IgG4相关性疾病靶抗原的鉴定及糖基化研究

IgG4 related disease (IgG4-RD) is a autoimmune disease with multiple organ involvement recognized in recent years, with the characteristic features of organ tissue hyperplasia, swelling, infiltration of IgG4 positive cells, and elevated serum IgG4 level. The inflammatory of the organ is reversible at the early stage of IgG4-RD and good respond to treatment. But delayed treatment can lead to irreversible fibrosis and sclerosis of a variety of important organs, which result in disability and death. As serum IgG4 is not specific for IgG4-RD,over emphasized on the role of serum elevated IgG4 resulted in many patients misdiagnosed as IgG4-RD. There is lack of predictive markers for up to 40% patients ,who are hormone therapy ineffective patients. Glycosylation has been proved to be closely related to the occurrence, development and prognosis of many kinds of autoimmune diseases and tumors. In this study, we will employ the high-throughput proteome microarray encoded by the human genome to identify target antigen of IgG4-RD and employ the human lectin microarray to perform glycosylation research. We expect to find the IgG4-RD specific antigens which can be used for the diagnosis, clinical phenotype, therapeutic prediction and the relationship with altered glycosylation; Explore the pathogenesis of glycosylation in the mechanism of the disease, to improve the accuracy of disease diagnosis, prognosis, which is benefit to reduce the burden of patients and society.

IgG4相关性疾病（IgG4-RD）是近年来新认识的一种多器官受累自身免疫病，以受累器官组织增生、肿大、IgG4 阳性淋巴细胞浸润，血清IgG4水平显著增高为主要特征。IgG4-RD早期病变器官炎症可逆，治疗效果较好；延误治疗则导致多种重要器官不可逆纤维化和硬化，致残致死。血清IgG4并非IgG4-RD的特异性标志，目前大量IgG4-RD患者被误诊误治。更缺乏针对高达40%激素治疗无效患者的预测指标。糖基化改变已被研究证明与多种自身免疫病及肿瘤的发生发展及预后密切相关。本研究拟采用人类全基因组编码蛋白高通量芯片技术鉴定IgG4-RD靶抗原并采用人凝集素芯片进行糖基化研究，寻找诊断IgG4-RD的特异性标志物和IgG4-RD疾病临床分型、疗效预测的相关标志物以及与糖基化改变在该病发病机制中的作用，提高该病诊断的准确率，改善患者预后，减少患者和社会的经济负担。

IgG4相关性疾病（IgG4-RD）是近年来新认识的一种多器官受累自身免疫病，以受累器官组织增生、肿大、IgG4 阳性淋巴细胞浸润，血清IgG4水平显著增高为主要特征。血清IgG4并非IgG4-RD的特异性标志，目前大量IgG4-RD患者被误诊误治。糖基化改变已被研究证明与多种自身免疫病及肿瘤的发生发展及预后密切相关。本研究采用人类全基因组编码蛋白高通量芯片技术鉴定IgG4-RD靶抗原，本课题研究采用包含47616蛋白点的高密度蛋白芯片筛选IgG4相关性疾病相关自身抗体。挑选经筛选确认的IgG4-RD候选自身抗原所对应的154个基因克隆，重新表达相关重组蛋白，制备IgG4-RD自身抗原蛋白芯片。并采用IgG4-RD自身抗原蛋白芯片对IgG4-RD： 231例，病对照组：209例（SLE70, RA70, SS29 , 胰腺炎40，血管炎17）和正常人：110例扩大样本大规模筛选验证。在IgG型中确认出与IgG4-RD相关标志物1个，在IgG4型中确认出与IgG4-RD相关标志物1个。在IgG4型中确认出与AIP诊断相关标志物1个，与MD诊断相关标志物1个。在IgG型中确认出与RPF诊断相关标志物1个，在IgG4型中确认出与RPF诊断相关标志物2个。采用人类凝集素芯片进行IgG4-RD 糖基化改变的研究，结果显示LTL凝集素结合聚糖水平降低可作为自身免疫性胰腺炎疾病诊断的生物学标志物；降低的HPA凝集素结合聚糖水平可被用作诊断腹膜后纤维化的生物学标志物；高甘露糖基化可以反映IgG4-RD患者疾病活动性，可被用作IgG4-RD疾病活动性的生物标志物；DSL凝集素结合聚糖水平与多器官受累相关，如胰腺、唾液腺、泪腺、腹膜后纤维化等，DSL凝集素结合聚糖水平可作为IgG4-RD多器官受累的生物学标志物。

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