抗肾小球基底膜（GBM）病是最严重的肾小球肾炎，抗GBM自身抗体如何产生并导致肾脏损伤，尚未完全阐明。申请者首先发现正常人体内存在天然的抗GBM抗体，在疾病发生和进展过程中，天然抗体向致病性抗体转变，随后致病性抗体亦发生免疫学特性的改变，并且与疾病的临床表型密切相关，说明自身抗体的免疫学特性的转变是疾病发生和进展的重要决定因素。其中抗原表位的扩展起关键作用，初始阶段中自身免疫性T细胞和自身抗体共同识别的线性抗原表位可能是疾病的始动因素。研究结果对自身抗体的产生机制提出了创新的观点。拟进一步明确启动疾病的线性抗原表位和关键氨基酸序列，根据分子模拟机制寻找可能病因；阐明自身免疫性T细胞活化后的免疫炎症反应和介导肾脏损伤的机制。已发表SCI论文第一/责任作者21篇，肾病领域高影响力杂志Kidney Int（IF 8.563）5篇，受邀为Nat Rev Nephrol（IF 8.542）撰写综述。

Anti-glomerular basement membrane (GBM) disease is the most severe glomerulonephritis. Anti-GBM autoantibody has been demonstrated to be pathogenic in the disease. However, the mechanisms on antibody production and antibody-mediated kidney injury are still unclear. The applicant innovatively identified natural autoantibody against GBM in normal healthy person. During disease onset and progress, the immune characteristics of anti-GBM antibody shift patterns from natural autoantibody to pathogenic autoantibody. These immune characters also present close relationship with the clinical phenotype of patients with anti-GBM disease. These findings imply that the changing immune characters of anti-GBM antibody may be the key point of disease pathogenesis. Among these characters, epitope-spreading process is the determining factor. The initial linear peptide, which is recognized by both auto-reactive T cells and B cells, may be the initiation of epitope-spreading process and therefore the initiation of disease. The above works provide novel ideas on autoantibody pathogenesis. Next, the applicant plans to define the initial linear epitope and its critical amino acid motif at the onset of disease and explore possible etiology according to molecular mimicry theory. She will also try to elucidate the autoimmune and inflammatory process after the recognition of auto-reactive T cells to the critical motif, which may add more light on the pathogenesis of anti-GBM disease. The applicant has ten publications on SCI journals as first author and thirteen publications as corresponding author. Five of them were published on Kidney Int, which is in the top 5% journals on kidney diseases. The applicant was invited to write a review for Nat Rev Nephrol to summarize the advances on human anti-GBM disease.