathoracic disease. Plasma MCP-1 and MIP-1α levels in all patients at the time of diagnosis were above the highest levels of plasma MCP-1 and MIP-1α in normal controls, and even five patients without clinical evidence of extrathoracic disease had higher levels of plasma MCP-1 and MIP-1α than normal controls. In addition, there was no significant difference in plasma MCP-1 or MIP-1α levels between 21 patients with extrathoracic disease and five patients without it. These results indicate that the elevation of plasma MCP-1 and MIP-1α levels might reflect subclinical evidence of extrathoracic sarcoidosis and patients without extrathoracic sarcoidosis might have subclinical evidence of extrathoracic disease.
A longitudinal evaluation of plasma MCP-1 and MIP-1α levels showed that plasma MCP-1 and MIP-1α levels decreased according to remission of disease, and plasma levels were consistently elevated in cases with no spontaneous remission of disease, indicating that plasma MCP-1 and MIP-1α levels are closely related to the clinical course of sarcoidosis. At the time of diagnosis, all patients in this study were regarded as having active disease. Plasma MCP-1 and MIP-1α levels at the time of diagnosis in five untreated patients with no spontaneous remission were compatible with those in 15 untreated patients with no spontaneous remission. Therefore, the patient group with no spontaneous remission was not different from the patient group with spontaneous remission, at least in terms of plasma MCP-1 and MIP-1α levels. Over the 2-year period of study, a consistent elevation of plasma MCP-1 and MIP-1α levels was observed in the patient group with no spontaneous remission of pulmonary and extrathoracic sarcoidosis, while a decrease in plasma MCP-1 and MIP-1α levels was observed in the patient group with spontaneous remission of disease. These results indicate that plasma MCP-1 and MIP-1α could consistently play some role in the maintenance of sarcoid lesions through monocyte/macrophage migration into the tissue and the induction of inflammatory cytokines.
MCP-1 and MIP-1α are produced by a variety of cells such as monocytes/macrophages, lymphocytes, vascular endothelium and fibroblasts [3,4]. Although cellular sources of plasma MCP-1 and MIP-1α in this study were not determined, monocytes in blood might be important sources of plasma MCP-1 and MIP-1α, since peripheral blood monocytes in pulmonary sarcoidosis have been shown to be activated [21,22]. However, further study should be done to clarify cellular sources of plasma MCP-1 and MIP-1α.
In conclusion, our results, demonstrating the evidence for the elevation of plasma MCP-1 and MIP-1α levels in patients with active sarcoidosis, and the close linkage between changes in plasma MCP-1 and MIP-1α levels and the course of sarcoidosis, suggest that plasma MCP-1 and MIP-1α may be useful markers for monitoring the clinical course of sarcoidosis. In addition, plasma MCP-1 and MIP-1α may reflect subclinical evidence of extrathoracic sarcoidosis and may play a role in initiating monocyte migration into the tissue.
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