T Cells Control IgA Glycosylation, Evoke IgA Nephropathy

T细胞控制IgA糖基化，诱发IgA肾病

• 批准号: 6846556
• 负责人: STEVEN N EMANCIPATOR
• 金额: $ 26.01万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846556
• 关键词: B lymphocyte; IgA nephropathy; SCID mouse; cytokine; disease /disorder etiology; disease /disorder model; genetic susceptibility; glycosylation; helper T lymphocyte; human subject; immunogenetics; immunoglobulin A; laboratory mouse; molecular chaperones; mucosal immunity; parainfluenza virus type 1; pathologic process

DESCRIPTION (Provided by applicant): As the most common form of glomerulonephritis throughout the world, IgA nephropathy (IgAN) continues to be a major financial and social burden. We believe that the pathogenesis of IgAN is usually related to dysregulation of the mucosal immune response, particularly to viral pathogens. We have therefore established an experimental model of IgAN in mice by immunization and challenge with a common rodent respiratory pathogen (Sendai virus), for which the immune response is genetically restricted. Based upon prior clinical and experimental observations and our new data, we hypothesize that the genetically determined T cell repertoire of a host determines susceptibility to IgAN, in association with other factors. We will emphasize complementary studies in two strains of mice (BALB/c and C57B1/6) that differ in severity of virally-induced IgAN. The Specific Aims of this proposal are to: 1) determine if the polarity of helper T cells towards type 2 (Th2) versus type 1 (Thi) is a critical determinant of the severity of IgAN; 2) offer direct assessment of the contribution of the B cell response to Th2 cytokines to the genesis of IgAN; 3) assess the role of non-lymphoid cells' response to T cell cytokines in the genesis of IgAN; 4) evaluate the applicability of our hypothesis to the immune response in humans. To achieve this last goal, we will reconstitute a functional human immune system in congenitally immunodeficient mice. In all experiments, we will compare the frequency and severity of IgAN provoked by immunization and challenge with virus among the various groups of mice, and correlate these parameters to the polarity of the antigen-specific T cell cytokine responses and IgA glycosylation. As our experiments unfold, we anticipate gaining insights not only to the pathogenesis of this currently incurable and poorly treated form of glomerulonephritis, but also to gain information about the factors that govern the character of immune responses to microbes and other antigens that gain access to mammals via mucosal routes.

描述（由申请人提供）：作为最常见的形式 肾小球肾炎在全世界范围内，IgA 肾病 (IgAN) 仍然是 造成重大的经济和社会负担。我们认为 IgAN 的发病机制 通常与粘膜免疫反应失调有关， 特别是针对病毒病原体。因此我们建立了一个实验 通过免疫和普通啮齿动物攻击建立小鼠 IgAN 模型 呼吸道病原体（仙台病毒），其免疫反应是 受基因限制。基于之前的临床和实验观察 和我们的新数据，我们假设基因决定的 T 细胞 宿主的全部功能决定了对 IgAN 的易感性，与 其他因素。我们将强调对两种小鼠品系的互补研究 （BALB/c 和 C57B1/6），病毒诱导的 IgAN 的严重程度不同。这 该提案的具体目标是： 1）确定辅助 T 的极性是否 细胞向 2 型 (Th2) 与 1 型 (Thi) 的方向变化是细胞分化的关键决定因素 IgAN 的严重程度； 2) 直接评估 B 细胞的贡献 对 Th2 细胞因子的反应对 IgAN 的发生； 3）评估角色 IgAN 发生过程中非淋巴细胞对 T 细胞细胞因子的反应； 4） 评估我们的假设对人类免疫反应的适用性。 为了实现最后一个目标，我们将重建功能性人体免疫系统 先天性免疫缺陷小鼠的系统。在所有的实验中，我们将 比较免疫引起的 IgAN 的频率和严重程度 对各组小鼠进行病毒攻击，并将这些结果关联起来 抗原特异性 T 细胞细胞因子反应极性的参数 和 IgA 糖基化。随着我们的实验展开，我们预计会获得 不仅了解这种目前无法治愈且效果不佳的发病机制 肾小球肾炎的治疗形式，还可以获取有关肾小球肾炎的信息 控制对微生物和其他物质的免疫反应特征的因素 通过粘膜途径进入哺乳动物的抗原。

项目成果

Antiviral innate immunity disturbs podocyte cell function.

• DOI: 10.1159/000345255
• 发表时间: 2013
• 期刊: Journal of innate immunity
• 影响因子: 5.3
• 作者: Yamashita M;Millward CA;Inoshita H;Saikia P;Chattopadhyay S;Sen GC;Emancipator SN
• 通讯作者: Emancipator SN