Nephritogenic autoantibodies in systemic lupus

 描述(由申请人提供)：高达60%的SLE患者出现肾脏损伤的临床证据，称为狼疮性肾炎(LN)。LN被认为是由于肾小球免疫复合物沉积激活炎症级联反应，损害肾小球细胞，导致蛋白尿和滤过能力丧失所致。LN根据肾脏组织病理学分为SI型，其中增生型LN(ISN/RPS III或IV级)最容易导致肾功能衰竭。 大多数关于增生性LN病因的研究都集中在抗核抗体的肾炎形成潜力上，而将注意力从组织/细胞特异性自身抗体的潜在作用上转移开。越来越多的证据表明，抗组织特异性靶抗原的自身抗体参与了包括LN在内的许多肾小球疾病的发病机制。我们的初步数据显示，增生性LN患者的血清中含有针对人肾小球蛋白的自身抗体，包括Annexin A2和Moesin。这些发现支持我们的中心假设，即针对肾小球蛋白的自身抗体，包括膜联蛋白A2和Moesin，会导致免疫复合体沉积，从而导致增生性LN。这份有指导的职业发展建议将侧重于进一步表征增生性LN中针对Annexin A2和Moesin的自身抗体，验证这些自身抗体作为疾病生物标记物的有效性，检查暴露于这些自身抗体的足细胞和系膜细胞的功能变化，以及在动物模型中评估这些抗体的肾炎形成潜力。随着对靶抗原识别后对原发性膜性肾病认识的进展，这将有助于更好地了解疾病的发病机制，并提供新的诊断和预后生物标志物。该指导职业发展奖还将通过由指导团队制定的个性化职业发展计划，为申请者提供发展成为独立医生-科学家所需的技能的时间，调查狼疮性肾炎的临床和基本方面。

 DESCRIPTION (provided by applicant): Up to 60% of SLE patients develop clinical evidence of kidney injury, termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells, leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes, of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure. Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies, diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases, including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins, including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins, including annexin A2 and moesin, result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN, validation of those autoantibodies as biomarkers for disease, examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies, and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens, this will lead to improved understanding of the pathogenic mechanisms of disease, and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist, investigating clinical and basic aspects of lupus nephritis, through an individualized career development plan which has been developed by the mentorship team.