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系統識別號 U0026-0608201314024100
論文名稱(中文) 探討B型肝炎相關疾病免疫球蛋白G醣化模式變異性及其免疫調節作用
論文名稱(英文) Elucidating Diversity of IgG Glycosyl Pattern and Its Immunomodulatory Effect in HBV-related Liver Diseases
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 劉珈卉
研究生(英文) Jia-Huei Liu
學號 t16001095
學位類別 碩士
語文別 中文
論文頁數 74頁
口試委員 指導教授-張定宗
口試委員-楊孔嘉
口試委員-陳淑慧
中文關鍵字 B型肝炎病毒  B型肝炎病毒相關疾病  免疫球蛋白G  醣化作用 
英文關鍵字 Hepatitis B Virus (HBV)  HBV-related diseases  Immunoglobulin G (IgG)  Glycosylation 
學科別分類
中文摘要 B型肝炎病毒,傾向感染哺乳類和鳥類的肝臟細胞,引發宿主免疫反應攻擊肝臟細胞,導致宿主急性與慢性的肝臟發炎。慢性的感染B型肝炎病毒,會導致慢性B型肝炎、肝硬化甚至肝細胞癌。全世界仍然超過三億五千萬人感染B型肝炎病毒,且每年約有一百萬人因B型肝炎病毒相關疾病而死亡。免疫球蛋白G在宿主的體液免疫反應對抗B型肝炎病毒感染時扮演重要角色,且免疫球蛋白G上的醣化結構可造成多種影響:包含維持免疫球蛋白G的完整性、影響其Fc區域與Fc接受器的結合力以及具有促進/抑制發炎作用的能力。免疫球蛋白G上連接的聚醣結構之異常,已在許多自體免疫疾病以及病毒感染症被提及。其中在C型肝炎病毒引起的肝硬化病人體內,亦發現免疫球蛋白G醣化異常的現象。然而,在B型肝炎病毒引起的相關疾病中,其免疫球蛋白G的醣化結構變化以及帶有不同醣化結構的免疫球蛋白G對於調節其免疫作用的影響,皆尚未明瞭。因此,我們執行橫向分析探討慢性B型肝炎和肝硬化患者其血清免疫球蛋白G的醣化結構,是否會隨著疾病的嚴重性增加而改變;接著以縱向分析探討隨著患者接受抗病毒治療的過程中獲得病情的緩解,而其血清免疫球蛋白G的醣化結構異常是否會隨之有所回復,並且觀察在治療過程中,其醣化結構的動態變化;我們進一步利用體外調理吞噬作用實驗,探討血清中帶有不同醣化結構的免疫球蛋白G是否具有影響免疫調節的能力。根據我們的研究結果顯示,B型肝炎病毒相關疾病嚴重度(慢性B型肝炎和肝硬化)與免疫球蛋白G上的聚醣結構變化無關,但B型肝炎病毒感染患者接受抗病毒治療後,隨著病毒量及肝指數下降,其血清中免疫球蛋白G的醣化結構,有隨之回復的現象,而且在服用不同的抗病毒藥物,其免疫球蛋白G的醣化結構的回復現象不同。從體內調理吞噬作用實驗中顯示,帶有不同醣化結構的免疫球蛋白G,其免疫調理活性在健康者與慢性B型肝炎患者之間存在差異性,且與免疫球蛋白G上帶有的半乳糖數量有關連性。本研究闡述B型肝炎病毒感染相關疾病與免疫球蛋白G上夾帶的聚醣結構變化的關係,並且在因疾病引起的血清免疫球蛋白G醣化結構異常現象,我們首先探討了疾病治療前治療後,其IgG醣化結構的改變,本研究成果有利於做為臨床上肝炎疾病緩解的指標之一。
英文摘要 Hepatitis B virus (HBV), belonging to hepadnaviridae, tends to infect hepatocytes and causes the inflammation of liver, which is also known as hepatitis. More than 350 million people worldwide have been chronically infected with hepatitis B virus. Chronic hepatitis B (CHB) results in a high risk of developing severe hepatic diseases including liver cirrhosis (LC) and hepatocellular carcinoma, which causes over one million deaths annually. Immunoglobulin G (IgG) plays a crucial role in humoral immune responses against HBV infection and its glycosylation mediates multiple events including its protein integrity, Fc receptor binding affinity, and pro/anti-inflammation activity. Aberrant N-link glycans on IgG-Fc fragment has been mentioned in many autoimmune diseases and viral infections, especially in patients with hepatitis C virus-induced LC; however, it is addressed less frequently in hepatitis B virus (HBV)-related liver diseases. Here, we conducted a comparative glycoproteomic-based study to assess the clinical significance of IgG-Fc glycosyl aberrancy on patients with CHB and LC. Moreover, a time course study was performed to trace the dynamic of IgG glycosyl patterns during the anti-viral treatment. In addition, an in vitro antibody-mediated opsonization and phagocytosis assay was applied to investigate the immunomodulatory effect of IgG glycovariants on opsonizing activities. Our cross-sectional data revealed that IgG galatosylation decreased in CHB and LC patients in comparison with healthy controls (HC). Moreover, the longitudinal data showed that the IgG galactose-deficiency in CHB and LC patients were restored under anti-HBV treatment, particularly entecavir. The time course study showed that altered IgG galactosylation patterns were correlated with the ALT and AST decline. We also analyzed the correlation between IgG1 and IgG2 subclasses and found a high similarity of their glycosylation pattern dynamics at baseline, week 24 and week 48 post-treatment. Intriguingly, IgG opsonizing activity was reduced upon CHB but rose in the remission of the disease, which was correspondent to the IgG-Fc galactosylation index. Our data revealed that the lack of IgG terminal galactose residues was not associated with the severity and progression of HBV-related liver diseases. Surprisingly, we found a different pharmaceutical effect of variable anti-HBV drugs on IgG glycosyl restoration. The activity of IgG opsonization was highly associated with the level of Fc-galactosylation. These findings portrayed the clinical significance of IgG glycosyl profiles on the status of HBV-related liver diseases, as well as the impact of IgG-Fc glycans on modulating immune responses.
論文目次 中文摘要 I
英文摘要 III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
附錄 X
壹、 序論 (Introduction) 1
一、 B型肝炎病毒 1
1. B型肝炎病毒的背景 1
2. 慢性B型肝炎的自然病程 4
3. B型肝炎病毒感染相關疾病 5
4. B型肝炎病毒感染與宿主免疫反應的相關性 6
5. B型肝炎的治療 8
6. 肝功能的血液檢查項目 10
二、 免疫球蛋白G 11
1. 免疫球蛋白G的結構 11
2. 免疫球蛋白G的生理特性 11
三、 B型肝炎病毒感染與免疫球蛋白G引發的免疫反應之相關性 12
四、 免疫球蛋白G上的N連結醣化作用 13
1. IgG-N連結之聚醣醣化結構 13
2. IgG夾帶之聚醣對免疫調控的重要性 14
3. 影響IgG醣化的因子 15
五、 免疫球蛋白G上的N連結醣化異常與疾病之相關性 16
貳、 研究動機、目標與策略 (Motivation and Strategies) 18
參、 材料與方法 (Materials and Methods) 20
肆、 結果(Results) 31
一、橫向分析探討慢性B型肝炎或肝硬化患者其血清IgG重鏈Asn-297連接之聚醣醣化結構與疾病發展相關性。 31
1. 貼附於IgG重鏈Asn-297之10種聚醣之分析 31
2. 收納檢體之挑選 31
3. HBV感染疾病嚴重度與IgG連接聚醣變異體的關聯性 32
二、縱向分析血清IgG重鏈Asn-297連接之聚醣結構異常,是否因HBV感染患者接受抗病毒藥物治療之病情緩解而隨之回復 34
1. 抗HBV病毒藥物種類 34
2. HBV感染患者病情緩解與IgG夾帶之聚醣結構回復的關聯性 34
三、 探討IgG重鏈Asn-297連接之聚醣結構在治療過程中的動態變化 38
1. 以時間點觀察IgG夾帶之聚醣與臨床數據在治療期間的動態趨勢 38
2. 分析IgG1和IgG2在其Fc區域上夾帶之聚醣變化的相關性 39
四、功能性實驗探討血清不同聚醣結構的IgG之免疫調節能力。 40
伍、 討論 (Discussion) 42
陸、 參考文獻 (References) 48
表/圖/附錄 (Tables, Figures, and Appendixes) 58
參考文獻 1 Dandri, M. & Locarnini, S. New insight in the pathobiology of hepatitis B virus infection. Gut 61 Suppl 1, i6-17, doi:10.1136/gutjnl-2012-302056 (2012).
2 Neuveut, C., Wei, Y. & Buendia, M. A. Mechanisms of HBV-related hepatocarcinogenesis. Journal of hepatology 52, 594-604, doi:10.1016/j.jhep.2009.10.033 (2010).
3 Dienstag, J. L. Hepatitis B virus infection. The New England journal of medicine 359, 1486-1500, doi:10.1056/NEJMra0801644 (2008).
4 Lavanchy, D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of viral hepatitis 11, 97-107 (2004).
5 Mohamed, R. et al. Practical difficulties in the management of hepatitis B in the Asia-Pacific region. Journal of gastroenterology and hepatology 19, 958-969, doi:10.1111/j.1440-1746.2004.03420.x (2004).
6 Sullivan, S. D. et al. Cost-effectiveness of peginterferon alpha-2a compared to lamivudine treatment in patients with hepatitis B e antigen positive chronic hepatitis B in Taiwan. Journal of gastroenterology and hepatology 22, 1494-1499, doi:10.1111/j.1440-1746.2006.04539.x (2007).
7 Chen, Y., Cheng, G. & Mahato, R. I. RNAi for treating hepatitis B viral infection. Pharmaceutical research 25, 72-86, doi:10.1007/s11095-007-9504-0 (2008).
8 Howard, C. R. The biology of hepadnaviruses. The Journal of general virology 67 ( Pt 7), 1215-1235 (1986).
9 Locarnini, S. Molecular virology of hepatitis B virus. Seminars in liver disease 24 Suppl 1, 3-10, doi:10.1055/s-2004-828672 (2004).
10 Ganem, D. & Prince, A. M. Hepatitis B virus infection--natural history and clinical consequences. The New England journal of medicine 350, 1118-1129, doi:10.1056/NEJMra031087 (2004).
11 Seeger, C. & Mason, W. S. Hepatitis B virus biology. Microbiology and molecular biology reviews : MMBR 64, 51-68 (2000).
12 Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature reviews. Immunology 5, 215-229, doi:10.1038/nri1573 (2005).
13 Wen, Y., Golubkov, V. S., Strongin, A. Y., Jiang, W. & Reed, J. C. Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. The Journal of biological chemistry 283, 2793-2803, doi:10.1074/jbc.M708419200 (2008).
14 Buddeberg, F., Schimmer, B. B. & Spahn, D. R. Transfusion-transmissible infections and transfusion-related immunomodulation. Best practice & research. Clinical anaesthesiology 22, 503-517 (2008).
15 Fairley, C. K. & Read, T. R. Vaccination against sexually transmitted infections. Current opinion in infectious diseases 25, 66-72, doi:10.1097/QCO.0b013e32834e9aeb (2012).
16 Hughes, R. A. Drug injectors and the cleaning of needles and syringes. European addiction research 6, 20-30, doi:19005 (2000).
17 Liaw, Y. F. et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update. Journal of gastroenterology and hepatology 18, 239-245 (2003).
18 Liang, T. J. Hepatitis B: the virus and disease. Hepatology 49, S13-21, doi:10.1002/hep.22881 (2009).
19 Iloeje, U. H., Yang, H. I. & Chen, C. J. Natural history of chronic hepatitis B: what exactly has REVEAL revealed? Liver international : official journal of the International Association for the Study of the Liver 32, 1333-1341, doi:10.1111/j.1478-3231.2012.02805.x (2012).
20 European Association For The Study Of The, L. EASL Clinical Practice Guidelines: management of chronic hepatitis B. Journal of hepatology 50, 227-242, doi:10.1016/j.jhep.2008.10.001 (2009).
21 Nguyen, T., Desmond, P. & Locarnini, S. The role of quantitative hepatitis B serology in the natural history and management of chronic hepatitis B. Hepatology international 3, 5-15, doi:10.1007/s12072-009-9149-7 (2009).
22 Jaroszewicz, J. et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. Journal of hepatology 52, 514-522, doi:10.1016/j.jhep.2010.01.014 (2010).
23 Brunetto, M. R. et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 139, 483-490, doi:10.1053/j.gastro.2010.04.052 (2010).
24 Chu, C. J., Hussain, M. & Lok, A. S. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 36, 1408-1415, doi:10.1053/jhep.2002.36949 (2002).
25 Bartosch, B. Hepatitis B and C viruses and hepatocellular carcinoma. Viruses 2, 1504-1509, doi:10.3390/v2081504 (2010).
26 Lebrec, D., De Fleury, P., Rueff, B., Nahum, H. & Benhamou, J. P. Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gastroenterology 79, 1139-1144 (1980).
27 Sort, P. et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. The New England journal of medicine 341, 403-409, doi:10.1056/NEJM199908053410603 (1999).
28 Butterworth, R. F. Complications of cirrhosis III. Hepatic encephalopathy. Journal of hepatology 32, 171-180 (2000).
29 de Franchis, R. et al. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). Journal of hepatology 39 Suppl 1, S3-25 (2003).
30 Perz, J. F., Armstrong, G. L., Farrington, L. A., Hutin, Y. J. & Bell, B. P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. Journal of hepatology 45, 529-538, doi:10.1016/j.jhep.2006.05.013 (2006).
31 Tabor, E. Hepatocellular carcinoma: global epidemiology. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 33, 115-117 (2001).
32 Wu, J. et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology 46, 1769-1778, doi:10.1002/hep.21897 (2007).
33 Boehme, K. W. & Compton, T. Innate sensing of viruses by toll-like receptors. J Virol 78, 7867-7873, doi:10.1128/JVI.78.15.7867-7873.2004 (2004).
34 Kolios, G., Valatas, V. & Kouroumalis, E. Role of Kupffer cells in the pathogenesis of liver disease. World journal of gastroenterology : WJG 12, 7413-7420 (2006).
35 Racanelli, V. & Rehermann, B. The liver as an immunological organ. Hepatology 43, S54-62, doi:10.1002/hep.21060 (2006).
36 Taams, L. S., Poulter, L. W., Rustin, M. H. & Akbar, A. N. Phenotypic analysis of IL-10-treated macrophages using the monoclonal antibodies RFD1 and RFD7. Pathobiology : journal of immunopathology, molecular and cellular biology 67, 249-252, doi:28103 (1999).
37 Cooper, A., Tal, G., Lider, O. & Shaul, Y. Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. Journal of immunology 175, 3165-3176 (2005).
38 Stetson, D. B. & Medzhitov, R. Type I interferons in host defense. Immunity 25, 373-381, doi:10.1016/j.immuni.2006.08.007 (2006).
39 Salazar-Mather, T. P. & Hokeness, K. L. Cytokine and chemokine networks: pathways to antiviral defense. Current topics in microbiology and immunology 303, 29-46 (2006).
40 Yoneyama, H. & Ichida, T. Recruitment of dendritic cells to pathological niches in inflamed liver. Medical molecular morphology 38, 136-141, doi:10.1007/s00795-005-0289-0 (2005).
41 Heydtmann, M. Macrophages in hepatitis B and hepatitis C virus infections. J Virol 83, 2796-2802, doi:10.1128/JVI.00996-08 (2009).
42 Kakimi, K., Lane, T. E., Chisari, F. V. & Guidotti, L. G. Cutting edge: Inhibition of hepatitis B virus replication by activated NK T cells does not require inflammatory cell recruitment to the liver. Journal of immunology 167, 6701-6705 (2001).
43 Tang, T. J. et al. The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection. Journal of viral hepatitis 10, 159-167 (2003).
44 Kakimi, K., Guidotti, L. G., Koezuka, Y. & Chisari, F. V. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. The Journal of experimental medicine 192, 921-930 (2000).
45 Kimura, K., Kakimi, K., Wieland, S., Guidotti, L. G. & Chisari, F. V. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol 76, 10702-10707 (2002).
46 Chang, J. J. & Lewin, S. R. Immunopathogenesis of hepatitis B virus infection. Immunology and cell biology 85, 16-23, doi:10.1038/sj.icb.7100009 (2007).
47 Jung, M. C. & Pape, G. R. Immunology of hepatitis B infection. The Lancet infectious diseases 2, 43-50 (2002).
48 Kimura, K., Kakimi, K., Wieland, S., Guidotti, L. G. & Chisari, F. V. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. Journal of immunology 169, 5188-5195 (2002).
49 Yang, B. et al. Increased Th17 cells and interleukin-17 contribute to immune activation and disease aggravation in patients with chronic hepatitis B virus infection. Immunology letters 149, 41-49, doi:10.1016/j.imlet.2012.12.001 (2013).
50 Kwon, H. & Lok, A. S. Hepatitis B therapy. Nature reviews. Gastroenterology & hepatology 8, 275-284, doi:10.1038/nrgastro.2011.33 (2011).
51 Lai, C. L. et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. The New England journal of medicine 339, 61-68, doi:10.1056/NEJM199807093390201 (1998).
52 Delaney, W. E. t. Molecular virology of chronic hepatitis B and C: Parallels, contrasts and impact on drug development and treatment outcome. Antiviral research 99, 34-48, doi:10.1016/j.antiviral.2013.04.010 (2013).
53 Doong, S. L., Tsai, C. H., Schinazi, R. F., Liotta, D. C. & Cheng, Y. C. Inhibition of the replication of hepatitis B virus in vitro by 2',3'-dideoxy-3'-thiacytidine and related analogues. Proceedings of the National Academy of Sciences of the United States of America 88, 8495-8499 (1991).
54 Lok, A. S. et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46, 254-265, doi:10.1002/hep.21698 (2007).
55 Lok, A. S. et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125, 1714-1722 (2003).
56 Liaw, Y. F. et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 136, 486-495, doi:10.1053/j.gastro.2008.10.026 (2009).
57 Hadziyannis, S. J. et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 131, 1743-1751, doi:10.1053/j.gastro.2006.09.020 (2006).
58 Tenney, D. J. et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 49, 1503-1514, doi:10.1002/hep.22841 (2009).
59 Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annual review of immunology 25, 21-50, doi:10.1146/annurev.immunol.25.022106.141702 (2007).
60 Shakib, F. & Stanworth, D. R. Human IgG subclasses in health and disease. (A review). Part I. La Ricerca in clinica e in laboratorio 10, 463-479 (1980).
61 French, M. Serum IgG subclasses in normal adults. Monographs in allergy 19, 100-107 (1986).
62 Anthony, R. M. & Ravetch, J. V. A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs. Journal of clinical immunology 30 Suppl 1, S9-14, doi:10.1007/s10875-010-9405-6 (2010).
63 Spiegelberg, H. L. Biological activities of immunoglobulins of different classes and subclasses. Advances in immunology 19, 259-294 (1974).
64 Spiegelberg, H. L. & Fishkin, B. G. The catabolism of human G immunoglobulins of different heavy chain subclasses. 3. The catabolism of heavy chain disease proteins and of Fc fragments of myeloma proteins. Clinical and experimental immunology 10, 599-607 (1972).
65 Smith, K. G. & Clatworthy, M. R. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nature reviews. Immunology 10, 328-343, doi:10.1038/nri2762 (2010).
66 Nimmerjahn, F. & Ravetch, J. V. Fcgamma receptors as regulators of immune responses. Nature reviews. Immunology 8, 34-47, doi:10.1038/nri2206 (2008).
67 Nicholas, R. & Sinclair, S. C. Regulation of the immune response. I. Reduction in ability of specific antibody to inhibit long-lasting IgG immunological priming after removal of the Fc fragment. The Journal of experimental medicine 129, 1183-1201 (1969).
68 Zhuang, Y., Xu, W., Shen, Y. F. & Li, J. Y. Fc gamma Receptor Polymorphisms and Clinical Efficacy of Rituximab in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Cl Lymph Myelom Leuk 10, 347-352, doi:Doi 10.3816/Clml.2010.N.067 (2010).
69 Sanchez-Mejorada, G. & Rosales, C. Signal transduction by immunoglobulin Fc receptors. Journal of leukocyte biology 63, 521-533 (1998).
70 Mimura, Y. et al. The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms. Molecular immunology 37, 697-706 (2000).
71 Mimura, Y. et al. Role of oligosaccharide residues of IgG1-Fc in Fc gamma RIIb binding. The Journal of biological chemistry 276, 45539-45547, doi:10.1074/jbc.M107478200 (2001).
72 Gala, F. A. & Morrison, S. L. The role of constant region carbohydrate in the assembly and secretion of human IgD and IgA1. The Journal of biological chemistry 277, 29005-29011, doi:10.1074/jbc.M203258200 (2002).
73 Bohm, S., Schwab, I., Lux, A. & Nimmerjahn, F. The role of sialic acid as a modulator of the anti-inflammatory activity of IgG. Seminars in immunopathology 34, 443-453, doi:10.1007/s00281-012-0308-x (2012).
74 Butler, M. et al. Detailed glycan analysis of serum glycoproteins of patients with congenital disorders of glycosylation indicates the specific defective glycan processing step and provides an insight into pathogenesis. Glycobiology 13, 601-622, doi:10.1093/glycob/cwg079 (2003).
75 Wormald, M. R. et al. Variations in oligosaccharide-protein interactions in immunoglobulin G determine the site-specific glycosylation profiles and modulate the dynamic motion of the Fc oligosaccharides. Biochemistry 36, 1370-1380, doi:10.1021/bi9621472 (1997).
76 Malhotra, R. et al. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nature medicine 1, 237-243 (1995).
77 Rademacher, T. W., Williams, P. & Dwek, R. A. Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proceedings of the National Academy of Sciences of the United States of America 91, 6123-6127 (1994).
78 Kaneko, Y., Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313, 670-673, doi:10.1126/science.1129594 (2006).
79 Stadlmann, J. et al. A close look at human IgG sialylation and subclass distribution after lectin fractionation. Proteomics 9, 4143-4153, doi:10.1002/pmic.200800931 (2009).
80 Gornik, O., Pavic, T. & Lauc, G. Alternative glycosylation modulates function of IgG and other proteins - implications on evolution and disease. Biochimica et biophysica acta 1820, 1318-1326, doi:10.1016/j.bbagen.2011.12.004 (2012).
81 Iida, S. et al. Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin G on antibody-dependent cellular cytotoxicity through its high binding to FcgammaRIIIa. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 2879-2887, doi:10.1158/1078-0432.CCR-05-2619 (2006).
82 Masuda, K. et al. Enhanced binding affinity for FcgammaRIIIa of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity. Molecular immunology 44, 3122-3131, doi:10.1016/j.molimm.2007.02.005 (2007).
83 Niwa, R. et al. Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional polymorphism. Clinical cancer research : an official journal of the American Association for Cancer Research 10, 6248-6255, doi:10.1158/1078-0432.CCR-04-0850 (2004).
84 Pucic, M. et al. High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Molecular & cellular proteomics : MCP 10, M111 010090, doi:10.1074/mcp.M111.010090 (2011).
85 Shinkawa, T. et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. The Journal of biological chemistry 278, 3466-3473, doi:10.1074/jbc.M210665200 (2003).
86 Preithner, S. et al. High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Molecular immunology 43, 1183-1193, doi:10.1016/j.molimm.2005.07.010 (2006).
87 Rook, G. A. et al. Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. Journal of autoimmunity 4, 779-794 (1991).
88 van de Geijn, F. E. et al. Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis research & therapy 11, R193, doi:10.1186/ar2892 (2009).
89 Parekh, R., Roitt, I., Isenberg, D., Dwek, R. & Rademacher, T. Age-related galactosylation of the N-linked oligosaccharides of human serum IgG. The Journal of experimental medicine 167, 1731-1736 (1988).
90 Yamada, E., Tsukamoto, Y., Sasaki, R., Yagyu, K. & Takahashi, N. Structural changes of immunoglobulin G oligosaccharides with age in healthy human serum. Glycoconjugate journal 14, 401-405 (1997).
91 Shikata, K. et al. Structural changes in the oligosaccharide moiety of human IgG with aging. Glycoconjugate journal 15, 683-689 (1998).
92 Ruhaak, L. R. et al. Decreased levels of bisecting GlcNAc glycoforms of IgG are associated with human longevity. PloS one 5, e12566, doi:10.1371/journal.pone.0012566 (2010).
93 Parekh, R. B. et al. Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316, 452-457 (1985).
94 Huhn, C., Selman, M. H., Ruhaak, L. R., Deelder, A. M. & Wuhrer, M. IgG glycosylation analysis. Proteomics 9, 882-913, doi:10.1002/pmic.200800715 (2009).
95 Mehta, A. S. et al. Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. J Virol 82, 1259-1270, doi:10.1128/JVI.01600-07 (2008).
96 van Zeben, D. et al. Early agalactosylation of IgG is associated with a more progressive disease course in patients with rheumatoid arthritis: results of a follow-up study. British journal of rheumatology 33, 36-43 (1994).
97 Rook, G. et al. The role of oil and agalactosyl IgG in the induction of arthritis in rodent models. European journal of immunology 21, 1027-1032, doi:10.1002/eji.1830210425 (1991).
98 Ji, H. et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157-168 (2002).
99 Carroll, M. C. The role of complement and complement receptors in induction and regulation of immunity. Annual review of immunology 16, 545-568, doi:10.1146/annurev.immunol.16.1.545 (1998).
100 Nimmerjahn, F., Anthony, R. M. & Ravetch, J. V. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proceedings of the National Academy of Sciences of the United States of America 104, 8433-8437, doi:10.1073/pnas.0702936104 (2007).
101 Nimmerjahn, F. & Ravetch, J. V. Antibody-mediated modulation of immune responses. Immunological reviews 236, 265-275, doi:10.1111/j.1600-065X.2010.00910.x (2010).
102 Knodell, R. G. et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1, 431-435 (1981).
103 Wu, I. C. et al. Characterization of viral kinetics in patients with hepatitis B e antigen-positive chronic hepatitis B. Journal of medical virology 79, 663-669, doi:10.1002/jmv.20822 (2007).
104 Sutton, B. J. & Phillips, D. C. The three-dimensional structure of the carbohydrate within the Fc fragment of immunoglobulin G. Biochemical Society transactions 11 Pt 2, 130-132 (1983).
105 Saphire, E. O. et al. Contrasting IgG structures reveal extreme asymmetry and flexibility. Journal of molecular biology 319, 9-18, doi:10.1016/S0022-2836(02)00244-9 (2002).
106 Masuda, K. et al. Pairing of oligosaccharides in the Fc region of immunoglobulin G. FEBS letters 473, 349-357 (2000).
107 Holland, M. et al. Differential glycosylation of polyclonal IgG, IgG-Fc and IgG-Fab isolated from the sera of patients with ANCA-associated systemic vasculitis. Biochimica et biophysica acta 1760, 669-677, doi:10.1016/j.bbagen.2005.11.021 (2006).
108 Wang, J. et al. Fc-glycosylation of IgG1 is modulated by B-cell stimuli. Molecular & cellular proteomics : MCP 10, M110 004655, doi:10.1074/mcp.M110.004655 (2011).
109 Kondo, Y., Ueno, Y. & Shimosegawa, T. Toll-like receptors signaling contributes to immunopathogenesis of HBV infection. Gastroenterology research and practice 2011, 810939, doi:10.1155/2011/810939 (2011).
110 Leu, R. W., Rummage, J. A. & Horn, M. J. Characterization of murine macrophage Fc receptor-dependent phagocytosis and antibody-dependent cellular cytotoxicity during in vitro culture with interferons-gamma, alpha/beta and/or fetal bovine serum. Immunobiology 178, 340-350, doi:10.1016/S0171-2985(89)80057-9 (1989).
111 Kunkel, H. G. & Tan, E. M. Autoantibodies and Disease. Advances in immunology 27, 351-395 (1964).
112 Winchester, R. J., Kunkel, H. G. & Agnello, V. OCCURRENCE OF gamma-GLOBULIN COMPLEXES IN SERUM AND JOINT FLUID OF RHEUMATOID ARTHRITIS PATIENTS: USE OF MONOCLONAL RHEUMATOID FACTORS AS REAGENTS FOR THEIR DEMONSTRATION. The Journal of experimental medicine 134, 286-295 (1971).
113 Nardella, F. A., Teller, D. C. & Mannik, M. Studies on the antigenic determinants in the self-association of IgG rheumatoid factor. The Journal of experimental medicine 154, 112-125 (1981).
114 Henney, C. S. & Stanworth, D. R. Reaction of Rheumatoid Factor with the Isolated Polypeptide Chains of Human 7s Gamma-Globulin. Nature 201, 511-512 (1964).
115 Randall, R. E., Williamson, W. C., Jr., Mullinax, F., Tung, M. Y. & Still, W. J. Manifestations of systemic light chain deposition. The American journal of medicine 60, 293-299 (1976).
116 Fung, S. K. & Lok, A. S. Management of patients with hepatitis B virus-induced cirrhosis. Journal of hepatology 42 Suppl, S54-64, doi:10.1016/j.jhep.2004.11.014 (2005).
117 Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory actions of intravenous immunoglobulin. Annual review of immunology 26, 513-533, doi:10.1146/annurev.immunol.26.021607.090232 (2008).
118 Durandy, A. et al. Intravenous immunoglobulins--understanding properties and mechanisms. Clinical and experimental immunology 158 Suppl 1, 2-13, doi:10.1111/j.1365-2249.2009.04022.x (2009).
119 Axford, J. S. Decreased B-cell galactosyltransferase activity in rheumatoid arthritis. British journal of rheumatology 27 Suppl 2, 170 (1988).
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