Acute Post-Streptococcal Glomerulonephritis in Children: A Comprehensive Review 儿童急性链球菌后肾小球肾炎:综合评价
Sérgio Veloso Brant Pinheiro ^(1){ }^{1}, Victor Buchini de Freitas ^(2){ }^{2}, Gustavo Valverde de Castro ^(2){ }^{2}, Beatriz Cronemberger Rufino Madeiro ^(2){ }^{2}, Stanley Almeida de Araújo ^(3){ }^{3}, Thomas Felipe Silva Ribeiro ^(2){ }^{2} and Ana Cristina Simões e Silva ^(1,2,**){ }^{1,2, *} 塞尔吉奥·维罗索·布兰特·皮涅罗 ^(1){ }^{1} , 维克托·布基尼·德·弗雷塔斯 ^(2){ }^{2} , 古斯塔沃·巴尔韦德·德·卡斯特罗 ^(2){ }^{2} , 比阿特丽斯·克罗南贝格 ^(2){ }^{2} 鲁菲诺·马德罗 , 斯坦利·阿尔梅达·德·阿劳霍 ^(3){ }^{3} , 托马斯·费利普·席尔瓦·里贝罗 ^(2){ }^{2} 和 安娜·克里斯蒂娜·西蒙斯 e 席尔瓦 ^(1,2,**){ }^{1,2, *}
^("l "){ }^{\text {l }} Department of Pediatrics, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; ^(2){ }^{2} Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, UFMG, Belo Horizonte, MG, Brazil; ^(3){ }^{3} Institute of Nephropatology & Center of Electronic Microscopy, UFMG, Belo Horizonte, MG, Brazil ^("l "){ }^{\text {l }} 巴西米纳斯吉拉斯联邦大学 (UFMG) 医学院儿科、儿科肾脏病科; ^(2){ }^{2} 巴西 MG 贝洛奥里藏特 UFMG 医学院医学调查跨学科实验室; ^(3){ }^{3} 巴西贝洛奥里藏特的 UFMG 肾病学研究所和电子显微镜中心
ARTICLE HISTORY 文章历史
Received: November 02, 2021 收稿日期: 2021-11-02
Revised: February 23, 2022 修订日期:2022 年 2 月 23 日
Accepted: March 17, 2022 录用日期: 2022-03-17
DOI: 二:
10.2174/0929867329666220613103316
Abstract 抽象
Background: Acute post-streptococcal glomerulonephritis (APSGN) is an im-mune-complex (ICs) mediated glomerular disease triggered by group A beta\beta-hemolytic streptococcus (GAS) or Streptococcus pyogenes infections. APSGN represents a major cause of acquired kidney injury in children. 背景:急性链球菌后肾小球肾炎 (APSGN) 是一种免疫复合物 (ICs) 介导的肾小球疾病,由 A beta\beta 组溶血性链球菌 (GAS) 或化脓性链球菌感染引发。APSGN 是儿童获得性肾损伤的主要原因。
Methods: This non-systematic review summarizes recent evidence on APSGN. We discuss the epidemiology, pathogenesis, clinical and laboratory findings, histopathology, treatment and prognosis of the disease. 方法: 本非系统综述总结了 APSGN 的最新证据。我们讨论了该病的流行病学、发病机制、临床和实验室检查结果、组织病理学、治疗和预后。
Results: The median APSGN incidence in children in developing countries is estimated at 24.3//100,00024.3 / 100,000 per year, compared with 6.2//100,0006.2 / 100,000 per year in developed countries. Nephritis-associated plasmin receptor, identified as glyceraldehyde-3-phosphate dehydrogenase, and the cationic cysteine proteinase streptococcal pyrogenic exotoxin B are thought to be two leading streptococcal antigens involved in the pathogenesis of APSGN, which activate the complement system, mainly via the alternative but also the lectin pathway. This process is critical for the generation of inflammation by the ICs deposited in the glomerulus. The classic phenotype is an acute diffuse proliferative glomerulonephritis leading to features of the nephritic syndrome, including hematuria, oliguria, hypertension and edema. The histopathology shows that the glomeruli are diffusely affected, mostly presenting enlarged glomerular tuffs due to hypercellularity. Proliferative endothelial and mesangial cells and inflammation have also been observed. APSGN frequently has spontaneous recovery. There is no specific therapy, but its morbidity and mortality are drastically reduced by the prevention and/or treatment of complications. 结果: 与发达国家相比,发展中国家儿童 APSGN 发病率的中位数估计为 24.3//100,00024.3 / 100,000 每年 6.2//100,0006.2 / 100,000 。肾炎相关纤溶酶受体,鉴定为 甘油醛-3-磷酸脱氢酶,和阳离子半胱氨酸蛋白酶链球菌热原外毒素 B 被认为是参与 APSGN 发病机制的两种主要链球菌抗原,它们主要通过替代途径和凝集素途径激活补体系统。这个过程对于沉积在肾小球中的 IC 产生炎症至关重要。典型表型是急性弥漫性增生性肾小球肾炎,导致肾炎综合征的特征,包括血尿、少尿、高血压和水肿。组织病理学显示肾小球受弥漫性受累,由于细胞增多,主要表现为增大的肾小球凝灰岩。还观察到增殖性内皮细胞和系膜细胞以及炎症。APSGN 经常自发恢复。没有特异性疗法,但通过预防和/或治疗并发症,其发病率和死亡率大大降低。
Conclusion: Despite recent advances, the pathogenesis of APSGN is not fully understood. There is no specific treatment for APSGN. The prognosis is generally good. However, some cases may evolve into chronic kidney disease. 结论: 尽管最近取得了进展,但 APSGN 的发病机制尚不完全清楚。APSGN 没有特定的治疗方法。预后通常良好。然而,有些病例可能会演变成慢性肾病。
Acute post-streptococcal glomerulonephritis (APSGN) is an immune-complex mediated glomerular disease triggered by group A beta\beta-hemolytic streptococcus 急性链球菌后肾小球肾炎 (APSGN) 是一种由 A beta\beta 族溶血性链球菌引发的免疫复合物介导的肾小球疾病
(GAS) or Streptococcus pyogenes infections [1-4]. APSGN represents a major cause of acquired kidney injury in children [1-4]. The essential pathophysiological mechanism comprises the activation of the complement system by the nephritogenic antigens of GAS [4-7]. The activation of the complement system involves mainly the alternative, but also the lectin pathways. This process is critical for the generation of inflammation by the immune complexes (ICs) deposited (GAS) 或化脓性链球菌感染 [1-4]。APSGN 是儿童获得性肾损伤的主要原因 [1-4]。基本的病理生理机制包括 GAS 的产肾抗原激活补体系统 [4-7]。补体系统的激活主要涉及替代途径,但也涉及凝集素途径。这个过程对于沉积的免疫复合物 (IC) 产生炎症至关重要
in the glomerulus [4-7]. Inflammatory response is characterized by an influx of effector immune cells, the release of cytokines, and secretion of proteases, which collectively damage the glomerular structure and function [4-7]. The classic phenotype is an acute diffuse proliferative glomerulonephritis (GN) typically leading to features of the nephritic syndrome, including hematuria, oliguria, hypertension, edema, and variable degrees of proteinuria [4-7]. 在肾小球中[4-7]。炎症反应的特征是效应免疫细胞流入、细胞因子释放和蛋白酶分泌,这些因素共同损害肾小球结构和功能[4-7]。典型表型为急性弥漫性增生性肾小球肾炎(glomerulonephritis, GN),通常可导致肾炎综合征的特征,包括血尿、少尿、高血压、水肿和不同程度的蛋白尿[4-7]。
APSGN is one of the most important and intriguing renal conditions in children. It accounts for more than 95%95 \% of infection-associated GN in children [8, 9]. Its incidence has decreased over the last few decades due to improvements in living standards and socioeconomic conditions, which reduced the transmission of infection and prevented disease epidemics [4, 5, 9-11]. Although the outcome is very good in most cases, APSGN remains an important cause of acute kidney injury (AKI) and hospitalization for children in low and mid-dle-income regions [4, 9]. Moreover, some authors suggest an APSGN episode in childhood as a risk factor for chronic kidney disease (CKD) [12-14]. Of note, recent studies have unveiled some critical pathogenic processes related to the activation of the complement system [15, 16]. APSGN 是儿童最重要和最有趣的肾脏疾病之一。它在儿童感染相关 GN 中的占比更大 95%95 \% [8, 9]。由于生活水平和社会经济条件的改善,其发病率在过去几十年中有所下降,这减少了感染的传播并预防了疾病流行 [4, 5, 9-11]。尽管在大多数情况下预后非常好,但 APSGN 仍然是中低收入地区儿童急性肾损伤 (AKI) 和住院的重要原因 [4, 9]。此外,一些作者认为儿童期 APSGN 发作是慢性肾脏病 (CKD) 的危险因素 [12-14]。值得注意的是,最近的研究揭示了一些与补体系统激活相关的关键致病过程 [15, 16]。
This review aimed to describe the general and particular features of APSGN in children and adolescents and shed light on the pathogenesis, clinical manifestations, histopathology, treatment, and long-term outcomes. 本综述旨在描述 APSGN 在儿童和青少年中的一般和特殊特征,并阐明其发病机制、临床表现、组织病理学、治疗和远期结局。
2. EPIDEMIOLOGY 2. 流行病学
In past decades, the epidemiology of APSGN has changed along with a decrease in its incidence worldwide and particularly in developed countries, where the disease is now uncommon [1,4,10,11,17,18][1,4,10,11,17,18]. Currently, APSGN can be considered a marker of socioeconomic development [1,4,5,18][1,4,5,18]. According to the World Health Organization (WHO), of the estimated 470,000 new annual cases of APSGN worldwide, 77%77 \% occur in low and middle-income areas [1, 4, 5, 18]. The median APSGN incidence in children in developing countries is estimated at 24.3//100,00024.3 / 100,000 per year, compared with 6.2//100,0006.2 / 100,000 per year in developed countries [4, 18-21]. Moreover, 97% of deaths by APSGN (complicating about 1%1 \% of cases) occur in low-resource countries [18, 19]. Globally, APSGN continues to be the most common cause of acute nephritis in children, but mainly in developing countries [1,4,10,11[1,4,10,11, 17, 21]. 在过去的几十年里,APSGN 的流行病学发生了变化,其在全球范围内发病率下降,尤其是在发达国家,这种疾病现在并不常见 [1,4,10,11,17,18][1,4,10,11,17,18] 。目前,APSGN 可以被视为社会经济发展的标志 [1,4,5,18][1,4,5,18] 。根据世界卫生组织 (WHO) 的数据,全球每年估计有 470,000 例 APSGN 新病例 77%77 \% 发生在低收入和中等收入地区 [1, 4, 5, 18]。据估计,发展中国家儿童 APSGN 的中位发病率为 24.3//100,00024.3 / 100,000 每年,而 6.2//100,0006.2 / 100,000 发达国家为每年 [4, 18-21]。此外,APSGN 97% 的死亡(使 1%1 \% 病例复杂化)发生在资源匮乏的国家 [18, 19]。在全球范围内,APSGN 仍然是儿童急性肾炎的最常见原因,但主要在发展中国家 [1,4,10,11[1,4,10,11 ,17,21]。
In the majority of cases, APSGN is subclinical, which is thought to be 4 to 19 times more common than symptomatic disease [4, 22]. APSGN is usually 在大多数情况下,APSGN 是亚临床的,被认为比有症状的疾病常见 4 至 19 倍 [4, 22]。APSGN 通常为
initiated by upper respiratory tract infections (such as pharyngitis and tonsillitis) in colder climates and by skin infections or superimposed bacterial infection of skin disorders in warmer climates [4, 5, 7, 21]. It may occur as sporadic cases or as epidemic outbreaks [1, 4, 5]. Pyoderma-associated APSGN prevails in tropical areas, where streptococcal skin infections may be endemic [1, 4, 5]. In contrast, pharyngitis/tonsillitis-associated APSGN predominates in more temperate areas [1, 4, 5, 23, 24]. Interestingly, the risk of nephritis in epidemics ranges from 5%5 \% in throat infections to as high as 25%25 \% in pyoderma caused by a specific M-type GAS [1, 4, 21, 25-27]. It should also be noted that the incidence of APSGN remains extremely high in some isolated communities, including natives from Australia and New Zealand, some Pacific Islanders and African tribes [4, 28]. Consequently, ethnic background, socioeconomic conditions, living standards, hygiene practices and access to health care were significantly associated with disease incidence [1,4,5,29,30][1,4,5,29,30]. 在较冷的气候下由上呼吸道感染(如咽炎和扁桃体炎)引发,在较温暖的气候下由皮肤感染或皮肤病的重叠细菌感染引发[4,5,7,21]。它可能以散发病例或流行病暴发的形式发生 [1, 4, 5]。脓皮病相关 APSGN 在热带地区普遍存在,那里可能流行链球菌性皮肤感染 [1, 4, 5]。相比之下,咽炎/扁桃体炎相关的 APSGN 在温带地区占主导地位 [1, 4, 5, 23, 24]。有趣的是,流行病中肾炎的风险从 5%5 \% 咽喉感染到由 25%25 \% 特定 M 型 GAS 引起的脓皮病不等 [1, 4, 21, 25-27]。还应注意的是,在一些孤立社区,包括来自澳大利亚和新西兰的土著、一些太平洋岛民和非洲部落,APSGN 的发病率仍然非常高 [4, 28]。因此,种族背景、社会经济条件、生活水平、卫生习惯和获得医疗保健的机会与疾病发病率显著相关 [1,4,5,29,30][1,4,5,29,30] 。
3. PATHOGENESIS 3. 发病机制
APSGN is an acute GN caused by streptococcal skin or upper respiratory tract infection. The inflammatory process develops sometime after the resolution of the infectious disease and results from the immune response against bacterial antigens [4, 5, 7, 21]. Certain strains of streptococcus are more likely to trigger APSGN [4,5,28,31][4,5,28,31]. Many of them have been identified from epidemic outbreaks of APSGN in different communities [28, 31]. The M-protein is a surface antigen located on the bacterial cell wall that serves as the basis for the determination of the GAS M type [28, 31]. Currently, there are more than 250 M types of GAS with over 1,900 distinct M sub-types [31]. Classically, GAS M types 49, 55, 57 and 60 are the main agents of pyoderma-associated APSGN, whereas GAS M types 1,2,4 and 12 are the major cause of APSGN triggered by pharyngitis/tonsillitis [4, 5, 28, 31]. A systematic review has recently evaluated the global distribution of APSGN-associated GAS and identified 46 M types that cause GN [31]. On the other hand, many other M types of GAS may not induce APSGN [5, 28]. The association of APSGN with acute rheumatic fever in the same patient, although occasionally reported, remains a rare event, and subsequent episodes of APSGN occur exceptionally [16,28][16,28]. Of note is the fact that infections by other streptococci, including Streptococcus zooepidemicus, Streptococcus pneumonia, Streptococcus constellatus and Streptococcus anginosus, may also lead to APSGN [4, 16, 32-37]. Thus, M-protein does not appear to be a putative antigen implicated in the generation of the APSGN [5]. APSGN 是由链球菌皮肤或上呼吸道感染引起的急性 GN。炎症过程在传染病消退后的某个时间发展,由对细菌抗原的免疫反应引起 [4, 5, 7, 21]。某些链球菌菌株更有可能触发 APSGN [4,5,28,31][4,5,28,31] 。其中许多是从不同社区的 APSGN 流行病爆发中发现的 [28, 31]。M 蛋白是位于细菌细胞壁上的表面抗原,是确定 GAS M 型的基础 [28, 31]。目前,GAS 有超过 250 种 M 类型,其中有 1,900 多种不同的 M 亚型 [31]。通常,GAS M 49、55、57 和 60 型是脓皮病相关 APSGN 的主要病原体,而 GAS M 1、2、4 和 12 型是咽炎/扁桃体炎引发 APSGN 的主要原因 [4, 5, 28, 31]。最近一项系统评价评估了 APSGN 相关 GAS 的全球分布,并确定了 46 种导致 GN 的 M 型 [31]。另一方面,许多其他 M 型 GAS 可能不会诱导 APSGN [5, 28]。APSGN 与同一患者的急性风湿热的关联,虽然偶尔报道,但仍然是一种罕见的事件,随后的 APSGN 发作异常 [16,28][16,28] 。值得注意的是,其他链球菌感染,包括动物流行性链球菌、肺炎链球菌、星形链球菌和心绞痛链球菌感染,也可能导致 APSGN [4, 16, 32-37]。因此,M 蛋白似乎不是与 APSGN 的产生有关的推定抗原 [5]。
Nephritis-associated plasmin receptor (NAPlr), identified as glyceraldehyde- 3 -phosphate dehydrogenase, and the cationic cysteine proteinase streptococcal pyrogenic exotoxin B (SPEB) are thought to be two leading streptococcal antigens involved in the pathogenesis of APSGN [5, 16, 38-43]. Accordingly, high titers of antibodies against NAPlr and SPEB were detected in the serum of convalescent patients with APSGN, and were co-localized with plasmin (NAPlr), or complement C3 and immunoglobulin (Ig) G against SPEB in the glomeruli of affected patients [5, 16, 39, 40]. SPEB was also demonstrated within the classic subepithelial hump in glomeruli of patients with APSGN [5, 42]. Moreover, both antigens induce the release of matrix metalloproteinases (MMPs) and collagenases, and the production of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 by mesangial cells in association with overexpression of adhesion molecules. Peripheral blood leukocytes can then be attracted and infiltrate the renal mesangium, contributing to the amplification of the local inflammatory response through the release of IL-6, tumor necrosis factor (TN-F)-alpha\mathrm{F})-\alpha, IL- 8 , and transforming growth factor (TGF)- beta[4\beta[4, 5,16]. Consequently, changes in the mesangial extracellular matrix (ECM) and glomerular basement membrane (GBM) occur, allowing the IC to reach the filtration barrier and accumulate as subepithelial humps [4, 5, 16]. Although significant evidence supports the nephritogenicity of these streptococcal antigens, SPEB may not be the main nephritogenic antigen in some patients with APSGN. The gene encoding SPEB was not isolated from strains of streptococci in the APSGN outbreak in the Brazilian city of Nova Serrana [43]. 肾炎相关纤溶酶受体 (NAPlr),鉴定为甘油醛-3-磷酸脱氢酶,和阳离子半胱氨酸蛋白酶链球菌热原外毒素 B (SPEB) 被认为是参与 APSGN 发病机制的两种主要链球菌抗原 [5, 16, 38-43]。因此,在 APSGN 恢复期患者的血清中检测到高滴度的 NAPlr 和 SPEB 抗体,并与纤溶酶 (NAPlr) 或补体 C3 和免疫球蛋白 (Ig) G 共定位于受影响患者肾小球中的抗 SPEB [5, 16, 39, 40]。SPEB 也出现在 APSGN 患者肾小球的典型上皮下隆起内 [5, 42]。此外,这两种抗原都诱导基质金属蛋白酶 (MMP) 和胶原酶的释放,以及系膜细胞产生单核细胞趋化蛋白 (MCP)-1 和白细胞介素 (IL)-6,这与粘附分子的过表达有关。然后外周血白细胞可以被吸引并浸润肾系膜,通过释放 IL-6、肿瘤坏死因子(TN- F)-alpha\mathrm{F})-\alpha 、IL-8 和转化生长因子 (TGF)- beta[4\beta[4 ,5,16] 促进局部炎症反应的放大。因此,系膜细胞外基质 (ECM) 和肾小球基底膜 (GBM) 发生变化,使 IC 能够到达滤过屏障并积聚为上皮下隆起 [4, 5, 16]。尽管重要证据支持这些链球菌抗原的致肾性,但 SPEB 可能不是某些 APSGN 患者的主要致肾抗原。编码 SPEB 的基因并未从巴西新塞拉纳市 APSGN 暴发的链球菌菌株中分离出来 [43]。
Exogenous antigens are pivotal agents for the formation of subepithelial ICs in APSGN. However, the intense exudative glomerular inflammatory response observed in patients with APSGN is not well explained by passively trapped circulating ICs and humps [4, 5, 44, 45]. Accordingly, circulating ICs do not directly form subepithelial deposits. In turn, subepithelial ICs deposits do not appear to produce inflammation [44-49]. In addition, IgG is sometimes absent or is only a minor constituent of the deposits, whereas C3 deposition often both precedes and exceeds detectable IgG in the kidneys of patients with APSGN [38, 50, 51]. Thus, the current concept is that ICs may be formed from the binding of antibodies to soluble streptococcal antigens that become localized independently in the glomerulus, on the basis of nonspecific uptake by the mesangium or charge interactions with anionic sites [4, 5, 44, 45]. Of note is the fact that cross-reactivity of streptococcal antigens and the GBM components, laminin and type IV collagen, has been demons- 外源性抗原是 APSGN 中形成上皮下 IC 的关键因子。然而,在 APSGN 患者中观察到的强烈渗出性肾小球炎症反应并不能用被动捕获的循环 IC 和驼峰来解释 [4, 5, 44, 45]。因此,循环 IC 不会直接形成上皮下沉积物。反过来,上皮下 IC 沉积似乎不会产生炎症 [44-49]。此外,IgG 有时不存在或只是沉积物的次要成分,而 C3 沉积通常先于或超过 APSGN 患者肾脏中可检测到的 IgG [38, 50, 51]。因此,目前的概念是,IC 可能是由抗体与可溶性链球菌抗原结合形成的,这些链球菌抗原根据系膜的非特异性摄取或与阴离子位点的电荷相互作用而独立定位于肾小球中 [4, 5, 44, 45]。值得注意的是,链球菌抗原和 GBM 成分、层粘连蛋白和 IV 型胶原蛋白的交叉反应性一直是恶魔-
trated before [5, 52]. Although few studies have evaluated the cross-reactivity of streptococcal and constituents of normal glomerular structures, the possibility that these antigens contribute to the formation of subepithelial deposits in APSGN cannot be excluded [5, 52]. 在 [5, 52] 之前。尽管很少有研究评估链球菌和正常肾小球结构成分的交叉反应性,但不能排除这些抗原有助于 APSGN 中上皮下沉积物形成的可能性 [5, 52]。
Complement activation is a central element in the generation of inflammation by the IC deposited in the glomerulus of patients with APSGN [4, 5, 44, 45, 53, 54]. The reduction in serum C3 levels is one of the universal characteristics of the acute phase of APSGN. As serum C 1 q and C 4 levels are usually within the normal range, the decline in the circulating level of C3 indicates transient activation of the alternative pathway of the complement system [4, 5, 44, 45]. Briefly, the alternative pathway (Fig. 1) initiates when water binds and hydrolyses C3 - a process called “tickover”, forming a molecule with C3 convertase activity [ C3(H_(2)O)\mathrm{C} 3\left(\mathrm{H}_{2} \mathrm{O}\right) ] [53, 54]. Hydrolyzed C3 is formed spontaneously or after contact with surfaces and then reacts with factor B [53, 54]. Factor B (FB) is cleaved by factor D , yielding the noncatalytic portion Ba and the active fragment Bb . The Bb fragment comprises two protein domains: a von Willebrand (vW) type A domain, which associates with C 3 b to form the C 3 convertase C 3 bBb , and an SP domain cleaves additional C3 [53, 54]. C3b generated by this convertase can, itself, form more C 3 bBb , providing further amplification of this process [53, 54]. This feedback mechanism results in robust amplification of the initial complement response, and as more C 3 bBb forms, the terminal pathway is activated by the generation of C 3 bBbC 3 b (and small amounts of C4b2aC3b) [53,54]. It is important to mention that C3 and factor B exist in high concentrations in the plasma, and, even so, the C3b generated from the “tickover” process does not spontaneously activate the alternative pathway in the presence of factor B [55]. This balance reflects the existence of fine mechanisms for self-control of the complement system [55, 56]. Accordingly, C 3 bBb , once formed, is so quickly degraded since its half-life is only ∼90\sim 90 seconds [55, 57]. A number of regulators of complement activation tightly control this process and inactivates C 3 b , including the factor I and its cofactors: membrane cofactor protein (MCP, or CD46), C receptor 1 (CR1), and the most abundant factor H , which controls complement in both the fluid phase and on cell surfaces [53-55] (Fig. 1). In addition, Factor H is also a decay accelerator for C3 convertase (C3bBb) and, together with C4 binding protein C4BP, a decay accelerator for C 3 convertase ( C 4 b 2 a ), counter regulates the activation of all complement pathways [53-55] 补体激活是 APSGN 患者肾小球中沉积的 IC 产生炎症的核心因素 [4, 5, 44, 45, 53, 54]。血清 C3 水平降低是 APSGN 急性期的普遍特征之一。由于血清 C 1 q 和 C 4 水平通常在正常范围内,因此 C3 循环水平的下降表明补体系统的替代途径短暂激活 [4, 5, 44, 45]。简而言之,当水结合并水解 C3 时,替代途径(图 1)开始——这一过程称为“豌豆溢出”,形成具有 C3 转化酶活性的分子 [ C3(H_(2)O)\mathrm{C} 3\left(\mathrm{H}_{2} \mathrm{O}\right) ] [53, 54]。水解的 C3 是自发形成的或与表面接触后形成的,然后与因子 B 反应[53,54]。因子 B (FB) 被因子 D 裂解,产生非催化部分 Ba 和活性片段 Bb 。Bb 片段包含两个蛋白质结构域:一个 von Willebrand (vW) A 型结构域,它与 C 3 b 结合形成 C 3 转化酶 C 3 bBb ,以及一个 SP 结构域裂解额外的 C3 [53, 54]。这种转化酶产生的 C3b 本身可以形成更多的 C 3 bBb ,从而进一步扩增这一过程 [53, 54]。这种反馈机制导致初始补体反应的稳健扩增,随着更多的 C 3 bBb 形成,末端通路被 C 3 bBbC 3 b(和少量 C4b2aC3b)的产生激活 [53,54]。值得一提的是,C3 和因子 B 在血浆中以高浓度存在,即便如此,在因子 B 存在的情况下,“tickover”过程产生的 C3b 不会自发激活替代途径 [55]。这种平衡反映了补体系统自我控制的良好机制的存在[55,56]。 因此,C 3 bBb 一旦形成,就会迅速降解,因为它的半衰期只有 ∼90\sim 90 几秒钟 [55, 57]。补体激活的许多调节因子严格控制这一过程并使 C 3 b 失活,包括因子 I 及其辅因子:膜辅因子蛋白(MCP 或 CD46)、C 受体 1 (CR1) 和最丰富的因子 H ,它控制液相和细胞表面的补体 [53-55](图 1)。此外,因子 H 还是 C3 转化酶 (C3bBb) 的衰变促进剂,并且与 C4 结合蛋白 C4BP 一起是 C 3 转化酶 (C 4 b 2 a) 的衰变促进剂,可反调节所有补体途径的激活 [53-55]
*Address correspondence to this author at the Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, UFMG, Avenida Alfredo Balena, 190, 2^("nd ")2^{\text {nd }} floor, room #281, Belo Horizonte, MG, Zip Code: 30130-100, Brazil, Tel: +55-31-34098073, E-mail: acssilva@hotmail.com *写给作者的信件地址是:UFMG 医学院医学调查跨学科实验室,Avenida Alfredo Balena,190,floor,room 2^("nd ")2^{\text {nd }} #281,Belo Horizonte,MG,邮编:30130-100,巴西,电话:+55-31-34098073,电子邮件:acssilva@hotmail.com