T淋巴细胞CD40L在川崎病发病机制中的作用研究
摘要
背景：川崎病（KD），是一种儿童较常见的血管炎综合征，由于在病程中、后期可发生冠状动脉损害（CAL），使其成为儿童后天性心脏病最常见的原因。本病的病因和发病机制尚不完全清楚。国内外普遍认为，T淋巴细胞异常活化是川崎病免疫激活导致血管免疫损伤的始动环节和关键步骤。在急性期（病程10天内）使用静脉注射免疫球蛋白（IVIG）能有效预防CAL发生，也提示急性期免疫紊乱在川崎病CAL发生中起重要作用。新近研究表明，儿童川崎病是成人冠状动脉粥样硬化的新型危险因素。基础和临床研究发现，T淋巴细胞CD40配体（CD40L）通过与多种靶细胞上CD40交联，在炎症反应中发挥重要作用，也在成人冠状动脉粥样硬化的发生发展中起核心作用。因此，本文研究T淋巴细胞CD40L在川崎病急性期血管炎的发病及冠状动脉病变中的作用。
目的 ：1观察急性期（IVIG治疗前）川崎病患儿T淋巴细胞表面CD40L表达水平，及IVIG治疗后CD40L的变化，探讨T淋巴细胞CD40L在急性期川崎病血管炎及冠状动脉病变发生中的可能作用。
2观察可溶性E选择素（sE-selectin）、可溶性细胞间粘附分子1（sICAM-1）、 基质金属蛋白酶9（MMP9）在IVIG治疗前、后川崎病患儿血浆中的变化，探明血浆中sE-selectin、sICAM-1、 MMP9是否可作为反映川崎病血管炎和预测冠状动脉病变的指标。
3 分析急性期川崎病患儿T淋巴细胞CD40L与血浆中
sE-selectin、sICAM-1、 MMP9的关系，初步探寻T淋巴细胞CD40L在急性期川崎病血管炎发病机制中的作用。
方法 ：1 用流式细胞术双标法，检测20例急性期及IVIG治疗后川崎病患儿，19例正常儿童T淋巴细胞CD40L表达的阳性细胞率及平均荧光强度。
2 用ELISA法，检测25例（其中20例同1）急性期及IVIG治疗后川崎病患儿，19例正常儿童血浆sE-selectin、sICAM-1、MMP9的水平。
3 将急性期川崎病T淋巴细胞CD40L表达水平与血浆中sE-selectin 、sICAM-1 、MMP9的水平作相关分析。
结果 ：1 急性期川崎病组T淋巴细胞表达CD40L阳性细胞率（27.91%±16.88%）及平均荧光强度（11.74±8.35）明显高于IVIG治疗后组（分别为23.09%±16.22%，P<0.05及8.18±6.71，P<0.01）；在体外培养系统中川崎病患儿T淋巴细胞CD40L表达较正常对照持久。
2 2例伴CAL的川崎病患儿，其急性期T淋巴细胞CD40L表达的阳性细胞率和平均荧光强度分别为54.62%，32.80及47.25%，18.40，高于无CAL者。
3急性期川崎病组血浆sICAM-1 (465.16±189.90ng/ml)、MMP9(180.00±119.08ng/ml)明显高于IVIG治疗后组(分别为417.78±163.05ng/ml及121.13±44.54ng/ml；P<0.05)，急性期川崎病患儿血浆sE-selectin （205.70±88.99ng/ml）、sICAM-1(465.16±189.90ng/ml)明显高于正常儿童（分别为135.85±39.54ng/ml及316.12±78.24ng/ml；P<0.05），急性期川崎病sICAM-1 、MMP9与sE-selectin有强相关关系（r分别为0.732，0.548；P<0.01）。
4 2例伴CAL的川崎病患儿，急性期其血浆sE-selectin、 sICAM-1、 MMP9水平（分别为277.5ng/ml、489.4ng/ml、176.4ng/ml 及127.5ng/ml、396.2ng/ml、105.6ng/ml），与无CAL者比较无明显差异。
5 急性期川崎病患儿T淋巴细胞CD40L表达水平与血浆中反映血管炎的指标sE-selectin 、sICAM-1 、MMP9，经相关分析无明确相关关系（P>0.05）。
结论： 1 T淋巴细胞CD40L在急性期川崎病患儿中有持续高表达现象，可能在川崎病急性期血管炎及冠状动脉病变中发挥一定作用。
2 川崎病患儿血浆sE-selectin 、sICAM-1 、MMP9水平可作为反映川崎病血管炎程度的指标
Background: Kawasaki disease (KD) is an acute, systemic vasculitis of unknown origin that affects primarily infants and young children. In untreated patients, there is a risk of coronary artery lesions (CAL) in the subacute and convalescent phase of the disease. KD is one of the most common causes of acquired heart disease in children. The etiology of this disease is still unknown. It is accepted that abnormal activation of T cell plays a central role in the pathogenesis of KD. High-dose intravenous immunoglobulin (IVIG) treatment within the first 10 d of the disease significantly reduces the frequency of CAL, which suggests over activation of immune system in the acute phase of KD is very important for CAL. Recently, it was hypothesized that Kawasaki disease was a risk factor for atherosclerosis in later life. Basic research found CD40 ligand (CD40L) on T cell had effects on inflammation by interaction with CD40 on target cells. And clinical research indicated that
the CD40-CD40L pathway was a key element in atherosclerosis.
Objective: The aim of the study was to investigate the role of T cell CD40L in the pathogenesis of vasculitis and CAL in KD.
1 To investigate the probable role of T cell CD40L in KD by observing the expression of CD40L on T cell in KD patient pre and post IVIG.
2 To investigate if plasma levels of soluble E-selectin (sE-selectin)，soluble intercellular adhesion molecule 1 (sICAM-1) and matrix metalloproteinase 9 (MMP9) can be used to reflect the degree of vasculitis of Kawasaki disease and if they can be used as predicators of CAL.
3 To investigate the effect of T cell CD40L in Kawasaki disease by correlation analysis between T cell CD40L and sE-selectin, sICAM-1 and MMP9 in the acute phase of KD.
Methods: 1 The expressions of CD40L on T cells were detected in 20 KD patients pre and post IVIG, and 19 normal children by 2-color flow cytometry.
2 The levels of plasma sE-selectin, sICAM-1 and MMP9 were detected by ELISA in 25 KD patients (including 20 patients mentioned above) pre and post IVIG and 19 normal children.
3 Correlation analysis was done between the expression of CD40L on T cell and plasma sE-selectin, sICAM-1 and MMP9 in the acute phase
of KD patients.
Results: 1 The percentage of T cells expressing CD40L and the mean fluorescence intensity of positive cells (MFI) of T cell CD40L expression were significantly higher compared pre-IVIG with post-IVIG in KD patients (27.91%±16.88% vs. 23.09%±16.22%(P<0.05), 11.74±8.35 vs. 8.18±6.71, (P<0.01)). The expressions of T cell CD40L in KD patients were prolonged compared with normal control.
2 The percentage of cells positive for CD40L and MFI for CD40L in 2 KD patients with CAL (54.62% and 32.80，47.25% and 18.40 , respectively) were higher than patients without CAL in the acute phase.
3 The plasma levels of sE-selectin (205.70±88.99ng/ml vs. 135.85±39.54ng/ml) and sICAM-1(465.16±189.90ng/ml vs. 316.12±78.24ng/ml) in the acute phase of KD patients were elevated in comparison to normal children (P<0.05). Paired analysis of KD patients pre and post IVIG revealed lowered levels of sICAM-1(465.16±189.90ng/ml vs. 417.78±163.05ng/ml, P<0.05) and MMP9 (180.00±119.08ng/ml vs. 121.13±44.54ng/ml, P<0.05). In the acute phase of KD, the plasma levels of sICAM-1(r=0.732, P<0.01) and MMP9(r=0.548, P<0.01) were related to the levels of sE-selectin.
4 The plasma levels of sE-selectin, sICAM-1 and MMP9 in 2 patients with CAL (277.5ng/ml, 489.4ng/ml, and 176.4ng/ml; 127.5ng/ml, 396.2ng/ml, and 105.6ng/ml, respectively) were not different from
patients without CAL in the acute phase.
5 Correlation was not found between T cell CD40L and plasma sE-selectin, sICAM-1 and MMP9 (P>0.05).
Conclusions: 1 The expression of CD40L on T cell is increased and prolonged in the acute phase of KD, it may probably play a role in the pathogenesis of vasculitis and coronary artery lesions of KD.
2 The plasma levels of sE-selectin, sICAM-1 and MMP9 may be used to reflect the degree of vasculitis of KD
目的 ：1观察急性期（IVIG治疗前）川崎病患儿T淋巴细胞表面CD40L表达水平，及IVIG治疗后CD40L的变化，探讨T淋巴细胞CD40L在急性期川崎病血管炎及冠状动脉病变发生中的可能作用。
2观察可溶性E选择素（sE-selectin）、可溶性细胞间粘附分子1（sICAM-1）、 基质金属蛋白酶9（MMP9）在IVIG治疗前、后川崎病患儿血浆中的变化，探明血浆中sE-selectin、sICAM-1、 MMP9是否可作为反映川崎病血管炎和预测冠状动脉病变的指标。
3 分析急性期川崎病患儿T淋巴细胞CD40L与血浆中
sE-selectin、sICAM-1、 MMP9的关系，初步探寻T淋巴细胞CD40L在急性期川崎病血管炎发病机制中的作用。
方法 ：1 用流式细胞术双标法，检测20例急性期及IVIG治疗后川崎病患儿，19例正常儿童T淋巴细胞CD40L表达的阳性细胞率及平均荧光强度。
2 用ELISA法，检测25例（其中20例同1）急性期及IVIG治疗后川崎病患儿，19例正常儿童血浆sE-selectin、sICAM-1、MMP9的水平。
3 将急性期川崎病T淋巴细胞CD40L表达水平与血浆中sE-selectin 、sICAM-1 、MMP9的水平作相关分析。
结果 ：1 急性期川崎病组T淋巴细胞表达CD40L阳性细胞率（27.91%±16.88%）及平均荧光强度（11.74±8.35）明显高于IVIG治疗后组（分别为23.09%±16.22%，P<0.05及8.18±6.71，P<0.01）；在体外培养系统中川崎病患儿T淋巴细胞CD40L表达较正常对照持久。
2 2例伴CAL的川崎病患儿，其急性期T淋巴细胞CD40L表达的阳性细胞率和平均荧光强度分别为54.62%，32.80及47.25%，18.40，高于无CAL者。
3急性期川崎病组血浆sICAM-1 (465.16±189.90ng/ml)、MMP9(180.00±119.08ng/ml)明显高于IVIG治疗后组(分别为417.78±163.05ng/ml及121.13±44.54ng/ml；P<0.05)，急性期川崎病患儿血浆sE-selectin （205.70±88.99ng/ml）、sICAM-1(465.16±189.90ng/ml)明显高于正常儿童（分别为135.85±39.54ng/ml及316.12±78.24ng/ml；P<0.05），急性期川崎病sICAM-1 、MMP9与sE-selectin有强相关关系（r分别为0.732，0.548；P<0.01）。
4 2例伴CAL的川崎病患儿，急性期其血浆sE-selectin、 sICAM-1、 MMP9水平（分别为277.5ng/ml、489.4ng/ml、176.4ng/ml 及127.5ng/ml、396.2ng/ml、105.6ng/ml），与无CAL者比较无明显差异。
5 急性期川崎病患儿T淋巴细胞CD40L表达水平与血浆中反映血管炎的指标sE-selectin 、sICAM-1 、MMP9，经相关分析无明确相关关系（P>0.05）。
结论： 1 T淋巴细胞CD40L在急性期川崎病患儿中有持续高表达现象，可能在川崎病急性期血管炎及冠状动脉病变中发挥一定作用。
2 川崎病患儿血浆sE-selectin 、sICAM-1 、MMP9水平可作为反映川崎病血管炎程度的指标
Background: Kawasaki disease (KD) is an acute, systemic vasculitis of unknown origin that affects primarily infants and young children. In untreated patients, there is a risk of coronary artery lesions (CAL) in the subacute and convalescent phase of the disease. KD is one of the most common causes of acquired heart disease in children. The etiology of this disease is still unknown. It is accepted that abnormal activation of T cell plays a central role in the pathogenesis of KD. High-dose intravenous immunoglobulin (IVIG) treatment within the first 10 d of the disease significantly reduces the frequency of CAL, which suggests over activation of immune system in the acute phase of KD is very important for CAL. Recently, it was hypothesized that Kawasaki disease was a risk factor for atherosclerosis in later life. Basic research found CD40 ligand (CD40L) on T cell had effects on inflammation by interaction with CD40 on target cells. And clinical research indicated that
the CD40-CD40L pathway was a key element in atherosclerosis.
Objective: The aim of the study was to investigate the role of T cell CD40L in the pathogenesis of vasculitis and CAL in KD.
1 To investigate the probable role of T cell CD40L in KD by observing the expression of CD40L on T cell in KD patient pre and post IVIG.
2 To investigate if plasma levels of soluble E-selectin (sE-selectin)，soluble intercellular adhesion molecule 1 (sICAM-1) and matrix metalloproteinase 9 (MMP9) can be used to reflect the degree of vasculitis of Kawasaki disease and if they can be used as predicators of CAL.
3 To investigate the effect of T cell CD40L in Kawasaki disease by correlation analysis between T cell CD40L and sE-selectin, sICAM-1 and MMP9 in the acute phase of KD.
Methods: 1 The expressions of CD40L on T cells were detected in 20 KD patients pre and post IVIG, and 19 normal children by 2-color flow cytometry.
2 The levels of plasma sE-selectin, sICAM-1 and MMP9 were detected by ELISA in 25 KD patients (including 20 patients mentioned above) pre and post IVIG and 19 normal children.
3 Correlation analysis was done between the expression of CD40L on T cell and plasma sE-selectin, sICAM-1 and MMP9 in the acute phase
of KD patients.
Results: 1 The percentage of T cells expressing CD40L and the mean fluorescence intensity of positive cells (MFI) of T cell CD40L expression were significantly higher compared pre-IVIG with post-IVIG in KD patients (27.91%±16.88% vs. 23.09%±16.22%(P<0.05), 11.74±8.35 vs. 8.18±6.71, (P<0.01)). The expressions of T cell CD40L in KD patients were prolonged compared with normal control.
2 The percentage of cells positive for CD40L and MFI for CD40L in 2 KD patients with CAL (54.62% and 32.80，47.25% and 18.40 , respectively) were higher than patients without CAL in the acute phase.
3 The plasma levels of sE-selectin (205.70±88.99ng/ml vs. 135.85±39.54ng/ml) and sICAM-1(465.16±189.90ng/ml vs. 316.12±78.24ng/ml) in the acute phase of KD patients were elevated in comparison to normal children (P<0.05). Paired analysis of KD patients pre and post IVIG revealed lowered levels of sICAM-1(465.16±189.90ng/ml vs. 417.78±163.05ng/ml, P<0.05) and MMP9 (180.00±119.08ng/ml vs. 121.13±44.54ng/ml, P<0.05). In the acute phase of KD, the plasma levels of sICAM-1(r=0.732, P<0.01) and MMP9(r=0.548, P<0.01) were related to the levels of sE-selectin.
4 The plasma levels of sE-selectin, sICAM-1 and MMP9 in 2 patients with CAL (277.5ng/ml, 489.4ng/ml, and 176.4ng/ml; 127.5ng/ml, 396.2ng/ml, and 105.6ng/ml, respectively) were not different from
patients without CAL in the acute phase.
5 Correlation was not found between T cell CD40L and plasma sE-selectin, sICAM-1 and MMP9 (P>0.05).
Conclusions: 1 The expression of CD40L on T cell is increased and prolonged in the acute phase of KD, it may probably play a role in the pathogenesis of vasculitis and coronary artery lesions of KD.
2 The plasma levels of sE-selectin, sICAM-1 and MMP9 may be used to reflect the degree of vasculitis of KD
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