Abnormal cytokine response and autoantigen production in IgA-producing subpopulations in IgA nephropathy

IgA 肾病中 IgA 产生亚群的异常细胞因子反应和自身抗原产生

• 批准号: 9807239
• 负责人: Colin Robert Reily
• 金额: $ 11.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807239
• 关键词: Affect; Agreement; Anabolism; Antigen-Antibody Complex; Autoantibodies; Autoantigens; B-Lymphocytes; Biological Assay; Biopsy; Blood Circulation; Cells; Characteristics; Complement; Complex; Data; Deposition; Development; Disease; Disease Progression; End stage renal failure; Enzymes; Exhibits; Galactose; Genes; Genetic Determinism; Glomerulonephritis; Goals; Helper-Inducer T-Lymphocyte; Hematuria; Human Herpesvirus 4; IGA Glomerulonephritis; IgA1; Immune; Immunoglobulin A; Immunoglobulin G; Infection; Inflammation; Inflammatory; Injury; Interleukin-4; Interleukin-6; Kidney; Mucosal Immune System; Mucous Membrane; Onset of illness; Pathogenesis; Pathway interactions; Patients; Pharmacology; Polymers; Population; Production; Protocols documentation; Publishing; Research; STAT3 gene; Serum; Signal Transduction; Small Interfering RNA; Stimulus; Structure of glomerular mesangium; TNFSF5 gene; Testing; To autoantigen; Upper Respiratory Infections; Validation; base; cytokine; disorder control; exome; genomic platform; glycosylation; glycosyltransferase; insight; knock-down; novel; novel strategies; novel therapeutics; response; stem; success; transcriptome; transcriptomics

Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis. It leads to end-stage kidney disease (ESKD) in 40-50% of patients. IgAN patients often exhibit macroscopic hematuria, commonly associated with upper-respiratory tract infections. This exacerbation of kidney injury seen during episodes of mucosal infection and inflammation suggests a connection between the two. In biopsies of IgAN patients, the defining characteristic of this disease is the deposits of polymeric IgA1, typically with IgG and complement C3 co- deposits. Analysis of the deposited IgA1 revealed enrichment for galactose-deficient IgA1 (Gd-IgA1) compared to circulatory IgA1. In addition, the co-deposited IgG is specific for Gd-IgA1. This appears to be immune complex deposition, which is also found in circulation of patients. Serum levels of Gd-IgA1 and anti-Gd-IgA1- IgG autoantibodies are elevated in IgAN patients, associate with disease progression, and can be found complexed in circulation. This circulatory autoantigen (Gd-IgA1) is typically found in the polymeric form, which is unique to the mucosal region. This suggests that a subset of IgA1-producing cells could be migrating from mucosal regions, or there is abnormal IgA1-producing cells formed elsewhere. Initial observations that mucosal infections associated with transient hematuria in IgAN patients led to the thesis that pro-inflammatory stimulation could increase circulatory Gd-IgA1-containing immune complexes, causing renal injury. We recently published that IL-6 stimulation in EBV-immortalized IgA1-producing cells from IgAN patients, but not controls, preferentially increased Gd-IgA1 production due to an enhanced and prolonged STAT3 activation. In addition, preliminary data in our lab from single-cell transcriptome profiling using immortalized IgA-producing cells from IgAN patients and healthy controls revealed multiple populations of IgA1-producing cells that have differential responses to cytokine stimulation. These observations led to our hypothesis that enhanced Gd- IgA1 production is a result of abnormal cytokine response in a subset of IgA1-producing cells. In Aim 1, we will test the hypothesis that cytokine exposure has differential effects on subsets of IgA1-producing cells in EBV- immortalized IgA1-producing cells from IgAN patients vs. healthy and disease controls. In Aim 2, we will test the hypothesis that subsets of IgA1-producing cells that have differential responses to cytokine stimulation are preferentially producing Gd-IgA1. The combination of these two aims will help identify the specific IgA1- producing cell subsets that contribute to autoantigen production. These studies will enable testing of novel research hypotheses and yield new preliminary data towards a competitive R01 proposal.

抽象的 IGA肾病（IGAN）是最常见的原发性肾小球肾炎。它导致末期肾脏疾病 （ESKD）40-50％的患者。 IGAN患者经常表现出宏观血尿，通常与 呼吸道感染。在粘膜感染发作中看到的这种肾脏损伤的加剧 炎症表明两者之间有联系。在Igan患者的活检中，定义 该疾病的特征是聚合物IgA1的沉积物，通常与IgG和补体C3共同 沉积物。对沉积IGA1的分析表明，半乳糖缺陷IgA1（GD-IGA1）的富集比较 循环IGA1。另外，共同沉积的IgG是GD-IGA1的特异性。这似乎是免疫的 复杂的沉积，也可以在患者的循环中发现。 gd-iga1和抗GD-iga1-的血清水平 IgG自身抗体在IGAN患者中升高，与疾病进展相关，可以发现 在循环中复杂化。该循环自动抗原（GD-IGA1）通常以聚合物形式找到，该形式是 是粘膜区域独有的。这表明产生IgA1的一个子集可以从 粘膜区域，或其他地方形成的IGA1产生异常的细胞。粘膜的初步观察 IGAN患者中与短暂性血尿相关的感染导致了促炎性的论点 刺激可能会增加循环系统含GD-IGA1的免疫复合物，从而导致肾脏损伤。我们 最近发表的，IL-6在IGAN患者中产生EBV的IgA1产生细胞的IL-6刺激，但不是 由于STAT3激活增强和延长，对控件优先增加GD-IGA1的产生。在 补充，我们实验室中的初步数据来自单细胞转录组分析，使用永生化的IgA产生 Igan患者和健康对照组的细胞显示，有多个具有IGA1产生细胞的人群 对细胞因子刺激的差异反应。这些观察结果导致了我们的假设，即增强了GD- IgA1产生是产生IgA1的细胞子集异常细胞因子反应的结果。在AIM 1中， 我们将检验以下假设：细胞因子暴露对IgA1产生细胞的子集具有不同的影响 来自IGAN患者与健康和疾病对照的EBV永生化IgA1产生细胞。在AIM 2中，我们将 检验以下假设：对细胞因子刺激有差异反应的产生IGA1的子集 优先生产GD-IGA1。这两个目标的结合将有助于确定特定的IGA1- 产生有助于自身抗原产生的细胞子集。这些研究将实现新颖的测试 研究假设并产生新的初步数据，以提高竞争性R01建议。