Pediatr Allergy Immunol 2009: 20: 266–272                                                   Ó 2008 The Authors
DOI: 10.111...
Role of eosinophil-related Th2 mediators in KD

patientsÕ characteristics as well as IVIG prepara-      Cytokine Beadmates...
Kuo et al.

Results                                                       (12.07 ± 1.36 pg/ml vs. 28.55 ± 3.84 pg/ml,
Role of eosinophil-related Th2 mediators in KD

Kuo et al.

 (a)                                                          (b)

 (c)                                    ...
Role of eosinophil-related Th2 mediators in KD

 (a)                                                           (b)

Kuo et al.

 2. Wang CL, Wu YT, Liu CA, Kuo HC, Yang KD.                         to coronary arteries in acute stage of Ka...
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Th2 cytokines

  1. 1. Pediatr Allergy Immunol 2009: 20: 266–272 Ó 2008 The Authors DOI: 10.1111/j.1399-3038.2008.00779.x Journal compilation Ó 2008 Blackwell Munksgaard PEDIATRIC ALLERGY AND IMMUNOLOGY Association of lower eosinophil-related T helper 2 (Th2) cytokines with coronary artery lesions in Kawasaki disease Kuo H-C, Wang C-L, Liang C-D, Yu H-R, Huang C-F, Wang L, Ho-Chang Kuo1,2, Chih-Lu Wang3, Chi- Hwang K-P, Yang KD. Association of lower eosinophil-related T Di Liang4, Hong-Ren Yu1,2, Chien-Fu helper 2 (Th2) cytokines with coronary artery lesions in Kawasaki Huang4, Lin Wang1,2, Kao-Pin Hwang5 disease. and Kuender D. Yang1,2 1 Pediatr Allergy Immunol 2009: 20: 266–272. Division of Allergy, Immunology and Rheumatology; Ó 2008 The Authors Department of Pediatrics, Chang Gung Memorial Journal compilation Ó 2008 Blackwell Munksgaard Hospital-Kaohsiung Medical Center; 2Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine; 3Department of Kawasaki disease (KD) is a systemic febrile vasculitis particular coro- Pediatrics, Po-Jen Hospital; Divisions of 4Cardiology nary artery involvement. Eosinophilia has been found in our and other and 5Infectious Disease, Department of Pediatrics, studies in KD. This study further investigates whether eosinophil- Chang Gung Memorial Hospital-Kaohsiung Medical related T helper 2 (Th2) cytokines or the activation marker (eosinophil Center, Kaohsiung, Taiwan cationic protein – ECP) is involved in KD with coronary artery lesions (CAL). A total of 95 KD patients were enrolled for this study. Plasma samples were subjected to the measurement of interleukin (IL)-4, IL-5, Key words: Kawasaki disease; coronary artery and eotaxin by Luminex-Bedalyte multiplex beadmates system and to lesions; eosinophils; T helper 2; interleukin-5; the measurement of ECP by fluoroimmunoassay. Patients with KD had eosinophil cationic protein higher eosinophils than controls. Eosinophil-related mediators: IL-4, IL-5, eotaxin, and ECP levels were also higher in KD patients than Kuender D. Yang, Department of Medical Research controls before intravenous immunoglobulin (IVIG) treatment. After and Pediatric Allergy, Immunology and Rheumatology, IVIG treatment, ECP decreased but IL-4, IL-5, and eotaxin increased Chang Gung Memorial Hospital-Kaohsiung Medical significantly. The higher the IL-5 and eosinophil levels after IVIG Center, 123 Ta-Pei Road, Niaosung Hsiang, Kaohsiung, Taiwan treatment, the lower rate of CAL was found. Changes of eosinophils Tel.: +886-7-7317123 after IVIG treatment were positively correlated to changes of IL-5 levels Fax: +886-7-7312867 but not ECP levels. An increase of eosinophils and IL-5, but not ECP E-mail: levels after IVIG treatment, was inversely correlated with CAL for- mation in KD. Accepted 28 May 2008 Kawasaki disease (KD) is an acute febrile multi- A complication of coronary artery aneurysm systemic vasculitis of unknown etiology, which develops in 20% of untreated KD affected was first reported by Kawasaki et al. (1) from children (3). A single high-dose (2 g/kg) of Japan in 1974 in the English language literature. intravenous immunoglobulin (IVIG) plus aspirin It occurs worldwide and mainly affects children can diminish the incidence of aneurysm from less than 5 yr old. The clinical characteristics of 20% to 3–5% (6). The IVIG treatment can also KD include prolonged fever, bilateral non-puru- shorten the fever duration when given within lent conjunctivitis, diffuse mucosal inflammation, 10 days after the disease onset (6, 7). As CAL polymorphous skin rashes, indurative angioe- occurs at a mean of 9.5 days after the onset of dema of the hands and feet, and non-suppurative KD, it is important to treat and prevent pro- cervical lymphadenopathy (1–4). The most seri- gression of coronary artery injury within 10 days ous complication of KD is coronary artery (2, 3). Kawasaki et al. (1) were the first to lesions (CAL) including myocardial infarction, describe eosinophilia in the peripheral blood of coronary artery dilatation, or coronary artery KD patients. Later, eosinophils were also found aneurysm (2, 3). In the developed countries, KD in coronary artery autopsies (8). We have is the leading cause of acquired heart diseases in recently shown that eosinophilia was positively children (2–5). correlated to IVIG treatment success (9), and 266
  2. 2. Role of eosinophil-related Th2 mediators in KD patientsÕ characteristics as well as IVIG prepara- Cytokine Beadmates system (Upstate Group, tions might affect eosinophilia (10). Inc., Billerica, MA, USA) for the 95 KD patients To explore the mechanism of eosinophilia in and 30 control samples. The study method was KD, this study was conducted to investigate modified from a previous report (13). In brief, whether eosinophil-related T helper 2 (Th2) 50 ll samples were mixed with multiplexed cytokines (IL-4, IL-5, and eotaxin) or the eosin- antibody-conjugated beads before being sub- ophil activation mediator (eosinophil cationic jected to multi-channel detection of the bead- protein – ECP) were associated with CAL array. Acquired fluorescence data were assessed formation in KD patients. by the MasterPlexTM QT software (Ver. 1.2; MiraiBio, Inc., South San Francisco, CA, USA). Calibration of cytokine concentrations was Patients and methods determined by interpolation of a series of well- known standard samples following the manufac- Patients studied turerÕs recommendation. In order to make sure All subjects studied were children who fulfilled that the effect seen is not an IVIG effect itself, we the criteria for KD (4) and were admitted for also measured the levels of IL-4, IL-5, and IVIG treatment at Chang Gung Memorial Hos- eotaxin in IVIG production (Gamimune N pital-Kaohsiung Medical Center from 2001 to 10%, Bayer Corporation, Elkhart, IN, USA) 2006. All patients were initially treated with a from eight different bottles of four different single dose of IVIG (2 g/kg) during a 12-h batches based on the normalization to average period. Aspirin (3–5 mg/kg/day) was given until blood immunoglobulin (Ig) G concentration all signs of inflammation were resolved or (2000 mg/dl) (14). The assay sensitivities of these regression of CAL under two-dimensional (2D) cytokines were 1.8 pg/ml of IL-4, 0.2 pg/ml of echocardiography was seen. This study was IL-5, and 1.4 pg/ml of eotaxin, respectively. To approved by the Institutional Review Board of avoid inter-assay bias of immunoassays, the Chang Gung Memorial Hospital. Blood samples cytokines in paired samples before and after were collected after informed consent was IVIG therapy were measured at the same time. obtained from the parents or guardians. Blood samples collected both before (within 24 h before IVIG treatment, pre-IVIG) and after IVIG Measurement of eosinophil activation mediator – ECP treatment (within 3 days after IVIG treatment, Concentrations of ECP were measured by post-IVIG) were subjected to this study. Patients Pharmacia CAP system fluoroimmunoassay whose symptoms did not fit the KD criteria, had (Pharmacia and Upjohn Diagnostics AB, an acute fever for less than 5 days, or incomplete Uppsala, Sweden) according to the instructions collection of pre- and post-IVIG blood samples of the manufacturer. In brief, 40 ll plasma were excluded. CAL was defined as the internal samples from the 95 KD patients and 30 diameter being at least 3 mm of the coronary controls as well as the eight different IVIG artery (4 mm if the subject was over the age of products were subjected to the automatic pro- 5 yr) or the internal diameter of a segment at cedure of analysis. least 1.5 times as large as that of an adjacent segment by echocardiogram (11, 12). We ana- lyzed the complete blood counts (CBC)/differen- Statistical analysis tial counts (DC) and C-reactive protein (CRP) from 95 KD patients and 30 age-matched febrile Data of CBC/DC and CRP levels between the KD controls (male/female = 16/14). Blood samples patients and controls were assessed by the from the febrile control patients who were StudentÕs t-test. Changes of IL-4, IL-5, eotaxin, admitted for upper and/or lower respiratory and ECP levels before and after IVIG treatment tract infections (including acute bronchiolitis, were tested by the paired sample t-test. Levels of acute pharyngitis, acute bronchitis, croup, and IL-4, IL-5, eotaxin, and ECP between KD patients acute tonsillitis) without a past history of allergic with and without CAL were tested by the Mann– disease were also included for comparison. Whitney U-test. Correlations between groups were tested by the PearsonÕs correlation. A p-value <0.05 was considered as statistically Measurement of eosinophil-related Th2 chemokines and significant. Data are presented as mean and cytokines by the Luminex-100 system standard error. All statistical tests were performed Plasma concentrations of IL-4, IL-5, and eotaxin using SPSS 12.0 for Windows XP (SPSS, Inc., were assessed by the Upstate Beadlyte Human Chicago, IL, USA). 267
  3. 3. Kuo et al. Results (12.07 ± 1.36 pg/ml vs. 28.55 ± 3.84 pg/ml, p < 0.001, Fig. 2a), IL-5 (5.17 ± 0.56 pg/ml Clinical features of the KD patients with and without CAL vs. 10.33 ± 0.92 pg/ml, p < 0.001, Fig. 2b), A total of 165 KD patients were admitted from and eotaxin (129.1 ± 14.3 pg/ml vs. 296.5 ± 2001 to 2006. Ninety-five of the KD patients 31.5 pg/ml, p < 0.001, Fig. 2c) were signifi- whose blood samples were collected both before cantly increased after IVIG treatment. In con- and after the IVIG treatment were enrolled in trast, the eosinophil activation mediator (ECP) this study. There were 31 girls (32.6%) and 64 levels were greatly decreased after IVIG treat- boys (67.4%). There were 20 patients (21.05%) ment (11.57 ± 1.98 pg/ml vs. 7.49 ± 1.22 pg/ with CAL formation. There were no significant ml, p = 0.03, Fig. 2d). difference of the rates of CAL formation between the study group (20/95) and the remainder KD Eosinophil and IL-5 but not CRP levels associated with KD with patients (13/70, p = 0.7). The age distribution of CAL after IVIG treatment KD patients with and without CAL was 18.36 ± 2.32 (median: 15.0 months) and 22.47 ± 1.55 After IVIG treatment, CRP levels decreased and (median: 17.0 months), respectively. The major revealed no significant difference between the KD clinical features including conjunctivitis, fissured patients with and without CAL (63.7 ± 8.4 mg/l lips, polymorphous skin rashes, indurative an- vs. 51.4 ± 4.3 mg/l, p = 0.15). In contrast, we gioedema of hands and feet, cervical lymphade- found that eosinophils were significantly higher nopathy, and Bacillus Calmette-Guerin (BCG) in the KD patients without CAL (5.09 ± 0.43% vaccination scar reaction between KD patients vs. 3.33 ± 0.54%; p = 0.03, Fig. 3a) than those with and without CAL showed no significant with CAL after IVIG treatment. The eosinophil- difference. There were also no difference between related Th2 cytokine (IL-5) was also significantly age distribution and total admission days higher in the KD patients without CAL than between the KD patients with and without CAL. those with CAL (11.4 ± 1.2 pg/ml vs. 5.5 ± 1.6 pg/ml; p = 0.02, Fig. 3b). The plasma levels of IL-4, eotaxin, and ECP between KD patients Peripheral leukocytes and eosinophil in the KD patients and with and without CAL showed no significant controls difference. Changes of eosinophils after IVIG The KD patients had higher leukocyte counts treatment had a positive correlation with changes and platelet counts than controls. There was a of IL-5 levels (p = 0.007, R2 = 0.19, Fig. 3c), significantly higher eosinophil percentage but had no significant correlation with changes (2.5 ± 0.2% vs. 0.4 ± 0.1%; p < 0.01) in KD of ECP levels (p = 0.29, Fig. 3d). patients than controls, but no statistical differ- ence in neutrophil, lymphocyte, monocyte, and Levels of cytokines: IL-4, IL-5, eotaxin, and ECP in the IVIG basophil percentages between the KD patients products and the controls (Table 1). The KD patients had lower hemoglobin levels than the controls. After In consideration of cytokines in the IVIG prod- IVIG treatment, eosinophils were greatly ucts, which may contribute to the elevation of increased (2.5 ± 0.2% vs. 4.7 ± 0.3%; p < 0.0- 01, Fig. 1), while the inflammatory marker CRP Table 1. Analysis of complete blood counts/differential counts in KD and age- levels were significantly decreased (105.7 ± 5.8 matched controls mg/L vs. 55.4 ± 4.1 mg/L; p < 0.001). Hence, experiments were next performed to assess eosin- KD (n = 95) Control (n = 30) p Values ophil-related Th2 cytokines and the eosinophil Total leukocyte/mm3 13792 € 733 9412 € 551 <0.01 activation mediator between the KD patients and Hemoglobin (g/dl) 10.8 € 0.1 12.2 € 0.1 <0.01 the controls as described below. Platelet (·104/mm3) 37.6 € 1.4 26.4 € 1.1 <0.01 Neutrophil (%) 65.9 € 1.4 62.4 € 2.7 0.23 Lymphocyte (%) 24.6 € 1.2 27.5 € 2.5 0.31 Eosinophil-related Th2 cytokines/eosinophils activation Monocyte (%) 5.7 € 0.3 6.8 € 0.7 0.20 mediator between the KD patients and controls Eosinophil (%) 2.5 € 0.2 0.4 € 0.1 <0.01 Basophil (%) 0.17 € 0.03 0.21 € 0.05 0.61 As shown in Table 2, we found that IL-4 (p < 0.001), IL-5 (p < 0.001), eotaxin (p = 0.004), Data in KD were measured before IVIG treatment (5.97 € 1.96 days after ECP (p < 0.001), and CRP (p = 0.003) were disease onset). Data in the control group were also collected in the acute stage of upper or lower respiratory tract infection (including acute bronchio- significantly higher in the KD patients before litis, acute pharyngitis, acute bronchitis, croup, and acute tonsillitis without IVIG treatment than the controls. Further past history of allergic disease). Values presented as mean € SE. p Values analysis found that the plasma levels of IL-4 were assessed by the StudentÕs t-test. 268
  4. 4. Role of eosinophil-related Th2 mediators in KD different studies (15–21), while the underlying mechanism of CAL remains unclear. Kawasaki et al. (22) first observed that 11 of 50 KD patients (22%) had eosinophilia in the peri- pheral blood. Terai et al. (8) found accumula- tion of eosinophils in the coronary micro-vessel lesions and eosinophilia in peripheral blood (PB) and postulated the involvement of eosin- ophils in the pathogenesis of KD vasculitis. We have recently shown that eosinophils were significantly elevated in KD both before and after IVIG treatment, and eosinophilia after IVIG treatment had an inverse correlation to the KD patients with IVIG-resistance (9). In this study, we have further shown that eosino- Fig. 1. Eosinophils were greatly increased after IVIG treat- phil-related Th2 mediators (IL-4, IL-5, and ment. Bars represent mean and standard error of mean eotaxin) increased, but ECP and CRP levels (n = 95, paired sample t test). IVIG, intravenous immuno- decreased after IVIG treatment in KD. globulin. Further analysis found that changes of eosin- ophil percentage after IVIG treatment were higher in KD patients without CAL than with Table 2. Comparison of eosinophil-related Th2 cytokines/eosinophil mediator CAL. The absolute cell counts of eosinophil were and CRP between the KD patients and age-matched controls not significantly different between the KD patients with and without CAL (367.1 ± 75.1 KD (n = 95) Control (n = 30) p value vs. 444.3 ± 48.5/mm3, p = 0.23, respectively). IL-4 (pg/ml) 12.07 € 1.36 5.96 € 0.54 <0.001 The higher eosinphil percentage in the KD IL-5 (pg/ml) 5.17 € 0.56 2.65 € 0.55 <0.001 patients without CAL may result from increased Eotaxin (pg/ml) 129.1 € 14.3 74.5 € 7.4 0.004 recruitment of eosinophils from the bone marrow ECP (pg/ml) 11.57 € 1.98 2.98 € 0.23 <0.001 CRP (mg/l) 105.7 € 5.8 39.5 € 14.8 0.003 or from the decrease of other leukocyte subpop- ulations. The changes of eosinophil percentage IL, interleukin; ECP, eosinophil cationic protein; CRP, C-reactive protein. Values were correlated to changes of IL-5 levels but not presented as mean € SE. p Values were assessed by the StudentÕs t-test. correlated to changes of ECP levels suggesting a Th2 reaction associated with an increase of eosinophil chemotactic factors but not eosinophil IL-4 and IL-5 levels after IVIG treatment, we activation factors associated with the decrease of measured IL-4, IL-5, eotaxin, and ECP levels in CAL in KD patients. The changes of absolute eight different bottles of four different batches of eosinophil counts did not positively correlate with IVIG products. Using a basis of the blood IgG changes of IL-5 levels (p = 0.12, R2 = 0.051). concentration at 2000 mg/dl, the ECP levels from This may be the reason that higher Th2 reaction eight different bottles of IVIG had a concentra- in KD could induce disproposrtion of eosinophils tion less than 2.0 pg/ml. The levels of IL-5, IL-4, but not eosinophil activation or absolute eosino- and eotaxin from eight different bottles of IVIG phil counts. This is compatible to our recent shown a median fluorescence intensity less than report that although a decline of total leukocyte basal fluorescence intensity detected by Luminex. count after IVIG treatment was found in both This suggests that exogenous cytokines in the KD patients with and without CAL, total leuko- IVIG preparation may not affect the levels of cyte count after IVIG treatment remained signif- blood cytokines that are measured 48–72 h after icant higher in KD patient with CAL (23). Taken IVIG treatment. together, a higher total leukocyte with lower eosinophil percentage after IVIG treatment is associated with CAL formation in KD patients. Discussion We have also measured the levels of IL-4, IL-5, A number of factors including prolonged fever, eotaxin, and ECP in IVIG products from eight young age, male gender, initially high CRP, different bottles. All cytokines were lower than higher neutrophil, and band form counts in KD those in plasma levels based on the normalization patients have been implicated in prediction of to average blood IgG concentration (2000 mg/ CAL (15–17). These predictors, however, dl). In consideration of the short half-life of revealed inconsistent correlation to CAL in cytokines of about 20 min in blood, the 269
  5. 5. Kuo et al. (a) (b) (c) (d) Fig. 2. Levels of eosinophil chemotactic factors and activation factor before and after IVIG treatment. Eosinophil-related Th2 mediators (IL-4, IL-5, and eotaxin) significantly increased after IVIG treatment (n = 95, p < 0.001) (a–c). Eosinophil activation mediator (ECP) significantly decreased after IVIG treatment (n = 95, p = 0.03) (d). Bars represent mean and standard error of mean. Values were tested by paired samples t-test. IVIG, intravenous immunoglobulin. exogenous cytokines in IVIG preparation may that release different cytokine profiles in response not affect the blood cytokines levels that are to different stimuli. They reciprocally constitute measured 48–72 h after IVIG treatment. There an immunoregulatory loop between Th1 and Th2 were four out of the 95 study KD patients had cytokines from Th1 cells inhibiting Th2 cells and allergy history before the diagnosis of KD. The vice versa (28). Th2 cells produce IL-4, IL-5, and Th2 cytokines measured in this study showed no other cytokines, which promote humeral immu- significant difference between KD patients with nity, allergic inflammation, and stimulate B cells and without allergic disease history (p > 0.1). to produce IgE as well as other Igs (29). In Therefore, the higher Th2 cytokines found in KD contrast, Th1 cells secrete IFN-c and IL-2, which patients may be the natural course of KD. initiate the killing of intracellular organisms and There are several lines of evidence pointing out viruses through activating cytotoxic T cells and an abnormal Th1/Th2 balance in KD patients. macrophages. In this study, we found that Th2 Brosius et al. (24) reported that the incidence of cytokines (IL-4, IL-5, and eotaxin) significantly atopic dermatitis among children with KD was increased in KD patients before and after IVIG nine times greater than that of controls. Serum treatment. It is controversial whether Th1 cyto- IgE and IL-4 levels were also significantly higher kines such as IFN-c increase or decrease in KD in KD patients than age-matched children (24– patients (30–32). It remains unclear why Th2 26). Matsubara et al. (27) found a decrease of mediators are increased but Th1 mediators do IFN-c expression in KD patients. These results not decrease in KD. We are the first to demon- suggest a skewed imbalance toward Th2 reaction strate that IL-5 and eosinophil levels were in KD. There are certain subpopulations of Th2s associated with the CAL in KD. Further studies 270
  6. 6. Role of eosinophil-related Th2 mediators in KD (a) (b) (c) (d) Fig. 3. Correlation of eosinophilia with IL-5 but not eosinophil cationic protein (ECP) levels in the KD patients before and after IVIG treatment. Eosinophils (p = 0.03) and IL-5 (p = 0.02) levels after IVIG treatment were significantly higher in the KD patients without CAL than with CAL (a, b) (Mann–Whitney U-test). Changes of eosinophils after IVIG treatment had a significant correlation with changes of IL-5 levels (p = 0.007, PearsonÕs correlation test, R2 = 0.19) but not significantly correlated with changes of ECP levels (p = 0.29) (c, d). Bars represent mean and standard error of mean. IVIG, intravenous immunoglobulin; CAL, coronary artery lesions; ECP, eosinophil cationic protein. to clarify whether genetic variants of Th2 genes this study, we found an increase in the Th2 are responsible for the susceptibility and mor- mediators (IL-4 and IL-5), but a decrease of bidity of KD are needed. ECP, was associated with eosinophilia and less Certain studies have shown that atheroscle- CAL formation in KD, suggesting eosinophilia rosis is related to a skewed Th1-like response in KD is a bystander of Th2 response, but not (33), and autoimmune disease such as BehcetÕs an effector of KD. disease is related to Th1 cytokine and pro- inflammatory cytokine (34, 35). We postulate Acknowledgment that the prominent Th2 reaction may be devel- This study was in part supported by a grant CCF07-01 from oped to combat the Th1-mediated vasculitis in the Foundation of Taiwanese Childhood Heart Diseases. KD after IVIG treatment. Th2-related cytokines such as IL-4 and IL-5 may not only suppress References Th1 reaction, but also promote B cell develop- 1. Kawasaki T, Kosaki F, Osawa S, Shigemitsu I, ment and eosinophil mobilization (28). We have Yanagawa S. A new infantile acute febrile mucocuta- previously shown that eosinophilia was associ- neous lymph node syndrome (MLNS) prevailing in ated with the less IVIG treatment failure (9); in Japan. Pediatrics 1974: 54: 271–6. 271
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