补体C3a、C5a及其受体在IgA肾病发病中的作用
摘要
背景和目的
1968年Berger首次发现IgA肾病(IgA nephropathy, IgAN)以来,IgAN已成为世界范围内最常见的一种原发性肾小球肾炎,北京大学第一医院统计资料显示在我国其发病率占所有原发性肾小球疾病的58.2%,IgAN并非良性过程,30%-40%IgAN患者在20年内会进展为终末期肾脏病。IgAN确切的发病机制至今尚不清楚。目前多数学者认为人类IgA1分子铰链区O-糖基化缺失,异常IgA1分子及其免疫复合物在肾小球系膜区沉积而导致IgAN。IgAN典型的临床特点为上呼吸道感染后1-3天内出现肉眼血尿,无论血循环中或肾小球系膜区沉积的异常IgA1分子,诱发机体获得性免疫反应需要一定的时间,完全由获得性免疫不能解释IgAN最典型的临床特点。日本一项510例肾移植前零点肾活检显示,16.1%健康供肾者存在肾小球系膜区IgA分子沉积,其中不伴C3沉积的则无现尿检异常,而伴有C3沉积的病例,出现微量白蛋白尿,且病理表现为系膜轻度增生和巨噬细胞浸润,提示肾小球系膜区IgA的沉积并不一定发生IgA肾病,而补体激活在IgA肾病发生中很可能有着不可或缺的作用。有文献报道补体通过旁路途径、MBL途径活化,参与IgA肾病的发病过程。补体活化过程中产生的C3a、C5a片段是补体活化过程中产生的最重要致炎症分子,本研究旨在探讨C3a、C5a在IgA肾病的发病机制中的作用,为进一步发现IgAN治疗的新靶点提供可能的理论依据。
方法
选取郑州大学第一附属医院肾脏内科2011年1月至12月住院行肾穿刺活检术,并经临床和病理诊断为IgAN患者的石蜡标本共83例,按照Lee氏病理分级标准,分为Ⅱ级(30例)、III级(30例)、Ⅳ级(23例),选取10例同期泌尿外科住院行肾脏肿瘤肾切除术患者远离肿瘤5cm以上的正常肾组织作为对照,采用免疫组织化学染色的方法分别检测IL-6、TNF-α、C3a、C5a、C3aR及C5aR在IgAN患者肾组织中的表达；收集这83例IgAN患者血清、尿液标本作为病例组,同时收集10例门诊体检健康成人血清、尿液标本作为正常对照,10例同期ICU住院确诊脓毒血症患者血清、尿液标本作为阳性对照,采用酶联免疫吸附双抗夹心法(enzyme linked immunosorbent assay-sandwich technique, ELISA)检测各组血清、尿液中C3a、C5a水平。
结果
(1)C3a、C5a在不同病理级别IgA肾病患者肾组织中沉积增多,且随病理严重程度增加而增多(P<0.05)。(2)C3aR、C5aR在不同病理级别IgAN患者肾组织中表达增强,且与病理损伤程度呈正比关系(P<0.05)。(3)IgAN患者肾组织中C3a、C5a的沉积分别与IL-6、TNF-a的表达呈正相关关系(P<0.05),且其相应受体C3aR、C5aR的表达亦与IL-6、TNF-α的表达呈现正相关关系。(4)C3a、C5a Ⅱ、Ⅲ、Ⅳ级IgAN、脓毒血症患者较健康人血清、尿液中C3a、C5a水平升高(P<0.05),且不同病理级别IgAN患者尿液中C3a、C5a水平与病理严重程度呈正比关系(P<0.05)。
结论
(1)C3a、C5a参与IgAN的发生,在IgAN的发展过程中有重要作用。
(2)C3a、C5a可能通过促进IgAN炎症反应的发生,影响IgAN进展。
Backgroud and Objective
IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide and leads to renal failure in a substantial number of patients. Recent studies have suggested that complement activation may play a part in the inflammatory injury process in IgAN. Complement activation products C3a and C5a have broad pro-inflammatory potential and contribute to the pathogenesis of several inflammatory and autoimmune diseases. However, their roles in IgAN are not well-defined. In this study, we investigated the role of C3a, C5a and their receptors in the pathogenesis of IgA nephropathy.
Methods
Eighty-three IgAN patients proved by renal biopsy were investigated,30patients as Lee's Ⅱ,30as Lee's Ⅲ,23as Lee's Ⅳ, meanwhile10cases of normal renal tissue from nephrectomy patients with kidney tumor were selected as controls. Immunhistochemistry of TNF-a and IL-6were performed to measure the pro-inflammatory mediators expression in the kidney tissue. The deposition of C3a and C5a was assessed using immunohistochemical staining. The expressions of C3aR and C5aR in renal tissue were detected respectively using immunohistochemical staining. These83IgA nephropathy patients'serum and urine samples were collected, meanwhile10healthy volunteers'as normal controls, and10sepsis patients' as positive controls. C3a and C5a levels in serum and urine in each group were detected respectively using ELIS A.
Results
(1) The deposition of C3a,C5a in renal tissue in IgAN increased with the degree of kidney pathological injury (P<0.05). Moreover, the deposition of C3a,C5a were proportional to the expression of TNF-a and IL-6(P<0.05).(2) Along with the increasing pathological injury levels, C3aR and C5aR expressed enhanced in renal tissue of IgAN patients. Furthermore, the expression had a positive correlation with the expression of TNF-a and IL-6(P<0.05).(3)The levels of serous and urinary C3a,C5a were significantly higher in those IgAN and sepsis patients than those healthy volunteers. Furthermore, the levels of urinary C3a,C5a in those IgAN patients were proportional to the degree of kidney pathological injury (P<0.05). However, it showed no significant difference between IgAN and sepsis patients (P>0.05).
Conclusions
(1) C3a and C5a play an important role in renal pathological injury and evidently contributes to the pathogenisis and progression of IgAN.
(2) C3a, C5a may promote the inflammatory response to induce the development of IgA nephropathy.
1968年Berger首次发现IgA肾病(IgA nephropathy, IgAN)以来,IgAN已成为世界范围内最常见的一种原发性肾小球肾炎,北京大学第一医院统计资料显示在我国其发病率占所有原发性肾小球疾病的58.2%,IgAN并非良性过程,30%-40%IgAN患者在20年内会进展为终末期肾脏病。IgAN确切的发病机制至今尚不清楚。目前多数学者认为人类IgA1分子铰链区O-糖基化缺失,异常IgA1分子及其免疫复合物在肾小球系膜区沉积而导致IgAN。IgAN典型的临床特点为上呼吸道感染后1-3天内出现肉眼血尿,无论血循环中或肾小球系膜区沉积的异常IgA1分子,诱发机体获得性免疫反应需要一定的时间,完全由获得性免疫不能解释IgAN最典型的临床特点。日本一项510例肾移植前零点肾活检显示,16.1%健康供肾者存在肾小球系膜区IgA分子沉积,其中不伴C3沉积的则无现尿检异常,而伴有C3沉积的病例,出现微量白蛋白尿,且病理表现为系膜轻度增生和巨噬细胞浸润,提示肾小球系膜区IgA的沉积并不一定发生IgA肾病,而补体激活在IgA肾病发生中很可能有着不可或缺的作用。有文献报道补体通过旁路途径、MBL途径活化,参与IgA肾病的发病过程。补体活化过程中产生的C3a、C5a片段是补体活化过程中产生的最重要致炎症分子,本研究旨在探讨C3a、C5a在IgA肾病的发病机制中的作用,为进一步发现IgAN治疗的新靶点提供可能的理论依据。
方法
选取郑州大学第一附属医院肾脏内科2011年1月至12月住院行肾穿刺活检术,并经临床和病理诊断为IgAN患者的石蜡标本共83例,按照Lee氏病理分级标准,分为Ⅱ级(30例)、III级(30例)、Ⅳ级(23例),选取10例同期泌尿外科住院行肾脏肿瘤肾切除术患者远离肿瘤5cm以上的正常肾组织作为对照,采用免疫组织化学染色的方法分别检测IL-6、TNF-α、C3a、C5a、C3aR及C5aR在IgAN患者肾组织中的表达；收集这83例IgAN患者血清、尿液标本作为病例组,同时收集10例门诊体检健康成人血清、尿液标本作为正常对照,10例同期ICU住院确诊脓毒血症患者血清、尿液标本作为阳性对照,采用酶联免疫吸附双抗夹心法(enzyme linked immunosorbent assay-sandwich technique, ELISA)检测各组血清、尿液中C3a、C5a水平。
结果
(1)C3a、C5a在不同病理级别IgA肾病患者肾组织中沉积增多,且随病理严重程度增加而增多(P<0.05)。(2)C3aR、C5aR在不同病理级别IgAN患者肾组织中表达增强,且与病理损伤程度呈正比关系(P<0.05)。(3)IgAN患者肾组织中C3a、C5a的沉积分别与IL-6、TNF-a的表达呈正相关关系(P<0.05),且其相应受体C3aR、C5aR的表达亦与IL-6、TNF-α的表达呈现正相关关系。(4)C3a、C5a Ⅱ、Ⅲ、Ⅳ级IgAN、脓毒血症患者较健康人血清、尿液中C3a、C5a水平升高(P<0.05),且不同病理级别IgAN患者尿液中C3a、C5a水平与病理严重程度呈正比关系(P<0.05)。
结论
(1)C3a、C5a参与IgAN的发生,在IgAN的发展过程中有重要作用。
(2)C3a、C5a可能通过促进IgAN炎症反应的发生,影响IgAN进展。
Backgroud and Objective
IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide and leads to renal failure in a substantial number of patients. Recent studies have suggested that complement activation may play a part in the inflammatory injury process in IgAN. Complement activation products C3a and C5a have broad pro-inflammatory potential and contribute to the pathogenesis of several inflammatory and autoimmune diseases. However, their roles in IgAN are not well-defined. In this study, we investigated the role of C3a, C5a and their receptors in the pathogenesis of IgA nephropathy.
Methods
Eighty-three IgAN patients proved by renal biopsy were investigated,30patients as Lee's Ⅱ,30as Lee's Ⅲ,23as Lee's Ⅳ, meanwhile10cases of normal renal tissue from nephrectomy patients with kidney tumor were selected as controls. Immunhistochemistry of TNF-a and IL-6were performed to measure the pro-inflammatory mediators expression in the kidney tissue. The deposition of C3a and C5a was assessed using immunohistochemical staining. The expressions of C3aR and C5aR in renal tissue were detected respectively using immunohistochemical staining. These83IgA nephropathy patients'serum and urine samples were collected, meanwhile10healthy volunteers'as normal controls, and10sepsis patients' as positive controls. C3a and C5a levels in serum and urine in each group were detected respectively using ELIS A.
Results
(1) The deposition of C3a,C5a in renal tissue in IgAN increased with the degree of kidney pathological injury (P<0.05). Moreover, the deposition of C3a,C5a were proportional to the expression of TNF-a and IL-6(P<0.05).(2) Along with the increasing pathological injury levels, C3aR and C5aR expressed enhanced in renal tissue of IgAN patients. Furthermore, the expression had a positive correlation with the expression of TNF-a and IL-6(P<0.05).(3)The levels of serous and urinary C3a,C5a were significantly higher in those IgAN and sepsis patients than those healthy volunteers. Furthermore, the levels of urinary C3a,C5a in those IgAN patients were proportional to the degree of kidney pathological injury (P<0.05). However, it showed no significant difference between IgAN and sepsis patients (P>0.05).
Conclusions
(1) C3a and C5a play an important role in renal pathological injury and evidently contributes to the pathogenisis and progression of IgAN.
(2) C3a, C5a may promote the inflammatory response to induce the development of IgA nephropathy.
引文
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