【作者】 陈金波；

【导师】 王宝玺； 马东来； 左亚刚；

【作者基本信息】 中国协和医科大学 ， 皮肤性病学， 2010， 博士

【摘要】 大疱性类天疱疮(Bullous pemphigoid, BP)是一种获得性自身免疫性皮肤病,大多发生于老年人。临床流行病学资料表明BP患者可同时患有神经系统疾病(Neurological diseases, ND),报道最多的为痴呆、脑血管病、帕金森病、多发性硬化、肌萎缩侧索硬化等。两者合并发生的机制尚未阐明,可能和BPAG1、BPAG2均存在皮肤亚型和神经亚型有关,有可能免疫交叉反应参与二者的合并发生。本研究从分析BP合并ND的临床特征开始,先后以鼠脑、人脑组织为底物通过免疫印迹方法检测患者血清中的自身抗体与BPAG1、BPAG2神经亚型的反应性,探讨BPAG1和BPAG2在BP与ND合并发病过程中的作用。第一部分：BP合并神经系统疾病患者血清对鼠脑BPAG1/BPAG2的识别目的：明确BP合并ND患者血清对鼠脑BPAG1和BPAG2的反应性。方法：先对BP合并神经系统疾病患者的临床资料进行分析,然后分别以正常人皮肤组织、完整的鼠脑组织提取物为底物,以BP合并ND的22例患者(BP+ND组)及性别、年龄1：1匹配的单纯BP患者(BP组)、单纯ND患者(ND组)及正常人(N组)血清为一抗行免疫印迹检测。结果：对22例BP合并神经系统疾病患者的临床资料进行分析,发现BP的发病年龄平均为77.7±7.9(60-97)岁,而相应神经系统的发病年龄平均为72.0±7.3(55-88)岁,22例患者BP均发生于神经系统疾病之后,两者相隔的时间平均为5.7±2.6(2-12)年。以正常人皮肤组织提取物为底物,在BP+ND组、BP组、ND组及N组患者血清中检测出抗230kDa抗体的阳性率分别为72.7%、50%、0%及0%,检测出抗180kDa抗体的阳性率分别为63.6%、59.1%、13.6%及4.5%,该结果印证了BP的诊断。以完整的鼠脑组织提取物为底物,四组患者血清中检测出抗230kDa抗体的阳性率分别为54.5%、4.5%、9.1%及O%,抗180kDa抗体的阳性率分别为59.1%、1 8.2%、36.4%及9.1%。结论：BP合并神经系统疾病患者血清中的自身抗体能识别鼠脑中的BPAG1抗原和BPAG2抗原。第二部分：BP合并神经系统疾病患者血清对人脑BPAG1/BPAG2的识别目的：明确BP合并ND患者血清对人脑BPAG1和BPAG2的反应性。方法：以正常人大脑组织提取物为底物,以BP+ND组、BP组、ND组及正常人血清为一抗行免疫印迹检测。结果：以人脑组织提取物为底物,四组患者血清中检测出抗230kDa抗体的阳性率分别为54.5%、9.1%、9.1%及4.5%,抗180kDa抗体的阳性率分别为59.1%、18.2%、27.3%及4.5%。结论：说明BP合并神经系统疾病患者血清中的自身抗体能识别人脑中的BPAG1及BPAG2抗原。推测BP合并神经系统疾病的可能机制为伴有血脑屏障破坏的神经系统疾病患者(包括脑出血、脑梗塞、痴呆)经过长时间的抗原暴露,可形成抗BPAG1、BPAG2神经亚型的抗体,该抗体可与分布于皮肤中的BPAG1、BPAG2发生免疫反应及免疫交叉反应,从而诱发BP。更多还原

【Abstract】 Bullous pemphigoid (BP) is an acquired autoimmue blistering diseases. It mainly occurs in the elderly. Many epidemiological studies suggested a possible relationship between BP and various neurological diseases (ND). The most common NDs reported were dementia, cerebral stroke, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis etc. The pathogenic relationship between BP and neurological diseases is not clear. Immunological cross-reactions may play a role in the association of these two diseases. We analyzed the clinical data of 22 BP patients with ND. To investigate the role of BPAG1 and BPAG2 in BP accompanied by ND. We tested the reactivity of the sera obtained from 22 BP patients with ND (BP+ND group), age and sex matched controls include 22 BP patients without ND (BP group), 22 patients with ND (ND group) and 22 normal controls (N group). The sera were assayed by immunoblotting against the human epidermis extract, the mouse brain extract and the human brain extract.Part 1. Objectives To investigate the reactivity of the sera of the four groups of patients with BPAG1 and BPAG2 in mouse brain. Methods The sera of BP+ND group, BP group, ND group and N group were assayed by immunoblotting against the human epidermis extract and the mouse brain extract. Results Analysis of patient’s clinical data revealed that the diagnoses of BP in all of these 22 BP+ND patients were at the age of 77.7±7.9 (60-97) years old. Whereas, the average age of onset of ND was at 72.0±7.3 (55-88). The onset of BP was after ND in all of these patients. The average interval between ND and BP was 5.7±2.6 (2-12) years. Both of the 230kDa protein and 180kDa proteins of human epidermis extract could be recognized by part of the collected serum samples. The positive rates of 230kDa protein in BP+ND group, BP group, ND group and N group were 72.73%,50%,0%,0%, respectively. The postive rate of 180kDa protein in the four groups were 63.6%,59.1%,13.6% and 4.5%. The 230kDa protein of mouse brain extract was recognized by 12 of 22 (54.5%) sera samples obtained from BP+ND group, and the positive rates of 230kDa protein in BP group, ND group and N group were 4.5%,9.1%,0%, respectively. The 180kDa protein of mouse brain extract was recognized by 13 of 22 (59.1%) sera samples obtained from BP+ND group, and the positive rates of 180kDa protein in BP group, ND group and N group were 18.2%,36.4%,9.1%, respectively. Conclusions Sera of patients of bullous pemphigoid associated with neurological diseases could recognize BPAG1 and BPAG2 in the mouse brain.Part 2. Objectives To investigate the reactivity of the sera of the four groups of patients with BPAG1 and BPAG2 in human brain. Methods The sera of BP+ND group, BP group, ND group and N group were assayed by immunoblotting against the human brain extract. Results A 230 kDa protein of human brain extract was recognized by 12 of 22 (54.5%) serum samples of BP+ND, whereas it was recognized by 9.1%,9.1% and 4.5% of serum samples of BP, ND, and N, respectively. A 180 kDa protein of human brain extract was recognized by 13 of 22 (59.1%) serum samples of BP+ND, whereas it was recognized by 18.2%,27.3% and 4.5% of serum samples of BP, ND, and N, respectively. Conclusions Sera of patients of bullous pemphigoid associated with neurological diseases could recognize BPAG1 and BPAG2 in the human brain. We speculate that alterations of the central nervous system in the course of neurological diseases of ND patients could expose the neural isoforms of BPAG1 and/or BPAG2. Cross reactions of these auto-antibodies with skin may underlie the pathological development of BP.更多还原