抗乙酰胆碱3受体抗体在干燥综合征中的临床意义
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摘要
背景
干燥综合征(Sjogren syndrome)常见于中年女性，是主要累及全身外分泌腺的慢性进展性自身免疫病。其外分泌腺受累以唾液腺和泪腺为主，此外还可累及呼吸、消化、肾脏、神经等多个系统。干燥综合征外分泌腺的损伤机制多样，包括淋巴细胞大量或灶性浸润导致正常腺体结构的破坏，以及某些抗体所介导的外分泌腺功能异常等。本研究通过检测抗乙酰胆碱3受体(M_3R)抗体在干燥综合征患者血清中的阳性率，分析其与临床表现的相关性，探讨其可能的临床应用价值。并利用动物模型研究抗M_3R抗体对唾液流率的影响，初步探讨该抗体的致病性。
目的
分别建立酶联免疫吸附法(ELISA)和免疫印迹法(Western blot)检测抗M_3R抗体在干燥综合征、系统性红斑狼疮和健康对照中的阳性率；分析抗M_3R抗体在干燥综合征中的临床意义；通过大鼠模型验证抗M_3R抗体抑制唾液腺分泌的作用。
方法
实验对象：自2005年-2007年于北京协和医院入组国际干燥综合征登记网络研究(SICCA)证实为肯定的干燥综合征患者共70例作为实验组；同期住院诊治的系统性红斑狼疮(SLE)患者且除外继发性干燥综合征共49例作为疾病对照组；并以同期健康献血者共76例作为健康对照组。三组间年龄、性别匹配。
实验方法：以重组的M_3R受体为抗原通过ELISA法检测三组血清中抗M_3R抗体，以健康对照组吸光度的(?)+SD为阳性界定，计算ss组和SLE组的抗M_3R抗体阳性率；并以重组的的抗原用Western法进一步验证ELISA法检测的可靠性；分析SS组中抗M_3R抗体阳性患者较阴性患者在Schirmer试验、BUT、角膜染色、结膜染色、五分钟唾液流率、下唇小唇腺灶性淋巴细胞浸润指数、RF、IgG、抗SSA抗体阳性例数、抗SSB抗体阳性例数间的差异。用亲和层析法纯化抗M_3R抗体阳性患者血清中的IgG型抗M_3R抗体，以15mg／kg的剂量(7．6mg／ml)注射大鼠尾静脉观察大鼠唾液腺流率的改变，阴性对照用相同浓度和剂量的人IVlO，阳性对照用阿托品(0.125mg／kg)。
结果
(1)ELISA法检测76例健康组的(?)+SD的值为0.1710+0．0723，以此为阳性界定值计算出SS患者的抗M_3R抗体的阳性率为47．10％(33／70)，SLE患者组中抗M_3R抗体的阳性率为4．02％(2／49)，健康对照组中抗M_3R抗体的阳性率为14．47％(11／76)；抗M_3R抗体在SS患者中的阳性率明显高于SLE组(47．10％vs 4．02％，p<0．05)健康对照组(47．10％vs 14．47％，p<0．05)，其间有统计学显著差异。而SLE组和健康对照组间的抗M_3R抗体阳性率无统计学差异(4．02％vs 14．47%,P>0．05)。
(2)Western法检测出SS患者的抗M_3R抗体的阳性率为60．00％(42／70)，SLE组巾的抗M3R抗体的阳性率则为12．20％(6／49)，健康对照组中抗M_3R抗体的阳性率为15．79％(12／76)；抗M3R抗体在SS患者中的阳性率明显高于SLE组(60．00％vs12．20％，p<0．05)和健康对照组(60．00% vs 15．79％，p<0．05)，有统计学显著差异。而SLE组和健康对照组间的抗M_3R抗体阳性率无统计学差异(12．20％vs15．79％，P>0．05)。Western法和ELISA法的符合率达74．9％。
(3)SS组中抗M_3R抗体阳性患者IgG(39．97 vs 29．64，p<0．05)、RF值(42．23vs 27．92，p<0．05)及抗SSB抗体阳性例数(31 vs 9，p<0．05)较阴性患者明显增高，其间有统计学显著差异。而抗M_3R抗体阳性组与阴性组相比，唇腺活检阳性率、Schirmer试验、BUT、五分钟唾液流率、角膜染色和结膜染色间无显著统计学差异。但是抗M_3R抗体阳性组的患者唇腺活检中淋巴细胞灶性浸润(?)3的患者例数较阴性组明显为高(27 vs 10)，p<0．05。
(4)以亲和层析柱纯化的含抗M_3R抗体的人血清IgG(实验组，剂量按15mg／kg，浓度为7．6mg／ml)注射大鼠尾静脉后可减少大鼠的唾液流率(0．0938g vs 0．0748g，P>0．05)，阿托品组(阳性对照组)用药后唾液流率较用药前显著减少(0．09327g vs0．02198g，P<0．05)，实验组与阳性对照组相比，减少的差值无显著统计学差异(-0．02227g vs -0．07128g，P>0．05)。正常人IVIG组(阴性对照组)用药后唾液流率较用药前显著增加(0．08230g vs 0．43425g，P<0．05)。比较实验组与阴性对照组用药后与用药前唾液流率改变的差值，两组间差异具有统计学意义(-0．02227gvs0.35195g,P<0．05)。
结论
(1)ELISA和Western法检测SS患者抗M_3R抗体阳性率明显高于SLE患者和健康对照者。
(2)SS患者中抗M_3R抗体阳性组较阴性组IgG值、RF值、抗SSB抗体阳性例数以及下唇小唇腺淋巴细胞浸润为高。
(3)纯化的含抗M_3R抗体的人血清IgG可部分阻断匹罗卡品刺激大鼠唾液腺分泌的功能。
Background
Sjogren syndrome (SS) is a chronic autoimmune disease which occurs mainly in the fourth and fifthdecades and characterized by histologic and functional alterations of exocrine glands with progressive loss of salivary and lacrimal gland secretion. Respiratory, digesting, renal and nervous system are as well involved in SS. There are many mechanisms of loss of exocrine glands such as destruction of the acinar cells by lymphocytes infiltration and the antibody-mediated destruction of the exocrine glands. It has been recently proposed that pathology underlying the glandular hypofunction contributes inhibitory autoantibodies especially the autoantibodies directed against mucarinic recptors. The aim of this work is to test the positive rate of the anti-M_3 receptor antibody in SS , the relationship between the antibody and other clinical manifestations and the salivary flow rate decreased by the affinity-purified antibody from SS patients in mice.
Objectives
To detect anti-M_3 receptor antibodies in Sjogren' s Syndrome (SS) patients, SLE patients and the donating controls by methods of Enzyme linked immunosorbent assay and Western blotting. And to explore its association with clinical manifestation. At last detect the affinity-purified antibody' s pathogenic mechanism in animal experiments.
Materials and Methods
Specimens:70 pieces serum of Sjogren syndrome patients from the SICCAobject in PUMCH from 2005-2007. 49 pieces serum of patients of SLE in-patients in PUMCH at the same time. 76 pieces serum of healthy donators in PUMCH. And the three groups match in sex and age.
Methods: With the muscarinic 3 receptor(from sigma) as the antigen ,to detect anti-muscarinic 3 receptor antibody in SS, SLE and donator controlsusing methods of ELISA. The positive cut-off is (?)+SD in donator controls.And test the positive rate of anti-muscarinic 3 receptor antibody in SS, SLE by means of western blotting. Analyze the differences of the antibody-positive patients and antibody-negative patients in SS in aspects of Schirmer test,BUT,PEE on the corneas,the conjunctival epithelial defects, whole saliva flow rate in 5 minutes,FI,RF,IgG,anti-SSA and anti-SSB.Affinity- purified of human polyclonal IgG antibodies (15mg/kg)by Protein A chromatography was passive transfered to mice and detect the differences of the salivary secrection in the groups of IVIG (15mg/kg)which is the negative controls, atropine(0.125mg/kg) which is the positive controls and the human IgG.
Results
1.Using ELISA the positive rate of anti-M_3 antibody in SS is 47. 10%(33/70), in SLE is 4.02%(2/49) and in donator controls is 14.47%(11/76).The rate in SS is much higher than in SLE(47.10% vs 4.02%,P<0.05). Compared with patients in donator control the antibody is more frequently found in patients with SS(47.10% vs 14.47%, P<0.05).
2. Using Western the positive rate of anti-M_3 antibody in SS is 60.0%, in SLE is 12.2% and in normal controls is 15.79%. Compared with patients with SLE and donator controls, the anti-M_3 antibody in SS is more frequently found,P<0.05.
3. The incidence of IgG,rheumatoid factor, anti-SSB and FI>3 are higher in positive group than in negative group using ELISA. And the differences are significant,P<0.05. But the differences between the two goups in Schirmer test,BUT,PEE on the corneas,the conjunctival epithelial defects, whole saliva flow rate in 5 minutes and anti-SSA are not significant.
4. The data of passive transfer to mice indicates that the recipient mice of purified human IgG from anti-M_3 antibody positive SS(15mg/kg) develop glandular hypofunction which is similar to those recipient mice of atropine. But that is not similar to those recipient mice of IVIG.And the differences between them are significant.P<0.05
Conclusions
1. The positive rate of anti-M_3 antibody in SS is much higher than that in SLE and in normal controls.
2. The IgG, RF, anti-SSB and FI in SS patients with positive anti-muscarinic 3 receptor antibody are much higher than in patients with negativeanti-muscarinic 3 receptor antibody.
3. The data of WS mice experiments indicates that the anti-muscarinic 3 antibody may decrease the salivary secretion.
干燥综合征(Sjogren syndrome)常见于中年女性，是主要累及全身外分泌腺的慢性进展性自身免疫病。其外分泌腺受累以唾液腺和泪腺为主，此外还可累及呼吸、消化、肾脏、神经等多个系统。干燥综合征外分泌腺的损伤机制多样，包括淋巴细胞大量或灶性浸润导致正常腺体结构的破坏，以及某些抗体所介导的外分泌腺功能异常等。本研究通过检测抗乙酰胆碱3受体(M_3R)抗体在干燥综合征患者血清中的阳性率，分析其与临床表现的相关性，探讨其可能的临床应用价值。并利用动物模型研究抗M_3R抗体对唾液流率的影响，初步探讨该抗体的致病性。
目的
分别建立酶联免疫吸附法(ELISA)和免疫印迹法(Western blot)检测抗M_3R抗体在干燥综合征、系统性红斑狼疮和健康对照中的阳性率；分析抗M_3R抗体在干燥综合征中的临床意义；通过大鼠模型验证抗M_3R抗体抑制唾液腺分泌的作用。
方法
实验对象：自2005年-2007年于北京协和医院入组国际干燥综合征登记网络研究(SICCA)证实为肯定的干燥综合征患者共70例作为实验组；同期住院诊治的系统性红斑狼疮(SLE)患者且除外继发性干燥综合征共49例作为疾病对照组；并以同期健康献血者共76例作为健康对照组。三组间年龄、性别匹配。
实验方法：以重组的M_3R受体为抗原通过ELISA法检测三组血清中抗M_3R抗体，以健康对照组吸光度的(?)+SD为阳性界定，计算ss组和SLE组的抗M_3R抗体阳性率；并以重组的的抗原用Western法进一步验证ELISA法检测的可靠性；分析SS组中抗M_3R抗体阳性患者较阴性患者在Schirmer试验、BUT、角膜染色、结膜染色、五分钟唾液流率、下唇小唇腺灶性淋巴细胞浸润指数、RF、IgG、抗SSA抗体阳性例数、抗SSB抗体阳性例数间的差异。用亲和层析法纯化抗M_3R抗体阳性患者血清中的IgG型抗M_3R抗体，以15mg／kg的剂量(7．6mg／ml)注射大鼠尾静脉观察大鼠唾液腺流率的改变，阴性对照用相同浓度和剂量的人IVlO，阳性对照用阿托品(0.125mg／kg)。
结果
(1)ELISA法检测76例健康组的(?)+SD的值为0.1710+0．0723，以此为阳性界定值计算出SS患者的抗M_3R抗体的阳性率为47．10％(33／70)，SLE患者组中抗M_3R抗体的阳性率为4．02％(2／49)，健康对照组中抗M_3R抗体的阳性率为14．47％(11／76)；抗M_3R抗体在SS患者中的阳性率明显高于SLE组(47．10％vs 4．02％，p<0．05)健康对照组(47．10％vs 14．47％，p<0．05)，其间有统计学显著差异。而SLE组和健康对照组间的抗M_3R抗体阳性率无统计学差异(4．02％vs 14．47%,P>0．05)。
(2)Western法检测出SS患者的抗M_3R抗体的阳性率为60．00％(42／70)，SLE组巾的抗M3R抗体的阳性率则为12．20％(6／49)，健康对照组中抗M_3R抗体的阳性率为15．79％(12／76)；抗M3R抗体在SS患者中的阳性率明显高于SLE组(60．00％vs12．20％，p<0．05)和健康对照组(60．00% vs 15．79％，p<0．05)，有统计学显著差异。而SLE组和健康对照组间的抗M_3R抗体阳性率无统计学差异(12．20％vs15．79％，P>0．05)。Western法和ELISA法的符合率达74．9％。
(3)SS组中抗M_3R抗体阳性患者IgG(39．97 vs 29．64，p<0．05)、RF值(42．23vs 27．92，p<0．05)及抗SSB抗体阳性例数(31 vs 9，p<0．05)较阴性患者明显增高，其间有统计学显著差异。而抗M_3R抗体阳性组与阴性组相比，唇腺活检阳性率、Schirmer试验、BUT、五分钟唾液流率、角膜染色和结膜染色间无显著统计学差异。但是抗M_3R抗体阳性组的患者唇腺活检中淋巴细胞灶性浸润(?)3的患者例数较阴性组明显为高(27 vs 10)，p<0．05。
(4)以亲和层析柱纯化的含抗M_3R抗体的人血清IgG(实验组，剂量按15mg／kg，浓度为7．6mg／ml)注射大鼠尾静脉后可减少大鼠的唾液流率(0．0938g vs 0．0748g，P>0．05)，阿托品组(阳性对照组)用药后唾液流率较用药前显著减少(0．09327g vs0．02198g，P<0．05)，实验组与阳性对照组相比，减少的差值无显著统计学差异(-0．02227g vs -0．07128g，P>0．05)。正常人IVIG组(阴性对照组)用药后唾液流率较用药前显著增加(0．08230g vs 0．43425g，P<0．05)。比较实验组与阴性对照组用药后与用药前唾液流率改变的差值，两组间差异具有统计学意义(-0．02227gvs0.35195g,P<0．05)。
结论
(1)ELISA和Western法检测SS患者抗M_3R抗体阳性率明显高于SLE患者和健康对照者。
(2)SS患者中抗M_3R抗体阳性组较阴性组IgG值、RF值、抗SSB抗体阳性例数以及下唇小唇腺淋巴细胞浸润为高。
(3)纯化的含抗M_3R抗体的人血清IgG可部分阻断匹罗卡品刺激大鼠唾液腺分泌的功能。
Background
Sjogren syndrome (SS) is a chronic autoimmune disease which occurs mainly in the fourth and fifthdecades and characterized by histologic and functional alterations of exocrine glands with progressive loss of salivary and lacrimal gland secretion. Respiratory, digesting, renal and nervous system are as well involved in SS. There are many mechanisms of loss of exocrine glands such as destruction of the acinar cells by lymphocytes infiltration and the antibody-mediated destruction of the exocrine glands. It has been recently proposed that pathology underlying the glandular hypofunction contributes inhibitory autoantibodies especially the autoantibodies directed against mucarinic recptors. The aim of this work is to test the positive rate of the anti-M_3 receptor antibody in SS , the relationship between the antibody and other clinical manifestations and the salivary flow rate decreased by the affinity-purified antibody from SS patients in mice.
Objectives
To detect anti-M_3 receptor antibodies in Sjogren' s Syndrome (SS) patients, SLE patients and the donating controls by methods of Enzyme linked immunosorbent assay and Western blotting. And to explore its association with clinical manifestation. At last detect the affinity-purified antibody' s pathogenic mechanism in animal experiments.
Materials and Methods
Specimens:70 pieces serum of Sjogren syndrome patients from the SICCAobject in PUMCH from 2005-2007. 49 pieces serum of patients of SLE in-patients in PUMCH at the same time. 76 pieces serum of healthy donators in PUMCH. And the three groups match in sex and age.
Methods: With the muscarinic 3 receptor(from sigma) as the antigen ,to detect anti-muscarinic 3 receptor antibody in SS, SLE and donator controlsusing methods of ELISA. The positive cut-off is (?)+SD in donator controls.And test the positive rate of anti-muscarinic 3 receptor antibody in SS, SLE by means of western blotting. Analyze the differences of the antibody-positive patients and antibody-negative patients in SS in aspects of Schirmer test,BUT,PEE on the corneas,the conjunctival epithelial defects, whole saliva flow rate in 5 minutes,FI,RF,IgG,anti-SSA and anti-SSB.Affinity- purified of human polyclonal IgG antibodies (15mg/kg)by Protein A chromatography was passive transfered to mice and detect the differences of the salivary secrection in the groups of IVIG (15mg/kg)which is the negative controls, atropine(0.125mg/kg) which is the positive controls and the human IgG.
Results
1.Using ELISA the positive rate of anti-M_3 antibody in SS is 47. 10%(33/70), in SLE is 4.02%(2/49) and in donator controls is 14.47%(11/76).The rate in SS is much higher than in SLE(47.10% vs 4.02%,P<0.05). Compared with patients in donator control the antibody is more frequently found in patients with SS(47.10% vs 14.47%, P<0.05).
2. Using Western the positive rate of anti-M_3 antibody in SS is 60.0%, in SLE is 12.2% and in normal controls is 15.79%. Compared with patients with SLE and donator controls, the anti-M_3 antibody in SS is more frequently found,P<0.05.
3. The incidence of IgG,rheumatoid factor, anti-SSB and FI>3 are higher in positive group than in negative group using ELISA. And the differences are significant,P<0.05. But the differences between the two goups in Schirmer test,BUT,PEE on the corneas,the conjunctival epithelial defects, whole saliva flow rate in 5 minutes and anti-SSA are not significant.
4. The data of passive transfer to mice indicates that the recipient mice of purified human IgG from anti-M_3 antibody positive SS(15mg/kg) develop glandular hypofunction which is similar to those recipient mice of atropine. But that is not similar to those recipient mice of IVIG.And the differences between them are significant.P<0.05
Conclusions
1. The positive rate of anti-M_3 antibody in SS is much higher than that in SLE and in normal controls.
2. The IgG, RF, anti-SSB and FI in SS patients with positive anti-muscarinic 3 receptor antibody are much higher than in patients with negativeanti-muscarinic 3 receptor antibody.
3. The data of WS mice experiments indicates that the anti-muscarinic 3 antibody may decrease the salivary secretion.
引文
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12. Dawson LJ, Allison HE, Stanbury J, Fitzgerald D, Smith PM. Putative anti-muscarinic antibodies cannot be detected in patients with primary Sjogren' s syndrome using conventional iiranunological approaches. Rheumatology (Oxford) 2004;43:1488-95.
13. Smith PM. Mechanisms of secretion by salivary glands. In: O' Mullane D, editor. Saliva and oral health. London: British Dental Journal; 1996. p. 9-25.
14. Nakamura T, Matsui M, Uchida K, Futatsugi A, Kusakawa S, Matsumoto N, et al. M_3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol 2004;558:561-75.
15. Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000;97:9579-84.
16. Kidd JF, Thorn P. Intracellular Ca2_ and Cl- channel activation in secretory cells. Annu Rev Physiol 2000;62:493-513.
17. Ehlert FJ, Ostrom RS, Sawyer GW Subtypes of the muscarinic receptor in smooth muscle. Life Sci 61:1729-1740
18. Dai YS, Ambudkar IS, Horn VJ , Yeh CK, Evidence that M3 muscarinic receptors in rat parotid gland couple to two second messenger systems. Am J Physiol. 1991, 261(6 Pt 1):C1063-73.
19. Nakamura T, Matsui M, Uchida K, M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol. 2004, 558(Pt 2):561-75. Epub 2004 ,14.(74)
20. Li J, Ha YM, Ku NY, Choi SY, Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren's syndrome. Lab Invest. 2004, 84(11): 1430-8.(75)
21. Bacman S, Perez Leiros C, Sterin-Borda L. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren's syndrome. Invest Ophthalmol Vis Sci. 1998, 39(1):151-6
22. Sandra Bacman, Alejandro Berra, Leonor Sterin-Borda, Muscarinic Acetylcholine Receptor Antibodies as a New Marker of Dry Eye Sjo"gren Syndrome IOVS, 2001, 42(2)
23. Perez Leiros C, Sterin-Borda L, Borda E, Goin JC, Hosey MM. Desensitization and sequestration of human m2 muscarinic acetylcholine receptors by autoantibodies from patients with Chagas' disease. J Biol Chem. 1997, 272:12989-12993.
24. Bradley ME, Lambert RW, Lee LM, Mircheff AK. Isolation and subcellular fractionation analysis of acini from rabbit lacrimal glands. Invest Ophthalmol Vis Sci. 1992,33:2951-2965.
25. Nakamura M, Tada Y, Akaishi T, Nakata K. M3 muscarinic receptor mediates regulation of protein secretion in rabbit lacrimal gland. Curr Eye Res. 1997, 16:614-619.
26. Tsubota K, Fujihara T, Takeuchi T. Soluble interleukin-2 receptors and serum autoantibodies in dry eye patients: correlation with lacrimal gland function. Cornea. 1997, 16:339-344
27. Cavill D, Waterman SA, Gordon TP. Antibodies raised against the Cavill D, Waterman SA, Gordon TP. Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjogren' s syndrome. Scand J Immunol 2004, 59:261-6
28. Cavill D, Waterman SA, Gordon TP. Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission. Arthritis Rheum 2003, 48:3597-602.
29. Smith AJ, Jackson MW, Wang F, Cavill D, Rischmueller M, Gordon TP. Neutralization of muscarinic receptor autoantibodies by intravenous immunoglobulin in Sjogrens syndrome. Hum Immunol 2005, 66:411-6
30. Wang F, Jackson MW, Maughan V, Cavill D, Smith AJ, Waterman SA, et al. Passive transfer of Sjo'gren' s syndrome IgG produces the pathophysiology of overactive bladder. Arthritis Rheum 2004, 50:3637-45.
31. Bacman S, Perez Leiros C, Sterin-Borda L, et al. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren' s syndrome. Invest Ophthalmol Vis Sci 1998, 39:151-6. 2003;48:3187-201.
3. Jonsson MV, Szodoray P, Jellestad S, Jonsson R,Skarstein K. Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren' s syndrome. J Clin Immunol 2005;25:189-201.
4. Janeway CA, Trabvers P,Walport M,Schlomchik M(2005).Immunobiology:the immunesystem in health and disease. 6~(th)ed.New York:Garland Science publishing.
5. Weyand CM, Kurtin PJ, Goronzy JJ. Ectopic lymphoid organogenesis:a fast track for autoimmunity. Am J Pathol 2001;159:787-93.
6. M.V.Jonsson, S. Salomonsson, G.(?)ijordsbakken & K. Skarstein. Elevated Serum Levels of Soluble E-Cadherin in Patients with Primary Sjogren' s Syndrome.Scandinavian Journal of Immunology 2005,62, 552-559.
7. Hjelmstrom P.Lymphoid neogenesis:de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines.J Leukoc Biol 2001;69:331-9.
8. Malin V.Josson Kathrine Skarstein, Roland Josson, and Johang Brun.Serological Implications of Germinal Center-like Structures in Primary Sj(?)gren' s Syndrome. The Journal of Rheumatology 2007;34:2044-49.
9． 李峰．滤泡树突状细胞与生发中心反应研究的新进展．国际免疫学杂志，2006，(03)，172-5．
10．道书艳，郭葆玉．趋化因子CXCL13及其受体CXCR5研究进展．国外医学分子生物学分册2003：25：200-203．
11. Pascal S.The role of APRIL and BAFF in lymphocyte activation. Cur Opinion Immuno,2005, 17 (3): 282.
12. Burkley CD (2003).Micheal Mason prize essay 2003. Why do luecocytes accumulate within chronically inflamed joints? Rheumatology(Oxford)42(12):1433-1444.
13. Mackay F, Ambrose C: The TNF family members BAFF and APRIL: The growing complexity. Cytokine Growth Factor Rev 14:311-324, 2003.
14. Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM.Malignant lymphoma in primary Sjogren' s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren' s Syndrome. Arthritis Rheum 1999;42:1765-72.
15. Amft N, Curnow SJ, Scheel-Toellner D, et al. Ectopic expression of the B cell - attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjo"gren' s syndrome. Arthritis Rheum 2001:44:2633-41.
16. Barone F, Bombardieri M, Manzo A, et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. Arthritis Rheum. 2005 Jun;52 (6):1773-84.
1. Vitali.C, Bombardieri S,Jonsson R, Moutsopoulos HM(2002) Classification criteria for Sj(?)gren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis61:554-448
2. Routsias JG, Vlachoyiannopoulos PG, Tzioufas AG(2006) Autoantibodies to intracellular autoantigens and their B-cell epitopes: molecular probes to study the autoimmune response. Crit Rev Clin Lab Sci 43:203-248
3. Hammi AR, Al-Hashimi IH,Nunn ME(2005) Assessment of SS-A and SS-B in parotid saliva of patients with Sj(?)gren's syndrome.
4. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA , Hjelmstr(?)m P,Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sj(?)gren's syndrome.Arthritis Rheum. 2003 Nov;48(ll):3187-201.
5. Salomonsson S, Larsson P, Tengnér P, Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sj(?)gren's syndrome. Scand J Immunol. 2002 Apr;55(4):336-42.
6. Tzioufas AG, Hantoumi I,Polihronis M, Autoantibodies to La/SSB in patients with primary Sj(?)gren's syndrome (pSS) are associated with upregulation of La/SSB mRNA in minor salivary gland biopsies (MSGs). J Autoimmun.1999 Dec;13(4):429-34
7. Yannopoulos DI,Roncin S, Lamour A,Pennec YL, Conjunctival epithelial cells from patients with Sj(?)gren's syndrome inappropriately express major histocompatibility complex molecules, La(SSB) antigen, and heat-shock proteins. J Clin Immunol. 1992 Jul;12(4):259-65.
8. Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis Rheum. 2005 May;52(5):1517-21
9. Ben-Chetrit E, Chan EK, Sullivan KF, A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. J Exp Med. 1988 May 1; 167(5): 1560-71.
10. Krishna SS, Majumdar I, Grishin NV. Structural classification of zinc fingers: survey and summary. Nucleic Acids Res. 2003 Jan 15;31 (2):532-50.
11. Blange I, Ringertz NR, Pettersson I. Identification of antigenic regions of the human 52kD Ro/SS-A protein recognized by patient sera. J Autoimmun. 1994 Apr;7(2):263-74.
12. Salomonsson S, Dorner T, Theander E, Bremme K, A serologic marker for fetal risk of congenital heart block. Arthritis Rheum. 2002 May;46(5): 1233-41.
13. Salomonsson S, Sonesson SE, Ottosson L, MuhallabS. Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block. J Exp Med. 2005 Jan 3;201(1):11-7.
14. McClain MT, Heinlen LD, Dennis GJ, Roebuck J. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med. 2005 Jan;11(1):85-9. Epub 2004 Dec 26.
15.Manoussakis MN, Georgopoulou C,Zintzaras E, Sjogren's syndrome associated with systemic lupus erythematosus: clinical and laboratory profiles and comparison with primary Sjogren' s syndrome. Arthritis Rheum. 2004 Mar;50(3):882-91
16. Buyon JP, Clancy RM. Neonatal lupus: basic research and clinical perspectives. Rheum Dis Clin North Am. 2005 May;31 (2):299-313, (55)
17. Vlachoyiannopoulos PG, Drosos AA, Wiik A, Patients with anticentromere antibodies, clinical features, diagnoses and evolution. Br J Rheumatol. 1993 Apr;32(4):297-301.
18. Caramaschi P, Biasi D, Carletto A, Manzo T, Sjogren's syndrome with anticentromere antibodies. Rev Rhum Engl Ed. 1997 Dec;64(12):785-8.
19. Pillemer SR, Casciola-Rosen L, Baum BJ, Centromere protein C is a target of autoantibodies in Sjogren' s syndrome and is uniformly associated with antibodies to Ro and La. J Rheumatol. 2004 Jun;31(6):1121-5.
20.Hsu TC, Chang CH, Lin MC, Anti-CENP-H antibodies in patients with Sjogren' s syndrome. Rheumatol Int. 2006 Feb;26(4):298-303. Epub 2005 Feb8
21. Kino-Ohsaki J, Nishimori I, Morita M, Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjogren's syndrome. Gastroenterology. 1996 May;110(5):1579-86
22. Itoh Y, Reichlin M. Antibodies to carbonic anhydrase in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 1992 Jan; 35(1): 73-82
23. Inagaki Y, Jinno-Yoshida Y, Hamasaki Y, A novel autoantibody reactive with carbonic anhydrase in sera from patients with systemic lupus erythematosus and Sjogren's syndrome. J Dermatol Sci. 1991 May; 2 (3): 147-54.
24. Takemoto F, Hoshino J, Sawa N, Tamura Y, Autoantibodies against carbonic anhydrase II are increased in renal tubular acidosis associated with Sjogren syndrome. Am J Med. 2005 Feb;118(2):181-4.
25. Birdsall NJ, Hulme EC Stockton J Muscarinic receptor subclasses: evidence from binding studies. Adv Biochem Psychopharmacol. 1983;37:323-9.
26. Bonner TI, Buckley NJ, Young AC, Identification of a family of muscarinic acetylcholine receptor genes. Science. 1987 Jul 31;237(4814):527-32.
27. Peralta EG, Ashkenazi A, Winslow JW, Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J. 1987 Dec 20;6(13):3923-9.
28. Jensen RT, Battey JF, Spindel ER, International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev. 2008 Mar;60(1):1-42. Epub 2007 Nov 30.
29. Ehlert FJ, Ostrom RS , Sawyer GW Subtypes of the muscarinic receptor in smooth muscle. Life Sci. 1997;61(18):1729-40.
30. Dai YS, Ambudkar IS, Horn VJ , Yeh CK, Evidence that M3 muscarinic receptors in rat parotid gland couple to two second messenger systems. Am J Physiol. 1991 Dec;261(6 Pt 1):C1063-73.
31.Nakamura T, Matsui M, Uchida K, M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol. 2004 Jul 15;558(Pt 2):561～75. Epub 2004 May 14.
32. Li J, Ha YM, Ku NY, Choi SY, Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren' s syndrome. Lab Invest. 2004 Nov;84(11):1430-8.
33. Bacman S, Perez Leiros C, Sterin-Borda L. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren's syndrome. Invest Ophthalmol Vis Sci. 1998 Jan;39(1):151-6.
34.Robinson CP, Brayer J, Yamachika S, Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjogren' s syndrome. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7538-43.
35. Cavill D, Waterman SA, Gordon TP Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjogren's syndrome. Scand J Immunol. 2004 Mar; 59 (3): 261-6.
36.Wang F, Jackson MW, Maughan V, Passive transfer of Sjogren's syndrome IgG produces the pathophysiology of overactive bladder. Arthritis Rheum. 2004 Nov;50(11):3637-45.
37. Cavill D, Waterman SA, Gordon TP. Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission. Arthritis Rheum. 2003 Dec;48(12):3597-602.
38. Berra A, Sterin-Borda L, Bacman S, Role of salivary IgA in the pathogenesis of Sjogren syndrome. Clin Immunol. 2002 Jul;104(1) : 49-57.
39. Dawson L, Tobin A , Smith P, Antimuscarinic antibodies in Sjogren's syndrome: where are we, and where are we going? Arthritis Rheum. 2005 Oct;52(10):2984-95.
40. Waterman SA, Gordon TP, Rischmueller M Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren's syndrome. Arthritis Rheum. 2000 Jul;43(7):1647-54.
41. Pedersen AM, Dissing S, Fahrenkrug J, Innervation pattern and Ca2+ signalling in labial salivary glands of healthy individuals and patients with primary Sjogren's syndrome (pSS). J Oral Pathol Med. 2000 Mar; 29 (3): 97-109.
42. Bacman S, Sterin-Borda L, Camusso JJ, Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjogren' s syndrome. Clin Exp Immunol. 1996 Jun;104(3):454-9.
43. Fox PC, Speight PM. Current concepts of autoimmune exocrinopathy: immunologic mechanisms in the salivary pathology of Sjogren' s syndrome. Crit Rev Oral Biol Med. 1996;7(2):144-58.
44. Walker J, Gordon T, Lester S, Increased severity of lower urinary tract symptoms and daytime somnolence in primary Sjogren's syndrome. J Rheumatol. 2003 Nov;30(ll):2406-12.
45. Rosztoczy A, Kovacs L, Wittmann T. Manometric assessment of impaired esophageal motor function in primary Sjogren's syndrome. Clin Exp Rheumatol. 2001 Mar-Apr;19(2):147-52.
46. Kovdcs L, Torok T, Bari F, Keri Z. Impaired microvascular response to cholinergic stimuli in primary Sjogren's syndrome. Ann Rheum Dis. 2000 Jan; 59(1): 48-53.
47. Tumiati B, Perazzoli F, Negro A. Heart rate variability in patients with Sjogren's syndrome. Clin Rheumatol. 2000;19(6):477-80.
48. Aoki A, Kirino Y, Ishigatsubo Y. Liver involvement in primary Sjogren's syndrome Nihon Rinsho Mencki Gakkai Kaishi. 2004 Dec;27(6):397-401.
49. Csepregi A, Szodoray P, Zeher M. Do autoantibodies predict autoimmune
2. Zeng F ,Wess J . Molecular aspects of muscarinic receptor dimerization. Neuropsychopharmacology, 2003 ,23 (4 Suppl): S 19-31
3. Rogers DF . Motor control of airway goblet cells and glands. Respir Physiol , 2001 ,125 :1292144.
4. 蒋明 , DAVID YU.中华风湿病学 华夏出版社
5. Humphreys-Beher MG, Brayer J, Yamachika S, Peck AB, Jonsson R. An alternative perspective to the immune response in autoimmune exocrinopathy: induction of functional quiescence rather than destructive autoaggression. Scand J Immunol 1999;49:7 - 10.
6. Fox PC, Speight PM. Current concepts of autoimmune exocrinopathy: immunologic mechanisms in the salivary pathology of Sjogren' s syndrome. Crit Rev Oral Biol Med 1996;7:144-58.
7. Dawson LJ, Smith PM, Moots RJ, Field EA. Sjogren' s syndrome: time for a new approach. Rheumatology (Oxford) 2000;39:234 - 7.
8. Dawson LJ, Field EA, Harmer AR, Smith PM. Acetylcholineevoked calcium mobilization and ion channel activation in human labial gland acinar cells from patients with primary Sjogren' s syndrome. Clin Exp Immunol 2001; 124:480 - 5.
9. Pedersen AM, Dissing S, Fahrenkrug J, Hannibal J, Reibel J, Nauntofte B. Innervation pattern and Ca2_ signalling in labial salivary glands of healthy individuals and patients with primary Sjogren' s syndrome (pSS). J Oral Pathol Med 2000;29:97 - 109.
10. Bacman S, Sterin-Borda L, Camusso JJ, Arana R, Hubscher O, Borda E. Circulating antibodies against rat parotid gland M_3 muscarinic receptors in primary Sjogren' s syndrome. Clin Exp Immunol 1996; 104:454 - 9.
11. Waterman SA, Gordon TP, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren' s syndrome. Arthritis Rheum 2000;43:1647 - 54
12. Dawson LJ, Allison HE, Stanbury J, Fitzgerald D, Smith PM. Putative anti-muscarinic antibodies cannot be detected in patients with primary Sjogren' s syndrome using conventional iiranunological approaches. Rheumatology (Oxford) 2004;43:1488-95.
13. Smith PM. Mechanisms of secretion by salivary glands. In: O' Mullane D, editor. Saliva and oral health. London: British Dental Journal; 1996. p. 9-25.
14. Nakamura T, Matsui M, Uchida K, Futatsugi A, Kusakawa S, Matsumoto N, et al. M_3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol 2004;558:561-75.
15. Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000;97:9579-84.
16. Kidd JF, Thorn P. Intracellular Ca2_ and Cl- channel activation in secretory cells. Annu Rev Physiol 2000;62:493-513.
17. Ehlert FJ, Ostrom RS, Sawyer GW Subtypes of the muscarinic receptor in smooth muscle. Life Sci 61:1729-1740
18. Dai YS, Ambudkar IS, Horn VJ , Yeh CK, Evidence that M3 muscarinic receptors in rat parotid gland couple to two second messenger systems. Am J Physiol. 1991, 261(6 Pt 1):C1063-73.
19. Nakamura T, Matsui M, Uchida K, M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol. 2004, 558(Pt 2):561-75. Epub 2004 ,14.(74)
20. Li J, Ha YM, Ku NY, Choi SY, Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren's syndrome. Lab Invest. 2004, 84(11): 1430-8.(75)
21. Bacman S, Perez Leiros C, Sterin-Borda L. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren's syndrome. Invest Ophthalmol Vis Sci. 1998, 39(1):151-6
22. Sandra Bacman, Alejandro Berra, Leonor Sterin-Borda, Muscarinic Acetylcholine Receptor Antibodies as a New Marker of Dry Eye Sjo"gren Syndrome IOVS, 2001, 42(2)
23. Perez Leiros C, Sterin-Borda L, Borda E, Goin JC, Hosey MM. Desensitization and sequestration of human m2 muscarinic acetylcholine receptors by autoantibodies from patients with Chagas' disease. J Biol Chem. 1997, 272:12989-12993.
24. Bradley ME, Lambert RW, Lee LM, Mircheff AK. Isolation and subcellular fractionation analysis of acini from rabbit lacrimal glands. Invest Ophthalmol Vis Sci. 1992,33:2951-2965.
25. Nakamura M, Tada Y, Akaishi T, Nakata K. M3 muscarinic receptor mediates regulation of protein secretion in rabbit lacrimal gland. Curr Eye Res. 1997, 16:614-619.
26. Tsubota K, Fujihara T, Takeuchi T. Soluble interleukin-2 receptors and serum autoantibodies in dry eye patients: correlation with lacrimal gland function. Cornea. 1997, 16:339-344
27. Cavill D, Waterman SA, Gordon TP. Antibodies raised against the Cavill D, Waterman SA, Gordon TP. Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjogren' s syndrome. Scand J Immunol 2004, 59:261-6
28. Cavill D, Waterman SA, Gordon TP. Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission. Arthritis Rheum 2003, 48:3597-602.
29. Smith AJ, Jackson MW, Wang F, Cavill D, Rischmueller M, Gordon TP. Neutralization of muscarinic receptor autoantibodies by intravenous immunoglobulin in Sjogrens syndrome. Hum Immunol 2005, 66:411-6
30. Wang F, Jackson MW, Maughan V, Cavill D, Smith AJ, Waterman SA, et al. Passive transfer of Sjo'gren' s syndrome IgG produces the pathophysiology of overactive bladder. Arthritis Rheum 2004, 50:3637-45.
31. Bacman S, Perez Leiros C, Sterin-Borda L, et al. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren' s syndrome. Invest Ophthalmol Vis Sci 1998, 39:151-6. 2003;48:3187-201.
3. Jonsson MV, Szodoray P, Jellestad S, Jonsson R,Skarstein K. Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren' s syndrome. J Clin Immunol 2005;25:189-201.
4. Janeway CA, Trabvers P,Walport M,Schlomchik M(2005).Immunobiology:the immunesystem in health and disease. 6~(th)ed.New York:Garland Science publishing.
5. Weyand CM, Kurtin PJ, Goronzy JJ. Ectopic lymphoid organogenesis:a fast track for autoimmunity. Am J Pathol 2001;159:787-93.
6. M.V.Jonsson, S. Salomonsson, G.(?)ijordsbakken & K. Skarstein. Elevated Serum Levels of Soluble E-Cadherin in Patients with Primary Sjogren' s Syndrome.Scandinavian Journal of Immunology 2005,62, 552-559.
7. Hjelmstrom P.Lymphoid neogenesis:de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines.J Leukoc Biol 2001;69:331-9.
8. Malin V.Josson Kathrine Skarstein, Roland Josson, and Johang Brun.Serological Implications of Germinal Center-like Structures in Primary Sj(?)gren' s Syndrome. The Journal of Rheumatology 2007;34:2044-49.
9． 李峰．滤泡树突状细胞与生发中心反应研究的新进展．国际免疫学杂志，2006，(03)，172-5．
10．道书艳，郭葆玉．趋化因子CXCL13及其受体CXCR5研究进展．国外医学分子生物学分册2003：25：200-203．
11. Pascal S.The role of APRIL and BAFF in lymphocyte activation. Cur Opinion Immuno,2005, 17 (3): 282.
12. Burkley CD (2003).Micheal Mason prize essay 2003. Why do luecocytes accumulate within chronically inflamed joints? Rheumatology(Oxford)42(12):1433-1444.
13. Mackay F, Ambrose C: The TNF family members BAFF and APRIL: The growing complexity. Cytokine Growth Factor Rev 14:311-324, 2003.
14. Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM.Malignant lymphoma in primary Sjogren' s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren' s Syndrome. Arthritis Rheum 1999;42:1765-72.
15. Amft N, Curnow SJ, Scheel-Toellner D, et al. Ectopic expression of the B cell - attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjo"gren' s syndrome. Arthritis Rheum 2001:44:2633-41.
16. Barone F, Bombardieri M, Manzo A, et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. Arthritis Rheum. 2005 Jun;52 (6):1773-84.
1. Vitali.C, Bombardieri S,Jonsson R, Moutsopoulos HM(2002) Classification criteria for Sj(?)gren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis61:554-448
2. Routsias JG, Vlachoyiannopoulos PG, Tzioufas AG(2006) Autoantibodies to intracellular autoantigens and their B-cell epitopes: molecular probes to study the autoimmune response. Crit Rev Clin Lab Sci 43:203-248
3. Hammi AR, Al-Hashimi IH,Nunn ME(2005) Assessment of SS-A and SS-B in parotid saliva of patients with Sj(?)gren's syndrome.
4. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA , Hjelmstr(?)m P,Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sj(?)gren's syndrome.Arthritis Rheum. 2003 Nov;48(ll):3187-201.
5. Salomonsson S, Larsson P, Tengnér P, Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sj(?)gren's syndrome. Scand J Immunol. 2002 Apr;55(4):336-42.
6. Tzioufas AG, Hantoumi I,Polihronis M, Autoantibodies to La/SSB in patients with primary Sj(?)gren's syndrome (pSS) are associated with upregulation of La/SSB mRNA in minor salivary gland biopsies (MSGs). J Autoimmun.1999 Dec;13(4):429-34
7. Yannopoulos DI,Roncin S, Lamour A,Pennec YL, Conjunctival epithelial cells from patients with Sj(?)gren's syndrome inappropriately express major histocompatibility complex molecules, La(SSB) antigen, and heat-shock proteins. J Clin Immunol. 1992 Jul;12(4):259-65.
8. Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis Rheum. 2005 May;52(5):1517-21
9. Ben-Chetrit E, Chan EK, Sullivan KF, A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. J Exp Med. 1988 May 1; 167(5): 1560-71.
10. Krishna SS, Majumdar I, Grishin NV. Structural classification of zinc fingers: survey and summary. Nucleic Acids Res. 2003 Jan 15;31 (2):532-50.
11. Blange I, Ringertz NR, Pettersson I. Identification of antigenic regions of the human 52kD Ro/SS-A protein recognized by patient sera. J Autoimmun. 1994 Apr;7(2):263-74.
12. Salomonsson S, Dorner T, Theander E, Bremme K, A serologic marker for fetal risk of congenital heart block. Arthritis Rheum. 2002 May;46(5): 1233-41.
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