大疱性类天疱疮抗原1和2在大疱性类天疱疮合并神经系统损害中的作用机制的探讨
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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。
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.
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。
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.
引文
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[18]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6; 15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004, 41(6):e71.
[19]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
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[1]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[2]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[3]Young KG, Kothary R. Dystonin/Bpagl--a link to what?[J]. Cell Motil Cytoskeleton,2007,64(12):897-905.
[4]李丽,王宝玺,左亚刚等.大疱性类天疱疮抗原1各亚型在小鼠皮肤和神经组织中的表达[J].临床皮肤科杂志,2007,36(11)：691-693.
[5]李丽,王宝玺,左亚刚等.大疱性类天疱疮与某些神经系统疾病间发病机制的研究[J].中华皮肤科杂志,2008,41(1)：22-24.
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[7]Zhu XJ, Niimi Y, Bystryn JC. Identification of a 160-kD molecule as a component of the basement membrane zone and as a minor bullous pemphigoid antigen[J]. J Invest Dermatol,1990,94(6):817-821.
[8]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration[J]. Cell,1995,81(2):233-243.
[9]Meyer LJ, Taylor TB, Kadunce DP, et al. Bullous pemphigoid antigens: extraction and degradation of antigens during epidermal preparation [J]. J Invest Dermatol,1991,96(6):991-993.
[10]Labib RS. Heterogeneity of the bullous pemphigoid antigen:what is true and what is artifact?[J]. J Invest Dermatol,1991,96(4):527-529.
[11]Meyer LJ, Taylor TB, Kadunce DP, et al. Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies[J]. J Invest Dermatol, 1990,94(5):611-616.
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[13]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[14]Foureur N, Mignot S, Senet P, et al. [Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid][J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[15]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid[J]. Dermatology,2007,215(3):187-191.
[16]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[17]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[18]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[1]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[2]李丽,王宝玺,左亚刚等.大疱性类天疱疮抗原1各亚型在小鼠皮肤和神经组织中的表达[J].临床皮肤科杂志,2007,36(11)：691-693.
[3]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[4]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004,41(6):e71.
[5]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
[6]Seppanen A, Suuronen T, Hofmann SC, et al. Distribution of collagen XVII in the human brain[J]. Brain Res,2007,1158:50-56.
[7]Zhu XJ, Niimi Y, Bystryn JC. Identification of a 160-kD molecule as a component of the basement membrane zone and as a minor bullous pemphigoid antigen[J]. J Invest Dermatol,1990,94(6):817-821.
[8]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1:abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration[J]. Cell,1995,81(2):233-243.
[9]Meyer LJ, Taylor TB, Kadunce DP, et al. Bullous pemphigoid antigens: extraction and degradation of antigens during epidermal preparation [J]. J Invest Dermatol,1991,96(6):991-993.
[10]Labib RS. Heterogeneity of the bullous pemphigoid antigen:what is true and what is artifact?[J]. J Invest Dermatol,1991,96(4):527-529.
[11]Meyer LJ, Taylor TB, Kadunce DP, et al. Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies[J]. J Invest Dermatol, 1990,94(5):611-616.
[12]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[13]Foureur N, Mignot S, Senet P, et al. [Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid] [J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[14]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid[J]. Dermatology,2007,215(3):187-191.
[15]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[16]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[17]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[18]Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180[J]. J Clin Invest,1993,92(5):2480-2488.
[19]McKee PH, Calonje E, Ganter SR. pathology of the skin, with clinical correlations.3rd. USA:Philadelphia,2005:98-110.
[20]Foureur N, Mignot S, Senet P, et al. Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid[J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[1]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[2]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[3]Jedlickova H, Hlubinka M, Pavlik T, et al. Bullous pemphigoid and internal diseases-A case-control study[J]. Eur J Dermatol,2010,20(1):96-101.
[4]贾建平.神经病学[M].北京：人民卫生出版社,2008：171-232.
[5]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid [J]. Dermatology,2007,215(3):187-191.
[6]Foureur N, Descamps V, Lebrun-Vignes B, et al. Bullous pemphigoid in a leg affected with hemiparesia:a possible relation of neurological diseases with bullous pemphigoid?[J]. Eur J Dermatol,2001, 11(3):230-233.
[7]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[8]Okumus N, Esra Onal E, Turkyilmaz C, et al. A case report of neonatal convulsions due to maternal herpes gestationis[J]. J Child Neurol,2007, 22(4):488-491.
[9]McKee PH, Calonje E, Ganter SR. pathology of the skin, with clinical correlations.3rd. USA:Philadelphia,2005:98-110.
[10]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[11]Sonnenberg A, Liem RK. Plakins in development and disease[J]. Exp Cell Res, 2007,313(10):2189-2203.
[12]Thoma-Uszynski S, Uter W, Schwietzke S, et al. BP230-and BP180-specific auto-antibodies in bullous pemphigoid[J]. J Invest Dermatol,2004, 122(6):1413-1422.
[13]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[14]Young KG, Kothary R. Dystonin/Bpagl--a link to what?[J]. Cell Motil Cytoskeleton,2007,64(12):897-905.
[15]Ko MS, Marinkovich MP. Role of dermal-epidermal basement membrane zone in skin, cancer, and developmental disorders[J]. Dermatol Clin,2010, 28(1):1-16.
[16]Laffitte E, Burkhard PR, Fontao L, et al. Bullous pemphigoid antigen 1 isoforms:potential new target autoantigens in multiple sclerosis?[J]. Br J Dermatol,2005,152(3):537-540.
[17]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[18]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004, 41(6):e71.
[19]Li KH, Sawamura D, Giudice GJ, et al. Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium [J]. J Biol Chem, 1991,266(35):24064-24069.
[20]Giudice GJ, Emery DJ, Diaz LA. Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180[J]. J Invest Dermatol,1992, 99(3):243-250.
[21]Has C, Kern JS. Collagen XVII[J]. Dermatol Clin,2010,28(l):61-66.
[22]Zillikens D, Giudice GJ. BP180/type XVII collagen:its role in acquired and inherited disorders or the dermal-epidermal junction[J]. Arch Dermatol Res, 1999,291 (4):187-194.
[23]Wieland CN, Comfere NI, Gibson LE, et al. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects[J]. Arch Dermatol,2010, 146(1):21-25.
[24]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
[25]Seppanen A, Suuronen T, Hofmann SC, et al. Distribution of collagen XVII in the human brain[J]. Brain Res,2007,1158:50-56.
[26]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration [J]. Cell,1995,81(2):233-243.
[27]Li L, Chen J, Wang B, et al. Sera from patients with bullous pemphigoid (BP) associated with neurological diseases recognized BP antigen 1 in the skin and brain[J]. Br J Dermatol,2009,160(6):1343-1345.
[28]李丽,王宝玺,左亚刚等.大疱性类天疱疮与某些神经系统疾病间发病机制的研究[J].中华皮肤科杂志,2008,41(1)：22-24.
[29]Foureur N, Mignot S, Senet P, et al. Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid[J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[2]Zillikens D, Wever S, Roth A, et al. Incidence of autoimmune subepidermal blistering dermatoses in a region of central Germany[J]. Arch Dermatol,1995, 131(8):957-958.
[3]Sawamura D, Nomura K, Sugita Y, et al. Bullous pemphigoid antigen (BPAG1):cDNA cloning and mapping of the gene to the short arm of human chromosome 6[J]. Genomics,1990,8(4):722-726.
[4]Sawamura D, Li KH, Nomura K, et al. Bullous pemphigoid antigen:cDNA cloning, cellular expression, and evidence for polymorphism of the human gene[J]. J Invest Dermatol,1991,96(6):908-915.
[5]Leung CL, Liem RK, Parry DA, et al. The plakin family[J]. J Cell Sci,2001, 114(Pt 19):3409-3410.
[6]McKee PH, Calonje E, Ganter SR. pathology of the skin, with clinical correlations.3rd. USA:Philadelphia,2005:98-110.
[7]Li KH, Sawamura D, Giudice GJ, et al. Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium[J]. J Biol Chem, 1991,266(35):24064-24069.
[8]Zillikens D, Giudice GJ. BP180/type XVII collagen:its role in acquired and inherited disorders or the dermal-epidermal junction[J]. Arch Dermatol Res, 1999,291(4):187-194.
[9]朱文元.大疱和无菌性脓疱性皮肤病[A].见：赵辩主编.临床皮肤病学[M].南京：江苏科学技术出版社,2001：800-820.
[10]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[11]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid[J]. Dermatology,2007,215(3):187-191.
[12]Foureur N, Descamps V, Lebrun-Vignes B, et al. Bullous pemphigoid in a leg affected with hemiparesia:a possible relation of neurological diseases with bullous pemphigoid?[J]. Eur J Dermatol,2001, 11(3):230-233.
[13]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[14]Jedlickova H, Hlubinka M, Pavlik T, et al. Bullous pemphigoid and internal diseases-A case-control study[J]. Eur J Dermatol,2010,20(1):96-101.
[15]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[16]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[17]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[18]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6; 15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004, 41(6):e71.
[19]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
[20]Seppanen A, Suuronen T, Hofmann SC, et al. Distribution of collagen XVII in the human brain[J]. Brain Res,2007,1158:50-56.
[21]李丽,王宝玺,左亚刚等.大疱性类天疱疮抗原1各亚型在小鼠皮肤和神经组织中的表达[J].临床皮肤科杂志,2007,36(11)：691-693.
[22]李丽,王宝玺,左亚刚等.大疱性类天疱疮与某些神经系统疾病间发病机制的研究[J].中华皮肤科杂志,2008,41(1)：22-24.
[23]Li L, Chen J, Wang B, Yao Y, Zuo Y Sera from patients with bullous pemphigoid (BP) associated with neurological diseases recognized BP antigen 1 in the skin and brain[J]. Br J Dermatol.2009,160(6):1343-1345.
[1]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[2]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[3]Young KG, Kothary R. Dystonin/Bpagl--a link to what?[J]. Cell Motil Cytoskeleton,2007,64(12):897-905.
[4]李丽,王宝玺,左亚刚等.大疱性类天疱疮抗原1各亚型在小鼠皮肤和神经组织中的表达[J].临床皮肤科杂志,2007,36(11)：691-693.
[5]李丽,王宝玺,左亚刚等.大疱性类天疱疮与某些神经系统疾病间发病机制的研究[J].中华皮肤科杂志,2008,41(1)：22-24.
[6]贾建平主编.神经病学[M].北京：人民卫生出版社,2008：171-232.
[7]Zhu XJ, Niimi Y, Bystryn JC. Identification of a 160-kD molecule as a component of the basement membrane zone and as a minor bullous pemphigoid antigen[J]. J Invest Dermatol,1990,94(6):817-821.
[8]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration[J]. Cell,1995,81(2):233-243.
[9]Meyer LJ, Taylor TB, Kadunce DP, et al. Bullous pemphigoid antigens: extraction and degradation of antigens during epidermal preparation [J]. J Invest Dermatol,1991,96(6):991-993.
[10]Labib RS. Heterogeneity of the bullous pemphigoid antigen:what is true and what is artifact?[J]. J Invest Dermatol,1991,96(4):527-529.
[11]Meyer LJ, Taylor TB, Kadunce DP, et al. Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies[J]. J Invest Dermatol, 1990,94(5):611-616.
[12]Kawahara Y, Matsumura K, Hashimoto T, et al. Immunoblot analysis of autoantigens in localized pemphigoid and pemphigoid nodularis[J]. Acta Derm Venereol,1997,77(3):187-190.
[13]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[14]Foureur N, Mignot S, Senet P, et al. [Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid][J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[15]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid[J]. Dermatology,2007,215(3):187-191.
[16]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[17]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[18]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[1]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[2]李丽,王宝玺,左亚刚等.大疱性类天疱疮抗原1各亚型在小鼠皮肤和神经组织中的表达[J].临床皮肤科杂志,2007,36(11)：691-693.
[3]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[4]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004,41(6):e71.
[5]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
[6]Seppanen A, Suuronen T, Hofmann SC, et al. Distribution of collagen XVII in the human brain[J]. Brain Res,2007,1158:50-56.
[7]Zhu XJ, Niimi Y, Bystryn JC. Identification of a 160-kD molecule as a component of the basement membrane zone and as a minor bullous pemphigoid antigen[J]. J Invest Dermatol,1990,94(6):817-821.
[8]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1:abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration[J]. Cell,1995,81(2):233-243.
[9]Meyer LJ, Taylor TB, Kadunce DP, et al. Bullous pemphigoid antigens: extraction and degradation of antigens during epidermal preparation [J]. J Invest Dermatol,1991,96(6):991-993.
[10]Labib RS. Heterogeneity of the bullous pemphigoid antigen:what is true and what is artifact?[J]. J Invest Dermatol,1991,96(4):527-529.
[11]Meyer LJ, Taylor TB, Kadunce DP, et al. Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies[J]. J Invest Dermatol, 1990,94(5):611-616.
[12]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[13]Foureur N, Mignot S, Senet P, et al. [Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid] [J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[14]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid[J]. Dermatology,2007,215(3):187-191.
[15]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[16]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[17]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[18]Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180[J]. J Clin Invest,1993,92(5):2480-2488.
[19]McKee PH, Calonje E, Ganter SR. pathology of the skin, with clinical correlations.3rd. USA:Philadelphia,2005:98-110.
[20]Foureur N, Mignot S, Senet P, et al. Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid[J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.
[1]Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases[J]. Acta Derm Venereol,2005,85(2):136-139.
[2]Chosidow O, Doppler Vr, Bensimon G, et al. Bullous pemphigoid and amyotrophic lateral sclerosis:a new clue for understanding ther bullous disease?[J]. Arch Dermatol,2000,136(4):521-524.
[3]Jedlickova H, Hlubinka M, Pavlik T, et al. Bullous pemphigoid and internal diseases-A case-control study[J]. Eur J Dermatol,2010,20(1):96-101.
[4]贾建平.神经病学[M].北京：人民卫生出版社,2008：171-232.
[5]Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid [J]. Dermatology,2007,215(3):187-191.
[6]Foureur N, Descamps V, Lebrun-Vignes B, et al. Bullous pemphigoid in a leg affected with hemiparesia:a possible relation of neurological diseases with bullous pemphigoid?[J]. Eur J Dermatol,2001, 11(3):230-233.
[7]李丽,王宝玺,陈霞.大疱性类天疱疮合并神经系统疾病22例临床分析[J].北京医学,2006,28(5)：286-288.
[8]Okumus N, Esra Onal E, Turkyilmaz C, et al. A case report of neonatal convulsions due to maternal herpes gestationis[J]. J Child Neurol,2007, 22(4):488-491.
[9]McKee PH, Calonje E, Ganter SR. pathology of the skin, with clinical correlations.3rd. USA:Philadelphia,2005:98-110.
[10]Leung CL, Zheng M, Prater SM, et al. The BPAG1 locus:Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles[J]. J Cell Biol,2001, 154(4):691-697.
[11]Sonnenberg A, Liem RK. Plakins in development and disease[J]. Exp Cell Res, 2007,313(10):2189-2203.
[12]Thoma-Uszynski S, Uter W, Schwietzke S, et al. BP230-and BP180-specific auto-antibodies in bullous pemphigoid[J]. J Invest Dermatol,2004, 122(6):1413-1422.
[13]Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII and BPAG1 expression in the retina:evidence for an anchoring complex in the central nervous system[J]. J Comp Neurol,2005,487(2):190-203.
[14]Young KG, Kothary R. Dystonin/Bpagl--a link to what?[J]. Cell Motil Cytoskeleton,2007,64(12):897-905.
[15]Ko MS, Marinkovich MP. Role of dermal-epidermal basement membrane zone in skin, cancer, and developmental disorders[J]. Dermatol Clin,2010, 28(1):1-16.
[16]Laffitte E, Burkhard PR, Fontao L, et al. Bullous pemphigoid antigen 1 isoforms:potential new target autoantigens in multiple sclerosis?[J]. Br J Dermatol,2005,152(3):537-540.
[17]Brown A, Dalpe G, Mathieu M, et al. Cloning and characterization of the neural isoforms of human dystonin[J]. Genomics,1995,29(3):777-780.
[18]Giorda R, Cerritello A, Bonaglia MC, et al. Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia[J]. J Med Genet,2004, 41(6):e71.
[19]Li KH, Sawamura D, Giudice GJ, et al. Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium [J]. J Biol Chem, 1991,266(35):24064-24069.
[20]Giudice GJ, Emery DJ, Diaz LA. Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180[J]. J Invest Dermatol,1992, 99(3):243-250.
[21]Has C, Kern JS. Collagen XVII[J]. Dermatol Clin,2010,28(l):61-66.
[22]Zillikens D, Giudice GJ. BP180/type XVII collagen:its role in acquired and inherited disorders or the dermal-epidermal junction[J]. Arch Dermatol Res, 1999,291 (4):187-194.
[23]Wieland CN, Comfere NI, Gibson LE, et al. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects[J]. Arch Dermatol,2010, 146(1):21-25.
[24]Seppanen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons[J]. Matrix Biol,2006,25(3):185-188.
[25]Seppanen A, Suuronen T, Hofmann SC, et al. Distribution of collagen XVII in the human brain[J]. Brain Res,2007,1158:50-56.
[26]Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration [J]. Cell,1995,81(2):233-243.
[27]Li L, Chen J, Wang B, et al. Sera from patients with bullous pemphigoid (BP) associated with neurological diseases recognized BP antigen 1 in the skin and brain[J]. Br J Dermatol,2009,160(6):1343-1345.
[28]李丽,王宝玺,左亚刚等.大疱性类天疱疮与某些神经系统疾病间发病机制的研究[J].中华皮肤科杂志,2008,41(1)：22-24.
[29]Foureur N, Mignot S, Senet P, et al. Correlation between the presence of type-2 anti-pemphigoid antibodies and dementia in elderly subjects with no clinical signs of pemphigoid[J]. Ann Dermatol Venereol,2006,133(5 Pt 1):439-443.