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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4447完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾賢忠(Shiang-Jong Tzeng) | |
| dc.contributor.author | Jyun-Pei Jhou | en |
| dc.contributor.author | 周峻霈 | zh_TW |
| dc.date.accessioned | 2021-05-14T17:42:19Z | - |
| dc.date.available | 2020-09-24 | |
| dc.date.available | 2021-05-14T17:42:19Z | - |
| dc.date.copyright | 2015-09-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-18 | |
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Xiu Y, Nakamura K, Abe M, Li N, Wen XS, Jiang Y, Zhang D, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T, Shimokawa T, Ra C, Shirai T, Hirose S. Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. J. Immunol. 2002, 169(8): 4340-4346. Yang W, Ng P, Zhao M, Hirankarn N, Lau CS, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Avihingsanon Y, Lee TL, Ho MH, Lee PP, Wong WH, Lau YL. Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun. 2009, 10(3): 219-226. Youinou P, Mackenzie L, Katsikis P, Merdrignac G, Isenberg DA, Tuaillon N, Lamour A, Le Goff P, Jouquan J, Drogou A, et al. The relationship between CD5-expressing B lymphocytes and serologic abnormalities in rheumatoid arthritis patients and their relatives. Arthritis Rheum. 1990, 33(3): 339-348. Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009, 31(3): 457-468. Yuasa T, Kubo S, Yoshino T, Ujike A, Matsumura K, Ono M, Ravetch JV, Takai T. Deletion of Fcγ receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis. J. Exp. Med. 1999, 189(1): 187-194. Zhang Y, Liu S, Liu J, Zhang T, Shen Q, Yu Y, Cao X. Immune complex/Ig negatively regulate TLR4-triggered inflammatory response in macrophages through FcγRIIb-dependent PGE2 production. J. Immunol. 2009, 182(1): 554-562. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, Nutt SL, Tarlinton DM. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 2010, 207(2): 365-378. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4447 | - |
| dc.description.abstract | 後天免疫系統包含體液性和細胞性兩種，主要由淋巴球負責。體液性免疫最重要的目的在產生具抗原專一性的高親和性抗體。而抗體的製造則必須透過脾臟和淋巴結的生發中心(germinal center)對B細胞進行挑選和使之分化成漿細胞，專司抗體分泌的漿細胞則經由血流定居骨髓。在疫苗反應時，生發中心B細胞須經歷體細胞高突變(somatic hypermutation)、親和力成熟(affinity maturation)和免疫球蛋白轉換(class switching)。B細胞抗原受器(B-cell antigen receptor, BCR)在體細胞高突變反應後，使生發中心B細胞對抗原具有各式不同親和力，接著抗原針對這些B細胞進行抗原親和力成熟反應，最重要的作用是去除低抗原親和性的生發中心B細胞，以確保產生高效價的高抗原親和性抗體。FcγRIIB是B細胞上抑制BCR最重要的受器，負責調節體內抗體製造量。此外，它也能夠單獨活化使B細胞凋亡。由於研究指出生發中心B細胞的FcγRIIB表現在疫苗反應會上升，而FcγRIIB基因剔除鼠脾臟的生發中心會自發性地增加和變大，導致自體免疫抗體產生，終致紅斑性狼瘡。因此，我們推論FcγRIIB在生發中心進行親和力成熟反應時，可能扮演促使低抗原親和性生發中心B細胞凋亡的角色。我們採用功能低下的人類FcγRIIB-T232基因多型性突變鼠來研究這個問題。FcγRIIB-I232T突變是FcγRIIB的第232個胺基酸位置由蘇胺酸(threonine)取代原本的異白胺酸(isoleucine)，這種多型性變異在亞洲人紅斑性狼瘡佔高比例。我們採用4-hydroxy-3-nitrophenylacetyl (NP) hapten-chicken gamma globulin (CGG)做為疫苗原來探討FcγRIIB-T232突變鼠是否比正常鼠殘留較多的低抗原親和性生發中心B細胞？結果顯示在單次疫苗接種時，FcγRIIB-T232突變鼠血液中的低抗原親和性B細胞和漿細胞的數量均增加和伴隨著血清中低抗原親和性抗體的增加。當再次疫苗接種，FcγRIIB-T232突變鼠脾臟和骨髓中分泌低抗原親和性IgG的B細胞和低抗原親和性抗體均顯著增加。脾臟生發中心在FcγRIIB-T232突變鼠也是變大和B細胞數量增加，尤以位在執行親和力成熟的亮區(light zone)最顯著。此外，我們更發現FcγRIIB-T232突變鼠的低抗原親和性B細胞和抗體的增加確實是因為亮區的低抗原親和性生發中心B細胞的細胞凋亡(apoptosis)減少，未能被清除所致。有趣的是，FcγRIIB-T232突變鼠的低抗原親和性抗體對於同源類似抗原NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl)的交互反應性(cross-reactivity)亦比正常鼠增加。總結來說，本研究提供多項證據顯示FcγRIIB在生發中心進行親和力成熟反應時，扮演積極去除低抗原親和性B細胞的關鍵角色。在臨床應用上，則建議在疫苗接種時，應可藉由調控FcγRIIB的表達使產生的抗體對同源相近的病原菌具有交叉中和的保護效果。 | zh_TW |
| dc.description.abstract | Germinal center (GC) reaction, which undergoes somatic hypermutation, affinity maturation and class switching, is the hallmark of humoral immunity. One important function of it is to eliminate GC B cells that secrete low-affinity antibody (Ab) to the antigen (Ag) to ensure successful generation of effective neutralizing Abs through affinity maturation. FcγRIIB, a critical inhibitory Fcγ receptor (FcγR) that can mediate apoptosis in B cells, has been found to up-regulate on the GC B cells. Interestingly FcγRIIB-deficient mice spontaneously develop lupus accompanied by retention of somatic mutated BCRs as well as increased number and increased size of GCs in the spleen, indicative of a failure in negative selection of GC B cells. Moreover, people carrying a functionally impaired variant of FcγRIIB, of which isoleucine at position 232 was replaced by threonine, are susceptible to lupus particularly in Asians. Here, we generated FcγRIIB-T232 mutant mice to investigate the functional role of FcγRIIB in GC reaction. We hypothesized that to some extent the GC phenotype of FcγRIIB-T232 mice should recapitulate that of FcγRIIB knockout mice after immunization. To address this, we immunized FcγRIIB-I232 (wild-type) and FcγRIIB-T232 mice respectively with 4-hydroxy-3-nitrophenylacetyl (NP) hapten-chicken gamma globulin (CGG), a model Ag that allows distinction of low vs. high affinity Ag-specific B cells. Indeed, we found an increase of low-affinity NP-specific IgG-expressing B cells and plasma cells in circulation and a concomitant increase of serum Abs in FcγRIIB-T232 mice than those of FcγRIIB-I232 mice after primary immunization. After secondary immunization, we detected a significant increase of NP-specific B cells and plasma cells in the blood, spleen and bone marrow of FcγRIIB-T232 mice compared to that of FcγRIIB-I232 mice, accompanying an accumulation of low-affinity NP-specific IgG-secreting B cells in the spleen and bone marrow of FcγRIIB-T232 mice. Furthermore, FcγRIIB-T232 mice increased the formation of low-affinity NP-specific IgG in the circulation. Consistent with these findings, the spleen of FcγRIIB-T232 mice displayed an increased size of the GC of lymphoid follicles and had a concomitant increase of the number of GC B cells, especially the light zone GC B cells. Moreover, a decrease of apoptosis of GC B cells in the light zone of FcγRIIB-T232 mice correlated with their increased levels of low-affinity NP-specific B cells and Abs, supporting an active and essential role of FcγRIIB in GC reaction. Finally, we also found that the increased low-affinity antibodies in FcγRIIB-T232 mice resulted in the increase of cross-reactive antibodies. Taken together, these results support the notion that FcγRIIB plays an important role in negative selection of GC B cells. In addition, FcγRIIB may be considered as an ideal target for immunomodulation if the expression level of FcγRIIB on GC B cells holds the key to determine the stringency of Ab affinity as well as Ab repertoire to be generated during vaccination. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-14T17:42:19Z (GMT). No. of bitstreams: 1 ntu-104-R02443015-1.pdf: 6559410 bytes, checksum: c2d625ce4ea395c80476051ec743333e (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書………………………………………………………i 誌謝………………………………………………………………………ii 中文摘要………………………………………………………………iii ABSTRACT…………………………………………………………………v CONTENTS………………………………………………………………vii LIST of FIGURES…………………………………………………………x LIST of TABLES…………………………………………………………xi LIST of ABBREVIATIONS………………………………………………xii Chapter 1 Introduction………………………………………………1 1.1 Fcγ receptors……………………………………………2 1.2 Fcγ receptor IIB (FcγRIIB)……………………………5 1.3 FcγRIIB triggers inhibitory signaling pathways to block B-cell function……………………………………6 1.4 Functions of FcγRIIB in innate immunity…………8 1.5 FcγRIIB and autoimmunity………………………………9 1.6 Polymorphisms of FCGR2B…………………………………11 1.6.1 Mouse fcgr2b polymorphisms……………………………11 1.6.1.1 Polymorphisms in the promoter and intron……………11 1.6.1.2 Polymorphisms in the coding region……………………12 1.6.2 Human FCGR2B polymorphisms………………………………12 1.6.2.1 Polymorphisms in the promoter…………………………12 1.6.2.2 Polymorphisms in the coding region……………………13 1.7 Germinal centers (GCs)…………………………………14 1.7.1 Somatic hypermutation (SHM)……………………………16 1.7.2 Affinity maturation………………………………………17 1.8 Motivation…………………………………………………20 Chapter 2 Materials and Methods…………………………………25 2.1 Mice……………………………………………………………26 2.2 Immunization………………………………………………27 2.2.1 Primary immunization……………………………………27 2.2.2 Secondary immunization…………………………………27 2.3 Flow cytometry to analyze cell populations in the blood, spleen, and bone marrow…………………………………28 2.3.1 Blood………………………………………………………28 2.3.2 Spleen…………………………………………………………29 2.3.3 Bone marrow…………………………………………………30 2.4 ELISPOT assay (Enzyme-linked immunosorbent spot)……………………………………………31 2.5 Detection of serum total and antigen-specific antibodies by ELISA…………………33 2.5.1 Blood collection and serum separation………………33 2.5.2 Detection of serum total or antigen-specific IgG and IgM………………33 2.6 Detection of the cross-reactivity of low-affinity antigen-specific antibodies by sequential ELISA……………34 2.7 Tissue preparation…………………………………………37 2.7.1 Tissue fixation and paraffin block trimming………37 2.7.2 Dewaxing and rehydration…………………………………37 2.7.3 H E staining…………………………………………………37 2.7.4 Immunohistochemistry (IHC)……………………………38 2.8 Statistics…………………………………………………39 Chapter 3 Results……………………………………………………41 3.1 FcγRIIB-T232 mice exhibit more Ag-specific B cells and plasma cells in the spleen and bone marrow during GC reaction………………………………42 3.2 FcγRIIB-T232 mice produce more low-affinity Ag-specific IgG-secreting cells in the spleen and bone marrow during GC reaction……………………………44 3.3 FcγRIIB-T232 mice increase the generation of low-affinity Ag-specific IgG in the circulation during GC reaction……………………………………………46 3.4 A functionally impaired FcγRIIB increases the number of GC B cells with a concomitant increase of the size of GCs…………………………………………47 3.5 TFH cells do not contribute to the increase of low-affinity Ag-specific B cells and antibodies in FcγRIIB-T232 mice……………………………………………49 3.6 The increased low-affinity Ag-specific B cells and antibodies in FcγRIIB-T232 mice are caused by a decrease of apoptosis of GC B cells……………50 3.7 The increased low-affinity Ag-specific antibodies in FcγRIIB-T232 mice have an increased cross-reactivity to homologous antigen……………………………51 Chapter 4 Discussion………………………………………………………………55 4.1 Using FcγRIIB-T232 mice as a model to investigate the role of FcγRIIB in the negative selection during GC reaction……………………………………56 4.2 Does FcγRIIB-T232 have a haploinsufficient effect or a dominant-negative role in the negative regulation of GC B cells?………………………………61 4.3 Potential strategies to induce SLE in FcγRIIB-T232 mice……………62 4.4 Potential strategies to treat SLE carrying FcγRIIB-I232T polymorphism…………64 4.5 Peritoneal B-1a cells express high level of FcγRIIB and are highly associated with autoimmune diseases……………………………………………65 4.6 TFH cells involve in the affinity maturation of GC B cells……………………67 4.7 FcγRIIB-T232 on FDCs seems to have no effect on the ICs trapping………………68 4.8 The effect of co-ligation of FcγRIIB-T232 and BCR on the increase of low-affinity Ag-specific antibodies………………………………………………69 4.9 Additional genes or molecules that are related to morphological change of GCs and involved in the affinity maturation………………………………………70 4.10 Reassessing the strategies to detect cross-reactivity of low-affinity Ag-specific antibodies…………73 Figures…………………………………………………………………75 Tables…………………………………………………………………119 References……………………………………………………………125 Supplementary Figures………………………………………………139 | |
| dc.language.iso | en | |
| dc.subject | 疫苗接種 | zh_TW |
| dc.subject | FcγRIIB | zh_TW |
| dc.subject | 基因多型性 | zh_TW |
| dc.subject | 生發中心 | zh_TW |
| dc.subject | 低親和性抗體 | zh_TW |
| dc.subject | 親和力成熟 | zh_TW |
| dc.subject | low-affinity antibody | en |
| dc.subject | immunization | en |
| dc.subject | affinity maturation | en |
| dc.subject | FcγRIIB | en |
| dc.subject | FcγRIIB-I232T polymorphism | en |
| dc.subject | germinal center | en |
| dc.title | FcγRIIB功能缺損導致生發中心反應異常使低抗原親和性抗體增加之研究 | zh_TW |
| dc.title | A functionally impaired FcγRIIB variant contributes to aberrant accumulation of low-affinity antibody-secreting cells as a result of defective germinal center reaction | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 江伯倫(Bor-Luen Chiang),林淑華(Shu-Wha Lin),陳基益(Ji-Yih Chen) | |
| dc.subject.keyword | FcγRIIB,基因多型性,生發中心,低親和性抗體,親和力成熟,疫苗接種, | zh_TW |
| dc.subject.keyword | FcγRIIB,FcγRIIB-I232T polymorphism,germinal center,low-affinity antibody,affinity maturation,immunization, | en |
| dc.relation.page | 142 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2015-08-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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