Serum levels of IgG4 and soluble interleukin-2 receptor in patients with coronary artery disease

Clinica Chimica Acta 413 (2012) 577–581

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Serum levels of IgG4 and soluble interleukin-2 receptor in patients with coronary artery disease Aiko Sakamoto a, Nobukazu Ishizaka a, b,⁎, Kan Saito a, Yasushi Imai a, Hiroyuki Morita a, Kazuhiko Koike c, Takahide Kohro a, Ryozo Nagai a,⁎ a b c

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan Department of Cardiology, Faculty of Medicine, Osaka Medical College, Osaka, Japan Department of Gastroenterology, University of Tokyo Graduate School of Medicine, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 30 July 2011 Received in revised form 22 November 2011 Accepted 23 November 2011 Available online 29 November 2011 Keywords: IgG4-related systemic sclerosing disease Lymphocyte activation Coronary artery disease Biomarkers

a b s t r a c t Background: Immunoglobulin G4 (IgG4)-related immuno-inflammation has been suggested to play a role in the development of remodeling of arterial wall. We investigated the association between serum concentrations of IgG4 or soluble interleukin-2 receptor (sIL-2R) and coronary artery disease (CAD). Methods: Serum concentrations of IgG4 and sIL-2R were measured in 286 patients who underwent coronary angiography. Results: In patients with CAD, the medians of serum concentrations of IgG4 (39.3 mg/dl) and sIL-2R (388 U/ml) were significantly higher than corresponding values in patients without CAD (IgG4 27.0 mg/dl, sIL-2R 312 U/ml). In receiver-operating characteristic curve analysis, the area under the curve of sIL-2R and IgG4 for the presence of CAD was 0.634 and 0.632, respectively. Age- and gender-adjusted logistic regression analysis showed that both of the fourth quartile of sIL-2R concentrations (≥509 U/ml) and that of IgG4 concentrations (≥57.7 mg/dl) were found to be associated with CAD with an odds ratio of 2.82 and 4.08, respectively, compared with the corresponding lowest quartile. Conclusions: Serum concentrations of IgG4 and sIL-2R were increased in patients with angiographically-proven CAD, suggesting that IgG4-related immuno-inflammation may also have a role in the development and/or progression of coronary artery atherosclerosis. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Recent studies have shown that the activation of immune system plays a pivotal role in various stages of atherosclerosis [1]. The focal recruitment of circulating monocytes and T lymphocytes is considered to be one of the earliest cellular responses in atherosclerotic lesion formation [2], and B lymphocytes are known to comprise the majority of adventitial inflammatory infiltrates in close proximity to intimal atherosclerotic plaques [3]. Interleukin-2 may modulate T-cell activation and responses [4], and a truncated form of the interleukin-2 receptor, termed soluble interleukin-2 receptor (sIL-2R), is secreted from activated T cells. Serum sIL-2R is elevated in a wide variety of diseases, such as hematological disorders [5], inflammatory bowel disease [6], sarcoidosis [7], and neoplastic diseases [8]. Until now, 4 immunoglobulin G (IgG) subclasses (IgG1, IgG2, IgG3 and IgG4) are known in humans, of which IgG4 is the rarest. It has become evident that increase of serum IgG4 concentrations and/or ⁎ Corresponding authors at: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo, Tokyo, Japan. Tel.: + 81 3 3815 5411x33016; fax: + 81 3 5800 8806. E-mail addresses: [email protected] (N. Ishizaka), [email protected] (R. Nagai). 0009-8981/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2011.11.023

increased infiltration of IgG4-positive cells in various organs can be observed in immuno-inflammation-related disorders such as autoimmune pancreatitis [9], Mikulicz's disease [10], and idiopathic retroperitoneal fibrosis [11], leading to the proposal of a new clinicopathological entity, IgG4-related sclerosing disease (IgG4-SD) [12,13]. Intriguingly, IgG4-related immune activation may also underlie the cardiovascular conditions, such as inflammatory abdominal aortic aneurysm, lymphoplasmacytic aortitis [14,15], and coronary periarteritis [16,17]. Although these findings suggest that IgG4-related periarteritis may involve arteries of various sizes, it has not been clarified whether or not patients with coronary artery disease (CAD) have higher serum concentrations of IgG4 compared with those without. To this end, we have investigated the serum concentrations of these biomarkers, IgG4 and sIL-2R, in patients who underwent coronary angiography. 2. Methods 2.1. Subjects The study was approved by the Ethical Committee of University of Tokyo, Tokyo, Japan. Written informed consent was obtained from all subjects. We enrolled 286 patients whose consent could be obtained

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and who underwent coronary artery angiography because of unstable angina, stable angina, silent myocardial ischemia, heart failure, and preoperative coronary artery screening between October 2005 and July 2008. The exclusion criteria were previous coronary artery interventions such as percutaneous coronary interventions (PCI) and coronary artery bypass graft surgery, acute myocardial infarction, and lack of informed consent for study enrollment. Among the 286 patients enrolled, 80 (28.0%) underwent preoperative screening for CAD before an operation for abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), arteriosclerosis obliterans (ASO), or valvular heart disease (Table 1). Such pre-operative CAD screening would be performed especially when other coronary artery estimation, such as exercise testing and computed tomography angiography (CTA), cannot be performed or will not provide appropriate information, considering the high rate of coexisting coronary artery lesions. In the current study, obesity was defined as a body mass index (BMI) of ≥25 kg/m2 [18]. Diagnosis of hypertension, hyperlipidemia, and diabetes, and assessment of smoking status were made by reference to those made at the time of admission, which were, in general, based on past history, laboratory data, and drugs taken.

2.3. Coronary angiography Angiographic images were analyzed by experienced observers who were unaware of the serum biomarkers tested: sIL-2R, IgG4, and hsCRP. CAD was defined to be present when narrowing of the normal contrast-enhanced lumen to b50% was identified within any of 13 segments (1–4, 5–9, 11–14) in accord with the American Heart Association coronary classification. 2.4. Statistical analysis Data analysis was performed using Dr. SPSS II for Windows (SPSS Inc., Chicago, IL). Differences between groups were calculated by Mann–Whitney, and χ 2 tests. Correlations between variables tested were assessed by using Spearman's rank correlation coefficient. Logistic regression analysis was performed for binominal variables. A P b 0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics

2.2. Laboratory measurements Blood samples were obtained by arterio- or venipuncture at the time of coronary artery angiography. The samples were then centrifuged within 15 min, and serum was stored at −80 °C. Serum concentrations of IgG4 were determined by turbidimetry. Serum concentrations of sIL-2R were measured by enzyme-linked immunosorbent assay (SRL, Tokyo, Japan). The measurements of serum IgG4 and sIL-2R concentrations were performed in duplicate (SRL, Tokyo, Japan) with coefficient variables of 5.2–5.7% and 1.7–3.9%, respectively. High-sensitivity C-reactive protein (hsCRP) was measured by an immunoturbidimetric assay.

Table 1 Baseline characteristics. Variables

No CAD (n=119)

CAD (n=167)

P value

Male gender, n (%) Age, years BMI, kg/m2 Old myocardial infarction, n (%) Congestive heart failure, n (%) Renal failure on hemodialysis, n (%) Coronary risk factors Age ≥ 70 y, n (%) Obesity, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes, n (%) Preoperative screening for AAA, n (%) TAA, n (%) ASO, n (%) Valvular heart disease, n (%) Smoking status Never, n (%) Former, n (%) Current, n (%) Angiographic findings 0 vessel disease, n (%) 1 vessel disease, n (%) 2 vessels disease, n (%) 3 vessels disease, n (%)

69 (58.0) 63.6 ± 11.8 23.7 ± 4.1 0 (0.0) 16 (13.4) 4 (3.4)

128 (76.6) 68.2 ± 8.5 23.6 ± 3.6 27 (16.2) 10 (6.0) 6(3.6)

0.001 0.001 0.775 b0.001 0.031 0.916

39 37 87 44 27

84 (50.3) 48 (28.7) 140 (83.8) 104 (62.3) 92 (55.1)

0.003 0.668 0.027 b0.001 0.000

11 (9.2) 15 (12.6) 5 (4.2) 18 (15.1)

14 (8.4) 9 (5.4) 16 (9.6) 8 (4.8)

0.800 0.030 0.086 0.003

56 (47.1) 37 (31.1) 26 (21.8)

58 (34.7) 76 (45.5) 33 (19.8)

119 (100) 0 0 0

0 61 (36.5) 40 (24.0) 66 (39.5)

(32.8) (31.1) (73.1) (37.0) (22.7)

Values are presented as the mean ± standard deviation unless described otherwise. CAD indicates coronary artery disease. BMI, AAA, TAA, and ASO indicate body mass index, abdominal aortic aneurysm, thoracic aortic aneurysm, and arteriosclerosis obliterans, respectively. Obesity was defined as a BMI of 25 kg/m2 or more.

The mean age of the 286 patients enrolled was 66.3 ± 10.3 y (range 34–86 y). CAD cases were significantly older than non-CAD cases, and the male gender was more prevalent in CAD cases than non-CAD cases (Table 1). Serum concentrations of sIL-2R were greater in patients with diabetes (median 406 U/ml, interquartile range [IR] 300–562) than in those without (median 331 U/ml, IR 264–450, P = 0.001 by Mann–Whitney test). In addition, sIL-2R concentrations were also greater in patients with hypertension (median 373 U/ml, IR 279–535) than in those without (median 312 U/ml, IR 247–412, P = 0.003 by Mann–Whitney test). The relationship between age, estimated glomerular filtration rate (eGFR), and the three biomarkers tested was assessed by Spearman's rank correlation. There was a weak, but significant correlation between sIL-2R and eGFR with a correlation coefficient of − 0.393 (Table 2). Although statistically significant, correlation between IgG4 and sIL-2R, between sIL-2R and hsCRP, and between IgG4 and hsCRP was found to be trivial. 3.2. Serum concentrations of sIL-2R, IgG4, and hsCRP and coronary artery disease The serum concentrations of sIL-2R (median 388 U/ml, IR 301–552) and IgG4 (median 39.3 mg/dl, IR 21.5–66.5) were statistically significantly higher in CAD cases than corresponding values in non-CAD cases (sIL-2R, 312 U/ml, IR 256–450, P b 0.001; IgG4, 27.0 mg/dl, IR 14.9–45.1, P b 0.001) (Fig. 1). On the other hand, in this study population, hsCRP did not significantly differ between CAD and non-CAD Table 2 Spearman's rank correlation coefficient of sIL-2R, IgG4, and hsCRP. Age Age r P value eGFR r P value sIL2R r P value IgG4 r P value hsCRP r P value

eGFR

sIL2R

IgG4

hsCRP

– – − 0.185 0.002

– –

0.183 0.002

− 0.393 b0.001

– –

0.005 0.937

− 0.048 0.423

0.205 0.001

– –

0.028 0.633

− 0.046 0.440

0.222 b0.001

0.136 0.023

– –

A. Sakamoto et al. / Clinica Chimica Acta 413 (2012) 577–581

A

B

P<0.001 1800

579

C

P<0.001

NS 5

600

1600 500

1200 1000 800 600 400

400 300 200

Non-CAD

0

CAD

3 2 1

100

200 0

4

hsCRP (mg/dL)

IgG4 (mg/dL)

sIL-2R (U/mL)

1400

Non-CAD

0

CAD

Non-CAD

CAD

Fig. 1. Scattered plot of soluble interleukin-2 receptor (sIL-2R) (A), immunoglobulin G4 (IgG4) (B), and hsCRP (C) in patients with and without coronary artery disease (CAD). The values of the upper normal limit of each biomarker were shown by dotted lines. P values were calculated by Mann–Whitney U test.

cases. The prevalence of an sIL-2R concentration greater than the upper normal limit, which is 519 U/ml, was higher in CAD than in non-CAD cases (46 [27.5%] vs. 20 [16.8%], P = 0.037, by χ2 test). In addition, the prevalence of an IgG4 concentration greater than the upper normal limit, which is 105 mg/dl, was higher in CAD than in non-CAD cases (25 [15.0%] vs. 4 [3.4%], P = 0.001, by χ2 test). The sensitivity, specificity, positive predictive value and negative predictive value of sIL-2R of >519 U/ml were 27.5%, 83.1%, 69.7%, and 44.7%, respectively, and those of IgG4 of >105 mg/dl were 15.3%, 96.6%, 86.2%, and 45.2%, respectively. Receiver operating characteristic (ROC) curve analysis of the serum concentrations of sIL-2R, IgG4, and hsCRP for CAD is shown in Fig. 2. The area under the curve (AUC) of sIL-2R, IgG4, and hsCRP for the presence of CAD was 0.634 (SE: 0.034, P b 0.001), 0.632 (SE: 0.033, Pb 0.001), and 0.509 (SE: 0.035, P=0.801), respectively. In the current study population, the AUC of age, hypertension, dyslipidemia, and diabetes for CAD was 0.612, 0.554, 0.627, and 0.662, respectively. When each gender was analyzed separately, for the presence of CAD, the AUC of sIL-2R was 0.719 in women and 0.571 in men, and the AUC of IgG4 was 0.672 in women and 0.594 in men. 3.3. Multivariate analysis Age- and gender-adjusted logistic regression analysis showed that the fourth quartile of sIL-2R concentrations (≥509 U/ml) and that of IgG4 concentrations (≥57.7 mg/dl) were both found to be associated with CAD with an odds ratio of 2.82 and 4.08, respectively, compared with the corresponding lowest quartile (Table 3). As compared with the lowest quartile, after adjusting for age and gender, the combined highest three quartiles of sIL-2R (≥275 U/ml) and those of IgG4 (≥18.1 mg/dl) were associated with CAD with an odds ratio of 2.60 (95% CI 1.45–4.68, P = 0.001) and 2.25 (95% CI 1.26–4.03, P = 0.006), respectively. When both IgG4 and sIL-2R were entered

0.75 0.5 0.25 0

4. Discussion We found that, among patients who underwent coronary angiography, serum concentrations of IgG4 and sIL-2R were higher in patient with CAD than in those without. The combined highest three quartiles of sIL-2R (≥275 U/ml) and those of IgG4 (≥18.1 mg/dl) were both found to be associated with the presence of CAD with an odds ratio of 2.60 (95% CI 1.45–4.68, P= 0.001) and 2.25 (95% CI 1.26–4.03, P= 0.006), respectively, as compared with the lowest quartile. These findings suggest that IgG4-related immuno-inflammatory process may play a role in the pathogenesis of coronary artery lesions. Several previous studies have also reported the relationship between serum sIL-2R concentrations and coronary artery atherosclerosis. Neri et al. have reported that patients with unstable angina (n = 29) had significantly higher serum sIL-2R concentrations than healthy subjects (n = 30) [19]. Similarly, Olsson et al. reported that sIL-2R concentrations were found to be increased in patients with stable angina than healthy controls [20]. Satoh et al. also found that

C

1 0.75

Sensitivity

B

1

Sensitivity

Sensitivity

A

into the statistical model (model 2), these biomarkers remained to be significantly associated with CAD, indicating that the association between sIL-2R (IgG4) and CAD was, at least in part, independent of IgG4 (sIL-2R) (Table 3). Furthermore, when eGFR and coronary risk factors were added into the statistical model as covariates (model 3), a graded association of sIL-2R concentrations remained significant and the highest quartile of IgG4 concentrations also remained to be positively associated with CAD. When the usage of statins and angiotensin II receptor blockers was added as an additional covariate, the fourth quartile of sIL-2R concentrations (≥509 U/ml) and that of IgG4 concentrations (≥57.7 mg/dl) remained to be associated with CAD with an odds ratio of 2.68 and 4.29, respectively, compared with the corresponding lowest quartile.

0.5 0.25

0.25 0.5 0.75

1 -Specificity

1

0.75 0.5 0.25 0

0 0

1

0

0.25 0.5 0.75

1 -Specificity

1

0

0.25 0.5 0.75

1

1 -Specificity

Fig. 2. Receiver-operating characteristic (ROC) curve analysis showing the prognostic value of biomarkers for coronary artery disease. ROC curves of sIL-2R (A), IgG4 (B), and hsCRP (C) for the presence of coronary artery disease are shown.

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Table 3 Logistic regression analysis using the presence of CAD as a dependent variable. Model 1

Model 2

Model 3

Independent variables

Odds ratio

(95% CI)

P value

Odds ratio

(95% CI)

P value

Odds ratio

(95% CI)

P value

sIL2R quartiles First (range 151–274) Second (range 275–354) Third (range 355–496) Fourth (range 509–1770)

1.00 2.33 2.71 2.82

Reference (1.15–4.73) (1.32–5.58) (1.37–5.80)

– 0.019 0.007 0.005

1.00 2.54 2.90 2.84

Reference (1.21–5.31) (1.35–6.22) (1.32–6.13)

– 0.014 0.006 0.008

1.00 2.41 2.54 2.72

Reference (1.08–5.38) (1.11–5.81) (1.08–6.86)

– 0.031 0.027 0.035

IgG4 quartiles First (range 3.0-17.8) Second (range 18.1–32.7) Third (range 33.4–57.6) Fourth (range 57.7–580.0)

1.00 1.92 1.64 4.08

Reference (0.95–3.88) (0.82–3.30) (1.90–8.76)

– 0.070 0.163 b 0.001

1.00 2.04 1.67 3.91

Reference (1.00–4.17) (0.82–3.38) (1.80–8.52)

– 0.051 0.158 0.001

1.00 1.59 1.60 3.75

Reference (0.73–3.48) (0.74–3.46) (1.64–8.57)

– 0.243 0.231 0.002

hsCRP quartiles First (range 0.01–0.05) Second (range 0.06–0.10) Third (range 0.11–0.31) Fourth (range 0.32–4.12)

1.00 0.53 0.80 0.89

Reference (0.26–1.08) (0.40–1.60) (0.44–1.82)

– 0.081 0.525 0.752

1.00 0.44 0.67 0.59

Reference (0.21–0.94) (0.32–1.40) (0.27–1.30)

– 0.033 0.290 0.191

1.00 0.46 0.65 0.87

Reference (0.20–1.05) (0.29–1.45) (0.36–2.08)

– 0.065 0.289 0.752

Model 1: Independent variables include gender, age, and either of IgG4, sIL-2R, or hsCRP. Model 2: Independent variables include gender, age, IgG4, sIL-2R, and hsCRP. Model 3: Independent variables include those in Model 2 + eGFR, hypertension, hyperlipidemia, and diabetes.

sIL-2R concentrations were higher in CAD patients (n = 85) than normal controls (n = 50) [21]. Together with our results, these observations suggest the presence of continuous immune system activation and antigenic stimulation although the nature of such antigen remains to be investigated. In the above-mentioned Satoh et al.'s report, it was also reported that sIL-2R concentrations showed further elevation 30 days after successful PCI in patients who experienced intraluminal restenosis, but not in those who did not experience restenosis [21], suggesting that the activation of T-lymphocyte activation may also play a role in the development of coronary artery restenosis after successful PCI. On the other hand, Wadwa et al. have reported that elevated plasma sIL-2R is associated with progression of coronary artery calcification assessed by electron beam tomography that was independent of traditional coronary artery disease risk factors [22], suggesting the role of T-lymphocyte activation in coronary arteriosclerosis. Possible involvement of IgG4-related autoimmunity in the development of fibrosclerotic lesion formation has been first discovered in autoimmune pancreatitis [9]. Growing body of evidence is accumulating that IgG4-SD may involve a wide variety of organs including cardiovascular system, including abdominal [14,15,23] and thoracic aorta, and pericardium [24]. Although it seems that only a few studies have analyzed the association between IgG4 and the presence or extent of coronary artery lesions thus far, several recent studies suggested the involvement of IgG4-related immuno-inflammation in coronary periarteritis. Matsumoto et al. presented a case with IgG4-related inflammatory pseudo-tumor in the peri-coronary artery region [16]. In addition, Maturen et al. have recently reported a patient with idiopathic retroperitoneal fibrosis, which is considered to belong, in part, to IgG4-SD, who had perivascular low-attenuation soft tissue surrounding the coronary arteries, illustrated by computed tomography [17]. In Matsumoto et al.'s and Maturen et al.'s papers, coronary periarterial fibrosclerosis was not seemed to be associated with flow-limiting coronary artery disease. In this sense, the current study is the first one that shows the possible relationship between CAD and serum IgG4 concentrations. It may be questioned whether IgG4-related peri-coronary arterial fibrosclerosis would be associated with CAD. We recently reported a case who was admitted to the hospital owing to the chest symptoms suggestive of acute coronary syndrome [25]. In this patient, CT coronary angiography revealed a fibrous thickening of the peri-coronary arterial regions, and the luminal stenosis at the site of coronary periarteritis.

Histologic and immunohistochemical analysis showed enhanced infiltration of IgG4-positive plasma cells in the observed periarterial lesion, and together with increased serum IgG4 concentrations (564 mg/dl), IgG4-related coronary periarteritis has been diagnosed in this patient. Although the causal role of IgG4-related immunoinflammation in the development in luminal stenosis could not be concluded from that patient, it is possible that the presence of coronary periarteritis had been underdiagnosed until now. In this study, hsCRP was not found to be higher in patients with CAD, which contrasted to the previous findings demonstrating that CRP and other circulating markers of inflammation, such as erythrocyte sedimentation rate and von Willebrand factor in the prediction of coronary heart disease [26]. Veselka et al. reported a similar observation, however, that CRP concentrations were not related to the extent or the presence of coronary atherosclerosis assessed by coronary angiography in patients referred for coronary angiography [27]. In addition, by prospectively analyzing the data from patients with stable angina or an abnormal stress test who were referred for diagnostic coronary angiography, Azar et al. reported that CRP concentrations were not correlated with the extent or severity of coronary narrowing; no significant difference in plasma CRP concentrations between subjects with normal coronary artery, mild CAD, single vessel disease, and multi-vessel disease [28]. Furthermore, Abdelmouttaleb et al. have found that CRP concentrations were higher in patients with unstable angina, but not in asymptomatic subjects or those with stable angina in which CAD was established by coronary angiography [29]. In the current study population, unstable angina was present in 21 (7.3%). It is possible that several factors, including the prevalence of acute coronary syndrome, may affect the relationship between CRP concentrations and CAD. In addition, statins and angiotensin II receptor blockers, which had already been taken in some patients, may have affected hsCRP concentrations [30–32]. In this study, subjects with aortic aneurysm but without CAD were also included in non-CAD cases, which may affect the inflammatory status in non-CAD subjects. In another set of on-going study, we are measuring serum IgG4 concentrations in the 127 subjects who have neither CAD nor aortic aneurysm. In that preliminary study, the median of serum IgG4 concentrations in subjects who had neither CAD nor aortic aneurysm was 28.5 mg/dl (IR 14.9–45.7) and that of sIL-2R concentrations was 317 U/ml (IR 260–450). Among them, 5 subjects (3.9%) were found to have serum IgG4 concentrations greater than 105 mg/dl, and 22 subjects (17.3%) were found to have serum sIL-2R

A. Sakamoto et al. / Clinica Chimica Acta 413 (2012) 577–581

concentrations greater than 519 U/ml. These observations confirm that serum IgG4 and sIL-2R concentrations are indeed elevated in subjects who have neither CAD nor aortic aneurysm. We may have to clarify whether non-CAD subjects with increased IgG4 or sIL-2R would have higher incidence of future CAD or CAD-associated events in the near future. There are several limitations of the current study. First, we investigated the relationship between these biomarkers and CAD in relatively high risk patients. Whether or not they represent a marker of coronary or peripheral atherosclerosis should be investigated in the general, i.e., relatively low risk, population. Second, due to the cross-sectional nature of the study, we cannot draw conclusions about the causal or resultant relationship between the elevation of sIL-2R and IgG4 concentrations and CAD. A longitudinal follow-up of the subjects should be performed to elucidate whether those subjects with higher concentrations of these markers would be more likely to experience the progression of CAD. Third, to assess the role of IgG4-related immuno-inflammation in the atherogenesis, we have to assess the IgG4-positivity in perivascular cells of coronary artery in CAD patients by histological and immunohistochemical approach as the degree of IgG4-positive staining does not necessarily correlate with elevated serum concentrations [33]. Finally, to elucidate the usefulness of the measurement of IgG4 and sIL-2R, whether the elevation of these biomarkers predicts the risk for future atherosclerotic episodes or restenosis following successful coronary intervention should be investigated. In conclusion, we have shown that higher serum concentrations of IgG4 and sIL-2R, markers for lymphocytic activation, were associated with CAD in patients who underwent coronary artery angiography. Further studies are warranted to clarify whether these biomarkers are useful in the prediction of coronary artery lesions in patients who have a relatively low-risk profile. Acknowledgments The work was supported in part by a grant from Chiyoda Mutual Life Foundation, the St Luke's Grant for Epidemiological Research, Daiwa Securities Health Foundation, Gerontology Research Grant of Kowa Life Science Foundation, Foundation for Total Health Promotion, Gout Research Foundation of Japan, a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Japan, and the Japan Society for the Promotion of Science (JSPS) through its “Funding Program for WorldLeading Innovative R&D on Science and Technology (FIRST Program)”. We are highly appreciative of Kyoko Furuta for her technical assistance and Dr. Hiroshi Noto for his comments on statistical analysis. References [1] Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006;47:C7–C12. [2] Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. [3] Koch AE, Haines GK, Rizzo RJ, et al. Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol 1990;137:1199–213. [4] Bachmann MF, Oxenius A. Interleukin 2: from immunostimulation to immunoregulation and back again. EMBO Rep 2007;8:1142–8. [5] Harrington DS, Patil K, Lai PK, et al. Soluble interleukin 2 receptors in patients with malignant lymphoma. Arch Pathol Lab Med 1988;112:597–601.

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