Can a dysregulated mucosal immune system in IgA nephropathy be controlled by tonsillectomy?
Can a dysregulated mucosal immune system in IgA nephropathy be controlled by tonsillectomy?
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DOI：
10.1093/ndt/gfq266
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发表时间：
2010-08-01
影响因子：
6.1
通讯作者：
Coppo, Rosanna
中科院分区：
文献类型：
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作者：
Coppo, Rosanna
尽管根据定义，IgA 肾病 (IgAN) 是一种需要在免疫组织学中进行肾活检组织检查的诊断，但在上呼吸道或胃肠道感染后同时或立即检测到的肉眼血尿的情况下，可能有充分根据的怀疑。许多年前，有人认为 IgAN 的这一特征支持了这样的假设：通过免疫组织学检测到的聚合 IgA 的系膜沉积是由于粘膜免疫系统对环境病原体的反应所致 [1]。粘膜（或先天）免疫通过吞噬细胞上表达的 Toll 样受体 (TLR) 识别病原体相关分子模式来发挥作用，有利于病毒或细菌的清除。 TLRs的激活诱导树突状细胞成熟并迁移至淋巴结，导致特异性T细胞的激活和抗体合成，从而促进粘膜和全身水平的先天性免疫和适应性免疫之间的联系[2]。然而，一般人群中病毒综合征的高发病率与 IgAN 的低患病率之间的差异表明，粘膜和/或全身免疫系统的异常对于 IgAN 的发展至关重要，而感染是触发事件。已证明，只有在粘膜耐受的自然过程被废除后，重复暴露于各种感染原才会在动物中诱导实验性 IgAN，粘膜耐受的自然过程有利于长期病原体暴露后的宿主防御[3]。根据关于粘膜耐受性检测作用的假设，IgAN 患者的粘膜抗原消除能力受损，导致持续的抗原攻击，从而引发肾炎性 IgA 的产生。 IgAN 中沉积在系膜中的聚合 IgA 分子大部分属于 IgA1 亚类，并存在糖基化缺陷以及半乳糖和/或 N-乙酰半乳糖胺残基减少 [4]。此外，在正常受试者中，对粘膜抗原或粘膜疫苗产生免疫反应后，低半乳糖基化的 IgA1 在血流中循环。目前认为循环中脱半乳糖基化 IgA1 的增加是由于粘膜 IgA1 定向浆细胞（由于未知机制而活性增加）将粘膜类型 IgA1 分泌到循环中的误导所致 [5]。在那里，糖基化不良的 IgA1 由于自身聚集或与针对这些糖型的抗原或 IgG 抗体反应而形成大分子。综上所述，IgAN 中先天免疫的失调可能导致粘膜抗原消除失败和/或 IgA1 合成和分泌改变。没有必要假设特殊抗原的作用，因为常见的微生物或食物抗原可能发挥这种作用。 IgAN 实验模型中使用了多种病原体，包括 Th2 易感小鼠中的金黄色葡萄球菌 [6]、副流感嗜血杆菌口服免疫和仙台病毒重复鼻内免疫 [3]。除了病原体之外，麦醇溶蛋白或其他成分
Even though IgA nephropathy (IgAN) is by definition a diagnosis requiring renal biopsy tissue examination in immunohistology, a well-grounded suspicion is possible in the presence of macroscopic haematuria, detected coincidently or immediately following an upper respiratory or gastrointestinal tract infection. Many years ago, it was suggested that this hallmark of IgAN supported the hypothesis that the mesangial deposits of polymeric IgA detected by immunohistology are due to a mucosal immune system response to environmental pathogens [1]. Mucosal (or innate) immunity acts through recognition of pathogenassociated molecular patterns by Toll-like receptors (TLRs) expressed on phagocytic cells favouring virus or bacteria removal. The activation of TLRs induces dendritic cell maturation and migration to lymph nodes, leading to activation of specific T-cells and antibody synthesis, thus promoting a link between innate and adaptive immunity played at the mucosal and systemic level [2]. However, the discrepancy between the high incidence of viral syndromes in the general population and low prevalence of IgAN suggests that abnormalities of the mucosal and/or systemic immune system are critical for the development of IgAN, with infections representing a triggering event. Repetitive exposure to various infectious agents has been proved to induce experimental IgAN in animals only after abrogation of the natural process of mucosal tolerance which favours host defence after protracted pathogen exposure [3]. According to the hypothesis concerning the role of detective mucosal tolerance, patients with IgAN should have impaired elimination of mucosal antigens leading to continuous antigenic challenge, which triggers the production of nephritogenic IgA. Polymeric IgA molecules deposited in the mesangium in IgAN are mostly of IgA1 subclass, and present with a defective glycosylation and a reduction of galactose and/or N-acetylgalactosamine residues [4]. Also, in normal subjects, poorly galactosylated IgA1 circulates in the bloodstream after immune response to mucosal antigens or mucosal vaccines. Increased presence of degalactosylated IgA1 in the circulation is presently considered due to the misdirection of mucosal IgA1-committed plasma cells (with increased activity due to unknown mechanisms) to secrete mucosal type IgA1 into the circulation [5]. There, poorly glycosylated IgA1 undergoes formation of macromolecules due to self-aggregation or the reaction with antigens or IgG antibodies directed towards these glycoforms. To sum up, the dysregulation of innate immunity in IgAN is likely to result in failure of mucosal antigen elimination and/or altered IgA1 synthesis and secretion. There is no need to postulate the action of peculiar antigens, as common microbial or food antigens may play this role. A variety of pathogens have been used in experimental models of IgAN, including Staphylococcus aureus in Th2-prone mice [6], oral immunization with Haemophilus parainfluenzae and repetitive intranasal immunization with Sendai virus [3]. Besides pathogens, gliadin or other com-