补体变化和重症肌无力病情的关系
|
摘要
目的:
全身型重症肌无力(GMG)的病情恶化,可以导致患者吞咽不能、呼吸困难、甚至危及生命,预测患者病情变化,防治GMG病情恶化极为重要,为达到防治的目的,就需要有预测患者病情恶化的指标,本试验目的就是监测患者病情变化,探索病情变化的有关检验指标,探求可靠性指标变化来预测病情变化,评价临床治疗效果,指导临床防治GMG。
方法:
对确诊入选的GMG患者病情利用标准病情评分量表进行定量评分(QMGS),并对GMG患者进行CHEI,GCS,IVIG规范化治疗前、治疗中,及治疗后的病情进行评分,治疗前、中、后利用免疫比浊法检测患者血清补体(C3)浓度和放射免疫法测定AchRAb滴度及其变化,分析患者C浓度、AchRAb滴度和GMG患者病情之间的关系。
结果:
①在治疗前,患者C3浓度水平和患者AChRAb滴度水平与患者的病情严重程度没有明显的相关性。②治疗过程中,患者病情好转,病情评分下降,AchRAb阳性患者C3浓度增加。③治疗过程中随患者病情好AChRAb阴性患者C3浓度变化不明显。④治疗过程中AChRAb阳性患者,AChRAb滴度降低。⑤治疗过程中,在AChRAb阳性患者,患者病情的变化和补体的变化负相关;在AChRAb阴性患者,病情的变化和补体的变化无明显的相关性,AChRAb滴度变化和病情的变化无明显的相关性。⑥在AChRAb阳性患者,补体变化和病情变化的相关强度和治疗方法有关。⑦典型相关分析显示,AChRAb阳性患者病情变化和补体浓度以及AChRAb滴度变化相关,并且补体浓度的相关性明显强于AChRAb滴度。
结论:
在AChRAb阳性患者,补体的变化和病情的变化相关,监测补体的变化趋势可以预测病情的发展,以使患者得到及时有效的治疗,防治GMG病情恶化,并能评估临床治疗效果,指导临床及时有效地调整治疗方案。
Acute exacerbation of generalized myasthenia gravis (MG) can cause swallowing impairment,respiratory failure or life-threatening. It is important to identify immunological factors reliably predict the severity variation of MG. The aim of present study to investigate correlations among the complement (C) 3, acetylcholine receptor antibody (AChRab) titer and clinical severity of generalized MG (GMG). AChRab titer and C component 3 concentration was tested by radioimmunoassay and nephelometry respectively. Correlations among MG score, AChRab titer and C3 concentration were dissected. C3 level did not correlate with the severity of MG and AChRab titer, but variation of GMG severity correlated with variation of C3 concentration in AChRab positive GMG patients. Current study indicates that monitoring the variation of C3 concentration can predict the variation of clinical severity of AChRab positive GMG.
全身型重症肌无力(GMG)的病情恶化,可以导致患者吞咽不能、呼吸困难、甚至危及生命,预测患者病情变化,防治GMG病情恶化极为重要,为达到防治的目的,就需要有预测患者病情恶化的指标,本试验目的就是监测患者病情变化,探索病情变化的有关检验指标,探求可靠性指标变化来预测病情变化,评价临床治疗效果,指导临床防治GMG。
方法:
对确诊入选的GMG患者病情利用标准病情评分量表进行定量评分(QMGS),并对GMG患者进行CHEI,GCS,IVIG规范化治疗前、治疗中,及治疗后的病情进行评分,治疗前、中、后利用免疫比浊法检测患者血清补体(C3)浓度和放射免疫法测定AchRAb滴度及其变化,分析患者C浓度、AchRAb滴度和GMG患者病情之间的关系。
结果:
①在治疗前,患者C3浓度水平和患者AChRAb滴度水平与患者的病情严重程度没有明显的相关性。②治疗过程中,患者病情好转,病情评分下降,AchRAb阳性患者C3浓度增加。③治疗过程中随患者病情好AChRAb阴性患者C3浓度变化不明显。④治疗过程中AChRAb阳性患者,AChRAb滴度降低。⑤治疗过程中,在AChRAb阳性患者,患者病情的变化和补体的变化负相关;在AChRAb阴性患者,病情的变化和补体的变化无明显的相关性,AChRAb滴度变化和病情的变化无明显的相关性。⑥在AChRAb阳性患者,补体变化和病情变化的相关强度和治疗方法有关。⑦典型相关分析显示,AChRAb阳性患者病情变化和补体浓度以及AChRAb滴度变化相关,并且补体浓度的相关性明显强于AChRAb滴度。
结论:
在AChRAb阳性患者,补体的变化和病情的变化相关,监测补体的变化趋势可以预测病情的发展,以使患者得到及时有效的治疗,防治GMG病情恶化,并能评估临床治疗效果,指导临床及时有效地调整治疗方案。
Acute exacerbation of generalized myasthenia gravis (MG) can cause swallowing impairment,respiratory failure or life-threatening. It is important to identify immunological factors reliably predict the severity variation of MG. The aim of present study to investigate correlations among the complement (C) 3, acetylcholine receptor antibody (AChRab) titer and clinical severity of generalized MG (GMG). AChRab titer and C component 3 concentration was tested by radioimmunoassay and nephelometry respectively. Correlations among MG score, AChRab titer and C3 concentration were dissected. C3 level did not correlate with the severity of MG and AChRab titer, but variation of GMG severity correlated with variation of C3 concentration in AChRab positive GMG patients. Current study indicates that monitoring the variation of C3 concentration can predict the variation of clinical severity of AChRab positive GMG.
引文
1许贤豪,加强重症肌无力临床和基础的协作研究[J].中国神经免疫学和神经病学杂志,2000,7(4):195-196.
2 Vinken PJ ,Bruya GW. Handbook of clinical neurology[M]. NewYork. Northe Holland Company, 1979: 95-122.
3 Engel AG, Santa T. Histometric analysis of the ultrastructure of the neuromuscular junction in myasthenia gravis and in the myasthenic syndrome [J]. Ann New York Acad Sci, 1971, 183: 46-63.
4 Engel AG, Lambert EH, Howard FM. Immune complexes ( IgG and C3 ) at the motor end-plate in myasthenia gravis [J]. Mayoclin Proc, 1977, 52: 276-280.
5 Whiting P, Lindstrom J. Purification and characterization of anticotinic acetylcholine receptor from rat brain [J]. Proc Natl Acad Sci USA, 1987, 84: 595-599.
6 Zhang GX, Xiao BG,Bakhiet M. Both CD4+ T cells are essential to induce experimental auto immune myasthenia grvis [J]. Exp Med, 1996, 184: 349-356.
7 Blount, P. and J.P. Merlie, Molecular basis of the two nonequivalent ligand binding sites of the muscle nicotinic acetylcholine receptor [J]. Neuron, 1989. 3(3): 349-357.
8 Paas Rozner M,Sela M,Mozes E.The nature of the active suppression of respons associated with the experimental anto immune [J]. Proc Natl Acad Sci USA,2001,98(22):12642-12647.
9李作孝,徐文桢,陈平.ELISA间接测定AchRab对重症肌无力的诊断价值[J].华西医学,1995, 10(1):46-49.
10 Engel AG,Arahata.K.The membrane attack complex of complement at the endplate in myasthenia gravis [J] . Ann NY AcadSci,1987,505:326-332.
11 Engel AG.Myasthenia gravis and myasthenic syndromes [J]. Ann Neural, 1984,16:519-534.
12 Dmehman DB,Angus DW ,Adams KN.Myasthenia antibodies cross link AchR to accelerate degradation [J].N Engl Med.1978,298:1116-1122.
13 Drachman DB, Adams RN,Josifek LF . Functional activities,of autoantibodies to AchR and the clinical severity of myasthenia gravis [J]. N Engl Med,1982,307:769-775.
14 Kupersmith MJ, Latkany R, Homel P. Beneficial effects of cortico steriods on ocular myasthenia gravis [J]. A rch N euro l, 1996, 53: 802-804.
15 Moiola,Galbiati,Martino . IL-12 is involved in the induction of experimental autoimmune myasthenia gravis,an antibody-mediated disease [J]. Eur J Immunol,1998,28:2487-2497.
16 Drachman DB. Masthenia gravis [J]. N Eng J Med. 1994, 330(25):1797-1810.
17 Bruges J. Passive transfer of seronegative myasthenia gravis to mice [J]. Muscle Nerve,1994,17:1393-1400.
18 Mossman S,Vincent A,Newsom-Davis J, Myasthenia gravis without acetylcholine receptor antibody:a distinct disease entity [J]. Lancet,1986,1: ll6-ll8.
19 Hoch W . Mclonville J,Melms A . Antibodies to the receplor tyrosinekinase MuSK in patients with myasthenia gravis without AchRab [J]. Nat Med.2001.7:365-368.
20 Yamamoto AM, Gajdos P, Eymard B.Anti-titin antibodies in myasthenia gravis: tight as sociation with thymoma and heterogeneity of non thymoma patients [J]. Arch Neurol 2001,58:885-890.
21陈向军,吕传真肌联蛋白抗体在诊断胸腺瘤重症肌无力中的意义[J].中华医学杂志,2001,81(18):1118-1120.
22赖祥青,杨明山.重症肌无力患者免疫发病机制的研究[J].中国病理生理杂志,2001,17(7):662-665.
23都爱莲,任惠民,吕传真.重症肌无力发病的非乙酰胆碱受体抗体机制[J] .中华神经科杂志,2003,36(1):57-58.
24 Osserman KE. Myasthenia gravis [M]. New york:Grune & Straton, 1958. 79-86.
25 Alfred J, Richard JB, Raina ME. Myasthenia gravis : recommendations for clinical research standards [J] . Ann thorac surg , 2000 , 70:327-334.
26 Monden Y, Nakahara K, Kagotani K. Effects of preoperative duration of symptoma on patients with myasthenia gravis. [J]. Ann Thorac Surg , 1984 , 38 :287-291.
27 Ciafaloni E , Massey JM , Tucker B. Mycophenolate mofetil for myasthenia gravis : an open-label pilot study. [J]. Neurology , 2001 , 56 :97-99.
28 Chiu HC, Chen WH, Yeh J H. The six year experenice of plasmapheresis in patients with myasthenia gravis. [J]. Ther Apher , 2000 , 4 :291-295.
29徐文桢,龚潮梁,高国勖.乙酰胆碱受体抗体测定对重症肌无力的诊断价值[J].中国神经精神疾病杂志, 1989, 15: 4-7.
30许贤豪.神经免疫学[M].北京:北京医科大学中国协和医科大学联合出版社,1992,119-287.
31 Torzewsjki J, Bowher DE, Wlatenberger J, Fitzsimmons C. Processes in atherogenesis: complement activation [J]. Atherosclerosis. 2007;132:131-138.
32 Arumugam TV, Shields IA, Woodruff TM, Granger DN, Taylor SM. The role of the complement system in ischemia-reperfusion injury [J]. Shock. 2004;21:401-409.
33 Del Conde I, Cruz MA, Zhang H, Lopez JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system [J]. J. Exp. Med. 2005;201:871-879.
34 Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuireSR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetse RA, Ward PA. Generation of C5a in the absence of C3: a new complement activation pathway [J]. Nat. Med. 2006;12:682-687.
35 Makrides SC. Therapeutic inhibition of the complement system [J]. Pharmacol. Rev. 1998;150:59-87.
36 Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight [J]. Am. J. Pathol. 2007;171:715-727.
37 Peerschke EIB, Yin W, Grigg SE, Ghebrehiwet B. Blood platelets activate the classical pathway of human complement [J]. J Thromb Haemost. 2006;4:2035-2042.
38 Mollnes TE. Hogasen K,De-Carolis C . High-dose intravenous immunoglobulin treatment activates complement in vivo scand [J]. Immunol,1998,48:312-317.
39 Tolnay M,Tsokos GC.Complement receptor 2 in the regulation of the immune esponse [J]. Clin Immuno Immunopatho1,1998,88:123-132.
40 Nielsen CH ,Fischer EM ,Leslie RG.The role of complement in the acquired immune response [J]. Immunology,2000, 100:4-12.
41 Korb LC.Ahearn JM.C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited [J]. Immunol,1997,1 58:4525-4528.
42 Navratil JS.Korb LC. Ahearn JM.Systemic lupus erythematosus and complement deficiency:clues to a novel role for the classical complement pathway in the maintenance of immune tolerance [J]. Immunopharmacol, 1999,42:47-52.
43 Reid RR.Prodeus AP,Khan W.Endotoxin shock in antibody-deficient mice:unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide [J]. J Immunol,1997,159:970-975.
44 Davout N.Nataf S.Reiman R.Central nervous sytem targeted expression of the complement inhibitor sCrry prevents experimental allergic encephalomyelitis [J]. Immunol, 1999, 163: 6551-6556.
45 Nikolajeva V,Eze D,Petrina Z, Muiznieks I. Treatment of experimental autoimmune encephalomyelitis with adenylate deaminase from penicillium lanoso-viride [J]. Journal Of Autoimmunity 2000, 2:107-113.
46 Richman DP, Agius MA, Treatment principles in the management of autoimmune myasthenia gravis [J]. Neurology ,2003,12: 1652-1661.
47 Fredrik R,Kristoffersen K,Johan A,et al. The role of complement in myasthenia gravis:serological evidence of complement consumption in vivo [J]. Neuroimmunol, 2005,158:191-194.
48 Ptak J,Lochman J.Immunoadsorption therapy and complement activation [J]. Trans and Aph Sci,2005,32:263-267.
49 Milan B,Isabel I,Marines C,et al.Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barre syndrome,myasthenia gravis and dermatomyositis [J]. Neuroimmunol, 1996,71:227-229.
50 Zander T,Schwab S,Laufenberg I. Immunohistochemical detection of complement factors: a reliable method for the diagnosis of myasthenia gravis [J]. Der Nervenarzt 2000,8: 666-669.
51 Kaminski HJ, Li Z, Richmonds C, Lin F, Medof ME. Complement regulators in extraocular muscle and experimental autoimmune myasthenia gravis [J]. Exp Neurol,2004,189:333-342.
52 Feng Lin, Henry J. Kaminski, et al. Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection [J]. The Journal of Clinical Investigation,2002, 9:1269-1274.
53 Biesecker G, Gomez CM.Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6 [J]. Journal Of Immunology ,1989,8: 2654-2659.
54 Barohn RJ, Brey, RL.Soluble terminal complement components in human myasthenia gravis [J]. Clinical Neurology And Neurosurgery ,1993, 4: 285-290.
55 Erdem N,Scott B,Benjamin G,et al.Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis[J]. Immunol,2003,171(7):3847-3854.
56 Lefvert AK, Bergstr?m K, Matell G, Osterman PO, Pirskanen R. Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications[J]. J Neurol Neurosurg Psychiatry 1978;41:394-403.
57 Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, et al. Treatment of MG exacerbation with intravenous immunoglobulin: A randomized double-blind clinical trial [J]. Arch Neurol 2005;62:1689-1693.
58 Husain AM, Massey JM, Howard JF, Sanders DB. Acetylcholine receptor antibody measurements in acquired myasthenia gravis. Diagnostic sensitivity and predictive value for thymoma [J]. Ann N Y Acad Sci 1998;841,471-474.
59 Jitpimolmard S, Taimkao S, Chotmongkol V, Sawanyawisuth K, Vincent A, Newsom-Davis J. Acetylcholine receptor antibody in Thai generalized myasthenia gravis patients [J]. J Med Assoc Thai 2006;89:68-71.
60 Chamberlain-Banoub J, Neal JW, Mizuno M, Harris CL, Morgan BP. Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats [J]. Clin Exp Immunol 2006;146:278-286.
61 Vergani D, Mieli-Vergani G. Autoimmune hepatitis [J]. Ann Ital Med Int 1996;11:119-124.
62 Loutrari H, Tzartos SJ, Claudio T. Use of Torpedo-mouse hybrid acetylcholine receptors reveals immunodominance of theαsubunit in myasthenia gravis antisera [J]. Eur J Immunol 1992;22:2949-2956.
63 Kuncl RW, Drachman DB, Adams R, Lehar M. 3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors [J]. J Pharmacol Exp Ther 1993;267:582-589.
64 Tüzün E, Saini SS, Ghosh S, Rowin J, Meriggioli MN, Christadoss P. Predictive value of serum anti-C1q antibody level in experimental autoimmune myasthenia gravis [J]. Neuromuscul Disord 2006;16:137-143.
65 Kuttner-Kondo LA, Dybvig MP, Mitchell LM, Muqim N, Atkinson JP, Medof ME,et al. A corresponding tyrosine residue in the C2/factor B type A domain is a hot spot in the decay acceleration of the complement C3 convertases [J]. J Biol Chem 2003;278:52386-52391.
66 Besinger UA, Toyka KV, H?mberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A. Myasthenia gravis: Long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity [J]. Neurology 1983;33:1316-1321.
67 Zimmermann-Nielsen E, Gr?nbaek H, Dahlerup JF, Baatrup G, Thorlacius-Ussing O. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis [J]. BMC Gastroenterol 2005;5:31-37.
68 Najam FI, Giasuddin AS, Shembesh AH. Complement components (C3, C4) in childhood asthma [J]. Indian J Pediatr 2005;72:745-749.
69 Zimmer B, Hartung HP, Scharfenberger G, Bitter-Suermann P, Hadding U. Quantitative studies of the secretion of complement C3 by resident, elicited and activated macrophages. Comparison with C2, C4 and lysosomal enzyme release [J]. Eur J Immunol 1982;12:426-430.
70 Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY: Reference distributions for complement proteins C3 and C4: a practical, simple and clinically relevant approach in a large cohort [J]. JClin Lab Anal 2004;18:1-8.
71 Engstr?m G, Hedblad B, Eriksson KF, Janzon L, Lindg?rde F. Complement C3 is a risk factor for the development of diabetes: a population-based cohort study [J]. Diabetes 2005;54:570-575.
72 Motomura M, Fukuda T, Yoshimura T, Tsujihata M. Overview: MuSK/Dok-7 [J]. Nippon Rinsho 2008;66:1140-1148.
73 Tüzün E, Scott BG, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune MG [J]. J Immunol 2003;171:3847-3854.
74 Kuncl RW, Drachman DB, Adams R, Lehar M. 3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors [J]. J Pharmacol Exp Ther 1993;267:582-589.
75 Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future [J]. J Clin Invest 2006;116:2843-2854.
76 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets [J]. Lancet Neurol 2003;2:99-106.
77 Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis [J]. Ann Neurol 2005;57:289-293.
78 Motomura M, Fukuda T, Yoshimura T, Tsujihata M. Overview: MuSK/Dok-7 [J]. Nippon Rinsho 2008;66:1140-1148.
79 Atkinson JP, Frank MM. Effect of cortisone therapy on serum complement components [J]. J Immunol 1973;111:1061-1066.
80 Jansen NJ, van Oeveren W, van Vliet M, Stoutenbeek CP, Eysman L, Wildevuur CR. The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass [J]. Eur J Cardiothorac Surg 1991;5:211-217.
81 Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practicaltherapeutic guidelines [J]. Muscle Nerve 1999;22:1479-1497.
82 Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor [J]. Science 2001;291:484-486.
83 Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments [J]. J Clin Invest 1994;94:1729-1735.
84 Lutz HU, Stammler P, Jelezarova E, Nater M, Sp?th PJ. High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes [J]. Blood 1996;88:184-193.
85 Lutz HU, Stammler P, Bianchi V, Trüeb RM, Hunziker T, Burger R, et al. Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level [J]. Blood 2004;103:465-472.
86 Christadoss P, Tüzün E, Li J, Saini SS, Yang H. Classical complement pathway in experimental autoimmune myasthenia gravis pathogenesis [J]. Ann N Y Acad Sci 2008;1132:210-219.
2 Vinken PJ ,Bruya GW. Handbook of clinical neurology[M]. NewYork. Northe Holland Company, 1979: 95-122.
3 Engel AG, Santa T. Histometric analysis of the ultrastructure of the neuromuscular junction in myasthenia gravis and in the myasthenic syndrome [J]. Ann New York Acad Sci, 1971, 183: 46-63.
4 Engel AG, Lambert EH, Howard FM. Immune complexes ( IgG and C3 ) at the motor end-plate in myasthenia gravis [J]. Mayoclin Proc, 1977, 52: 276-280.
5 Whiting P, Lindstrom J. Purification and characterization of anticotinic acetylcholine receptor from rat brain [J]. Proc Natl Acad Sci USA, 1987, 84: 595-599.
6 Zhang GX, Xiao BG,Bakhiet M. Both CD4+ T cells are essential to induce experimental auto immune myasthenia grvis [J]. Exp Med, 1996, 184: 349-356.
7 Blount, P. and J.P. Merlie, Molecular basis of the two nonequivalent ligand binding sites of the muscle nicotinic acetylcholine receptor [J]. Neuron, 1989. 3(3): 349-357.
8 Paas Rozner M,Sela M,Mozes E.The nature of the active suppression of respons associated with the experimental anto immune [J]. Proc Natl Acad Sci USA,2001,98(22):12642-12647.
9李作孝,徐文桢,陈平.ELISA间接测定AchRab对重症肌无力的诊断价值[J].华西医学,1995, 10(1):46-49.
10 Engel AG,Arahata.K.The membrane attack complex of complement at the endplate in myasthenia gravis [J] . Ann NY AcadSci,1987,505:326-332.
11 Engel AG.Myasthenia gravis and myasthenic syndromes [J]. Ann Neural, 1984,16:519-534.
12 Dmehman DB,Angus DW ,Adams KN.Myasthenia antibodies cross link AchR to accelerate degradation [J].N Engl Med.1978,298:1116-1122.
13 Drachman DB, Adams RN,Josifek LF . Functional activities,of autoantibodies to AchR and the clinical severity of myasthenia gravis [J]. N Engl Med,1982,307:769-775.
14 Kupersmith MJ, Latkany R, Homel P. Beneficial effects of cortico steriods on ocular myasthenia gravis [J]. A rch N euro l, 1996, 53: 802-804.
15 Moiola,Galbiati,Martino . IL-12 is involved in the induction of experimental autoimmune myasthenia gravis,an antibody-mediated disease [J]. Eur J Immunol,1998,28:2487-2497.
16 Drachman DB. Masthenia gravis [J]. N Eng J Med. 1994, 330(25):1797-1810.
17 Bruges J. Passive transfer of seronegative myasthenia gravis to mice [J]. Muscle Nerve,1994,17:1393-1400.
18 Mossman S,Vincent A,Newsom-Davis J, Myasthenia gravis without acetylcholine receptor antibody:a distinct disease entity [J]. Lancet,1986,1: ll6-ll8.
19 Hoch W . Mclonville J,Melms A . Antibodies to the receplor tyrosinekinase MuSK in patients with myasthenia gravis without AchRab [J]. Nat Med.2001.7:365-368.
20 Yamamoto AM, Gajdos P, Eymard B.Anti-titin antibodies in myasthenia gravis: tight as sociation with thymoma and heterogeneity of non thymoma patients [J]. Arch Neurol 2001,58:885-890.
21陈向军,吕传真肌联蛋白抗体在诊断胸腺瘤重症肌无力中的意义[J].中华医学杂志,2001,81(18):1118-1120.
22赖祥青,杨明山.重症肌无力患者免疫发病机制的研究[J].中国病理生理杂志,2001,17(7):662-665.
23都爱莲,任惠民,吕传真.重症肌无力发病的非乙酰胆碱受体抗体机制[J] .中华神经科杂志,2003,36(1):57-58.
24 Osserman KE. Myasthenia gravis [M]. New york:Grune & Straton, 1958. 79-86.
25 Alfred J, Richard JB, Raina ME. Myasthenia gravis : recommendations for clinical research standards [J] . Ann thorac surg , 2000 , 70:327-334.
26 Monden Y, Nakahara K, Kagotani K. Effects of preoperative duration of symptoma on patients with myasthenia gravis. [J]. Ann Thorac Surg , 1984 , 38 :287-291.
27 Ciafaloni E , Massey JM , Tucker B. Mycophenolate mofetil for myasthenia gravis : an open-label pilot study. [J]. Neurology , 2001 , 56 :97-99.
28 Chiu HC, Chen WH, Yeh J H. The six year experenice of plasmapheresis in patients with myasthenia gravis. [J]. Ther Apher , 2000 , 4 :291-295.
29徐文桢,龚潮梁,高国勖.乙酰胆碱受体抗体测定对重症肌无力的诊断价值[J].中国神经精神疾病杂志, 1989, 15: 4-7.
30许贤豪.神经免疫学[M].北京:北京医科大学中国协和医科大学联合出版社,1992,119-287.
31 Torzewsjki J, Bowher DE, Wlatenberger J, Fitzsimmons C. Processes in atherogenesis: complement activation [J]. Atherosclerosis. 2007;132:131-138.
32 Arumugam TV, Shields IA, Woodruff TM, Granger DN, Taylor SM. The role of the complement system in ischemia-reperfusion injury [J]. Shock. 2004;21:401-409.
33 Del Conde I, Cruz MA, Zhang H, Lopez JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system [J]. J. Exp. Med. 2005;201:871-879.
34 Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuireSR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetse RA, Ward PA. Generation of C5a in the absence of C3: a new complement activation pathway [J]. Nat. Med. 2006;12:682-687.
35 Makrides SC. Therapeutic inhibition of the complement system [J]. Pharmacol. Rev. 1998;150:59-87.
36 Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight [J]. Am. J. Pathol. 2007;171:715-727.
37 Peerschke EIB, Yin W, Grigg SE, Ghebrehiwet B. Blood platelets activate the classical pathway of human complement [J]. J Thromb Haemost. 2006;4:2035-2042.
38 Mollnes TE. Hogasen K,De-Carolis C . High-dose intravenous immunoglobulin treatment activates complement in vivo scand [J]. Immunol,1998,48:312-317.
39 Tolnay M,Tsokos GC.Complement receptor 2 in the regulation of the immune esponse [J]. Clin Immuno Immunopatho1,1998,88:123-132.
40 Nielsen CH ,Fischer EM ,Leslie RG.The role of complement in the acquired immune response [J]. Immunology,2000, 100:4-12.
41 Korb LC.Ahearn JM.C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited [J]. Immunol,1997,1 58:4525-4528.
42 Navratil JS.Korb LC. Ahearn JM.Systemic lupus erythematosus and complement deficiency:clues to a novel role for the classical complement pathway in the maintenance of immune tolerance [J]. Immunopharmacol, 1999,42:47-52.
43 Reid RR.Prodeus AP,Khan W.Endotoxin shock in antibody-deficient mice:unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide [J]. J Immunol,1997,159:970-975.
44 Davout N.Nataf S.Reiman R.Central nervous sytem targeted expression of the complement inhibitor sCrry prevents experimental allergic encephalomyelitis [J]. Immunol, 1999, 163: 6551-6556.
45 Nikolajeva V,Eze D,Petrina Z, Muiznieks I. Treatment of experimental autoimmune encephalomyelitis with adenylate deaminase from penicillium lanoso-viride [J]. Journal Of Autoimmunity 2000, 2:107-113.
46 Richman DP, Agius MA, Treatment principles in the management of autoimmune myasthenia gravis [J]. Neurology ,2003,12: 1652-1661.
47 Fredrik R,Kristoffersen K,Johan A,et al. The role of complement in myasthenia gravis:serological evidence of complement consumption in vivo [J]. Neuroimmunol, 2005,158:191-194.
48 Ptak J,Lochman J.Immunoadsorption therapy and complement activation [J]. Trans and Aph Sci,2005,32:263-267.
49 Milan B,Isabel I,Marines C,et al.Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barre syndrome,myasthenia gravis and dermatomyositis [J]. Neuroimmunol, 1996,71:227-229.
50 Zander T,Schwab S,Laufenberg I. Immunohistochemical detection of complement factors: a reliable method for the diagnosis of myasthenia gravis [J]. Der Nervenarzt 2000,8: 666-669.
51 Kaminski HJ, Li Z, Richmonds C, Lin F, Medof ME. Complement regulators in extraocular muscle and experimental autoimmune myasthenia gravis [J]. Exp Neurol,2004,189:333-342.
52 Feng Lin, Henry J. Kaminski, et al. Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection [J]. The Journal of Clinical Investigation,2002, 9:1269-1274.
53 Biesecker G, Gomez CM.Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6 [J]. Journal Of Immunology ,1989,8: 2654-2659.
54 Barohn RJ, Brey, RL.Soluble terminal complement components in human myasthenia gravis [J]. Clinical Neurology And Neurosurgery ,1993, 4: 285-290.
55 Erdem N,Scott B,Benjamin G,et al.Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis[J]. Immunol,2003,171(7):3847-3854.
56 Lefvert AK, Bergstr?m K, Matell G, Osterman PO, Pirskanen R. Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications[J]. J Neurol Neurosurg Psychiatry 1978;41:394-403.
57 Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, et al. Treatment of MG exacerbation with intravenous immunoglobulin: A randomized double-blind clinical trial [J]. Arch Neurol 2005;62:1689-1693.
58 Husain AM, Massey JM, Howard JF, Sanders DB. Acetylcholine receptor antibody measurements in acquired myasthenia gravis. Diagnostic sensitivity and predictive value for thymoma [J]. Ann N Y Acad Sci 1998;841,471-474.
59 Jitpimolmard S, Taimkao S, Chotmongkol V, Sawanyawisuth K, Vincent A, Newsom-Davis J. Acetylcholine receptor antibody in Thai generalized myasthenia gravis patients [J]. J Med Assoc Thai 2006;89:68-71.
60 Chamberlain-Banoub J, Neal JW, Mizuno M, Harris CL, Morgan BP. Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats [J]. Clin Exp Immunol 2006;146:278-286.
61 Vergani D, Mieli-Vergani G. Autoimmune hepatitis [J]. Ann Ital Med Int 1996;11:119-124.
62 Loutrari H, Tzartos SJ, Claudio T. Use of Torpedo-mouse hybrid acetylcholine receptors reveals immunodominance of theαsubunit in myasthenia gravis antisera [J]. Eur J Immunol 1992;22:2949-2956.
63 Kuncl RW, Drachman DB, Adams R, Lehar M. 3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors [J]. J Pharmacol Exp Ther 1993;267:582-589.
64 Tüzün E, Saini SS, Ghosh S, Rowin J, Meriggioli MN, Christadoss P. Predictive value of serum anti-C1q antibody level in experimental autoimmune myasthenia gravis [J]. Neuromuscul Disord 2006;16:137-143.
65 Kuttner-Kondo LA, Dybvig MP, Mitchell LM, Muqim N, Atkinson JP, Medof ME,et al. A corresponding tyrosine residue in the C2/factor B type A domain is a hot spot in the decay acceleration of the complement C3 convertases [J]. J Biol Chem 2003;278:52386-52391.
66 Besinger UA, Toyka KV, H?mberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A. Myasthenia gravis: Long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity [J]. Neurology 1983;33:1316-1321.
67 Zimmermann-Nielsen E, Gr?nbaek H, Dahlerup JF, Baatrup G, Thorlacius-Ussing O. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis [J]. BMC Gastroenterol 2005;5:31-37.
68 Najam FI, Giasuddin AS, Shembesh AH. Complement components (C3, C4) in childhood asthma [J]. Indian J Pediatr 2005;72:745-749.
69 Zimmer B, Hartung HP, Scharfenberger G, Bitter-Suermann P, Hadding U. Quantitative studies of the secretion of complement C3 by resident, elicited and activated macrophages. Comparison with C2, C4 and lysosomal enzyme release [J]. Eur J Immunol 1982;12:426-430.
70 Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY: Reference distributions for complement proteins C3 and C4: a practical, simple and clinically relevant approach in a large cohort [J]. JClin Lab Anal 2004;18:1-8.
71 Engstr?m G, Hedblad B, Eriksson KF, Janzon L, Lindg?rde F. Complement C3 is a risk factor for the development of diabetes: a population-based cohort study [J]. Diabetes 2005;54:570-575.
72 Motomura M, Fukuda T, Yoshimura T, Tsujihata M. Overview: MuSK/Dok-7 [J]. Nippon Rinsho 2008;66:1140-1148.
73 Tüzün E, Scott BG, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune MG [J]. J Immunol 2003;171:3847-3854.
74 Kuncl RW, Drachman DB, Adams R, Lehar M. 3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors [J]. J Pharmacol Exp Ther 1993;267:582-589.
75 Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future [J]. J Clin Invest 2006;116:2843-2854.
76 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets [J]. Lancet Neurol 2003;2:99-106.
77 Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis [J]. Ann Neurol 2005;57:289-293.
78 Motomura M, Fukuda T, Yoshimura T, Tsujihata M. Overview: MuSK/Dok-7 [J]. Nippon Rinsho 2008;66:1140-1148.
79 Atkinson JP, Frank MM. Effect of cortisone therapy on serum complement components [J]. J Immunol 1973;111:1061-1066.
80 Jansen NJ, van Oeveren W, van Vliet M, Stoutenbeek CP, Eysman L, Wildevuur CR. The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass [J]. Eur J Cardiothorac Surg 1991;5:211-217.
81 Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practicaltherapeutic guidelines [J]. Muscle Nerve 1999;22:1479-1497.
82 Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor [J]. Science 2001;291:484-486.
83 Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments [J]. J Clin Invest 1994;94:1729-1735.
84 Lutz HU, Stammler P, Jelezarova E, Nater M, Sp?th PJ. High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes [J]. Blood 1996;88:184-193.
85 Lutz HU, Stammler P, Bianchi V, Trüeb RM, Hunziker T, Burger R, et al. Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level [J]. Blood 2004;103:465-472.
86 Christadoss P, Tüzün E, Li J, Saini SS, Yang H. Classical complement pathway in experimental autoimmune myasthenia gravis pathogenesis [J]. Ann N Y Acad Sci 2008;1132:210-219.