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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳沛隆 | zh_TW |
| dc.contributor.advisor | Pei-Lung Chen | en |
| dc.contributor.author | 許慈恩 | zh_TW |
| dc.contributor.author | Tsz-En Shiu | en |
| dc.date.accessioned | 2023-09-25T16:10:39Z | - |
| dc.date.available | 2023-11-10 | - |
| dc.date.copyright | 2023-09-25 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-06 | - |
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Receptor selection in B and T lymphocytes. Annual review of immunology, 18, 19–51. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90265 | - |
| dc.description.abstract | 自體免疫疾病普遍為多基因性（polygenic），涉及眾多易感性基因（susceptibility gene），當中較為著名的例子是 MHC 基因。近年來，透過基因組關聯分析（genome-wide association studies, GWAS）與次世代定序（next generation sequencing, NGS）的研究，我們已經深入了解特定 MHC 等位基因與自體免疫疾病的發生有顯著相關性。然而，MHC 等位基因並非誘發疾病的主因。為了釐清 MHC 等位基因與人類自體免疫相關疾病的致病機制，本實驗室發展出擬人化主要組織相容性複合體（major histocompatibility complex, MHC）之小鼠模式，目前已透過基於 CRISPR-Cas9 技術之同源臂重組方法建立出擬人化 β2-微球蛋白（β2-microglobulin, B2M）剔入小鼠模式，利用此小鼠模式作為實驗手段，將研究聚焦在我們感興趣之人類免疫相關疾病。
本文旨在探討擬人化 B2M 剔入（gene knock-in）小鼠模式之表徵與可行性。透過DNA、mRNA和蛋白質水平上的研究，該小鼠模型的建立已獲得證實。同時，透過定期體重測量與生理觀察，證明該小鼠模式具備良好生長發育狀況。然而，研究結果顯示雄性擬人化 B2M 剔入小鼠的肝臟重量指數顯著降低，其丙氨酸氨基轉移酶(alanine aminotransferase, ALT)與天門冬氨酸氨基轉移酶(aspartate aminotransferase, AST)的含量於血清中異常升高，說明雄性擬人化 B2M 剔入小鼠的肝臟受到一定的影響。值得注意的是，臟器外觀與蘇木精-伊紅染色結果判讀並未發現異常變化。 B2M 蛋白為 MHC-I 分子呈獻至細胞表面的重要基礎。透過分析 MHC-I 分子的呈獻狀態，擬人化 B2M 剔入小鼠展示出呈獻 MHC-I 分子之能力，並對其重鏈分子的呈獻有所偏好。鑒於 MHC 分子與 T 細胞具有密不可分的關聯性，本文評估該小鼠模式胸腺與次級淋巴器官中的淋巴球組成，結果顯示，擬人化 B2M 剔入小鼠之 T 細胞於胸腺中得以順利發育，並正常分布於周邊淋巴器官。然而，DN1（CD25- CD44+）階段之胸腺細胞比例降低與脾臟淋巴球數目異常，仍有待釐清。此外，擬人化 B2M 剔入小鼠之 T 細胞具備正常的活化能力與產生 Interferon-gamma （IFN-γ） 的功能，同時，在 T 細胞受體特徵中展示出與一般野生型（wild-type）小鼠相似的 V(D)J 基因使用模式，並具有相對平衡與多樣的 T 細胞受體CDR3 克隆型（clonotype）。 綜觀本研究結果，擬人化 B2M 剔入小鼠的整體健康狀態並未受到顯著影響，儘管雄性擬人化 B2M 剔入小鼠的肝臟出現一些問題，限制了其作為肝臟相關疾病研究的應用，總括而言，擬人化 B2M 剔入小鼠在 MHC-I 重鏈分子呈獻上的差異，不影響其 T 細胞發育、組成與活化，並具有多樣的 T 細胞受體庫（TCR repertoire），因此，擬人化 B2M 剔入小鼠具備作為研究模式的潛力。 | zh_TW |
| dc.description.abstract | Autoimmune diseases are generally considered to be polygenic, involving numerous susceptibility genes. Among these, the most well-known examples are the MHC genes. In recent years, through genome-wide association studies (GWAS) and next-generation sequencing (NGS) research, we have gained deeper insights into the significant correlation between specific MHC alleles and the occurrence of autoimmune diseases. However, MHC alleles are not the primary cause of disease induction. To elucidate the pathogenic mechanisms underlying the association between MHC alleles and human autoimmune-related diseases, our laboratory has developed a humanized mouse model of the major histocompatibility complex (MHC). Currently, using the homologous arm recombination method based on CRISPR-Cas9 technology, we have successfully established a humanized β2-microglobulin (B2M) knock-in mouse model. By utilizing this mouse model as an experimental tool, our research focuses on investigating the human immune-related diseases of interest.
This study aims to explore the characterization and feasibility of the humanized β2-microglobulin (B2M) knock-in mouse model. The establishment of this mouse model has been confirmed through investigations at the DNA, mRNA, and protein levels. Additionally, regular measurements of body weight and physiological observations have demonstrated that the mouse model exhibits healthy growth and development. However, the research results indicate that the liver coefficient of male humanized B2M knock-in mice significantly decreased, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were abnormally elevated in the serum, suggesting the liver of male humanized B2M knock-in mice is affected to some extent. It is noteworthy that no abnormal changes were observed in organ appearance and histological analysis using hematoxylin-eosin staining. The B2M protein plays a crucial role in presenting MHC-I molecules on the cell surface. Through the analysis of MHC-I molecule presentation, the humanized B2M knock-in mouse model demonstrates the ability to present MHC-I molecules and exhibits a preference for the presentation of certain heavy chain molecules. Given the close association between MHC molecules and T cells, this study evaluates the lymphocyte composition in the thymus and secondary lymphoid organs of the mouse model. The results show that T cells in the humanized B2M knock-in mice undergo successful development in the thymus and exhibit normal distribution in the peripheral lymphoid organs. However, the decreased proportion of thymocytes at the DN1 (CD25- CD44+) stage and abnormal numbers of splenic lymphocytes still require further investigation. Additionally, the T cells of the humanized B2M knock-in mice possess normal activation capability and the ability to produce Interferon-gamma (IFN-γ). Furthermore, they exhibited similar V(D)J gene usage patterns in T cell receptor characteristics as the wild-type mice, along with a relative balance and diverse T cell receptor CDR3 clonotypes. Taking a comprehensive view of the research findings, the overall health of the humanized B2M knock-in mice was not significantly affected, although some issues were observed in the liver of male humanized B2M knock-in mice, limiting its application as a model for liver-related diseases. In summary, the differences in MHC-I heavy chain molecule presentation do not affect the development, composition, and activation of T cells in the humanized B2M knock-in mice, and they possess a diverse T cell receptor repertoire (TCR repertoire). Therefore, the humanized B2M knock-in mouse holds potential as a research model. | en |
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| dc.description.tableofcontents | Content
口試委員審定書 i 致謝 ii 中文摘要 iii Abstract v 1. Introduction 1 1.1 Genes of major histocompatibility complex (MHC) 1 1.1.1 Characteristics of major histocompatibility complex (MHC) 2 1.1.2 Composition of MHC class I molecules 2 1.1.3 Role of MHC class I molecules in antigen presentation 3 1.1.4 Composition of MHC class II molecules 4 1.1.5 Role of MHC class II molecules in antigen presentation 4 1.2 T cell receptor and its specificity for antigen recognition 5 1.2.1 Generation of TCR repertoire 6 1.2.2 The process of T cell maturation and selection in the thymus 7 1.2.3 CD8 and CD4 T cell development pathways 8 1.2.4 T cell activation and differentiation 8 1.3 The role of B2M molecules and B2M mouse model 9 1.4 Study purpose 10 2. Materials and Methods 12 2.1 Acquisition of experimental mice 12 2.2 Design and cloning of human B2M construct 13 2.3 CRISPR/Cas9-mediated knock-in for generating hB2M KI mice 13 2.4 Genotyping of hB2M KI mice 14 2.4.1 Extraction of genomic DNA (gDNA) 14 2.4.2 Polymerase Chain Reaction (PCR) for genotype identification 15 2.5 RNA extraction from hB2M KI mice 16 2.5.1 Ficoll density gradient separation for isolation of PBMCs 16 2.5.2 Collection of spleen tissue for isolation of splenocytes 17 2.5.3 RNA extraction for PBMCs and splenocytes 18 2.6 cDNA synthesis 19 2.7 Reverse Transcription-PCR (RT-PCR) 20 2.8 Reverse Transcription-quantitative PCR (RT-qPCR) 20 2.9 Flow cytometry analysis 21 2.9.1 Isolation of PBMCs for flow cytometry analysis 22 2.9.2 Isolation of splenocytes and thymocytes for flow cytometry analysis 23 2.9.3 Immunophenotyping 24 2.9.4 Intracellular protein staining 25 2.10 Body weight analysis 26 2.11 Measurements of body length, tail length, and limb length 27 2.12 Organ coefficient and immune organs analysis 27 2.13 Serum biochemical analysis 28 2.14 Complete blood count (CBC) 29 2.15 Hematoxylin and eosin stain (H&E stain) 29 2.16 T cell activation assay 30 2.16.1 T cell culture 31 2.17 Enzyme-linked immunosorbent assay (ELISA) 32 2.18 TCR library 33 2.18.1 Isolation of CD8+ and CD4+ T cells by sorting 34 2.18.2 RNA preparation and cDNA synthesis 34 2.18.3 Purification of cDNA 35 2.18.4 Nested PCR for enriching T cell receptor chains 36 2.18.5 Sequencing and data processing 38 2.19 Analysis of V(D)J usage patterns 38 2.20 Analysis of CDR3 clonotype diversity 39 2.21 Statistical analysis 40 3. Results 41 3.1 Generation of hB2M KI mice with modified mouse B2m gene 41 3.2 Genotyping strategy for genotype determination in hB2M KI mice 42 3.3 Analysis of mRNA expression level of human B2M gene in hB2M KI mice 43 3.4 Expression of human B2M molecules on the cell surface of hB2M KI mice 44 3.5 Intracellular staining of mouse B2M molecules 44 3.6 Evaluation of physiological parameters in hB2M KI mice 45 3.7 Evaluation of hematological parameters in hB2M KI mice 47 3.8 Evaluation of histological parameters in hB2M KI mice 48 3.9 Analysis of immune organ size in hB2M KI mice 48 3.10 Impact of human B2M molecules on MHC-I presentation in hB2M KI mice 49 3.11 Thymocyte differentiation and development in hB2M KI mice 50 3.12 Analysis of lymphocyte distribution in hB2M KI mice 51 3.13 Evaluation of T cell activation in hB2M KI mice 52 3.14 Assessing IFN-γ production after anti-CD3/28 stimulation 53 3.15 Comparative analysis of V(D)J gene usage frequencies in hB2M KI mice 53 3.16 V, D, and J gene segment usage patterns in hB2M KI mice 55 3.17 Diversity analysis of TCR repertoires in hB2M KI mice 56 4. Discussion 58 4.1. Successful knock-in of human B2M gene and protein phenotypic abnormalities 58 4.2. Physiological assessment and liver abnormalities in male hB2M KI mice 59 4.3. Partial hematologic parameter abnormalities in hB2M KI mice 61 4.4. Differential presentation of H-2Db and H-2Kb molecules 63 4.5. Immune organ structure and altered splenic lymphocytes in hB2M KI mice 64 4.6. Normal T cell activation in hB2M KI mice 66 4.7. Similarity in V(D)J gene usage and diversity of TCR CDR3 clones 66 5. Conclusion 69 6. Reference 71 List of Figures Fig. 1. Modification of humanized B2M loci and chimeric MHC Class I. 82 Fig. 2. Genotyping primer annealing sites and genotype analysis. 83 Fig. 3 Analysis of RT-PCR primer annealing sites and genotype-specific results. 84 Fig. 4. RT-qPCR results of mouse B2m gene and human B2M gene. 85 Fig. 5. The expression of B2M molecule on the surface of CD8+ T cells in PBMCs and splenocytes. 86 Fig. 5. The expression of B2M molecule on the surface of CD8+ T cells in PBMCs and splenocytes. 87 Fig. 6. The expression of mouse B2M molecule on cell surface and intracellularly. 88 Fig. 7. Gender-based assessment of phenotype and necropsy in hB2M KI mice. 89 Fig. 8. Normal body length and tail length in hB2M KI mice. 90 Fig. 9. Normal length of forelimb and hindlimb bones in hB2M KI mice. 91 Fig. 10. Normal body weight in hB2M KI mice. 92 Fig. 11. Gross appearance of various organs in hB2M KI mice. 93 Fig. 12. Organ weight-to-body weight ratios of brain, heart, lung, liver, thymus, spleen, and kidney in hB2M KI mice. 94 Fig. 13. Serum biochemical analysis in male hB2M KI mice. 95 Fig. 14. Characterization of red blood cell and platelet parameters in hB2M KI mice. 96 Fig. 15. Characterization of white blood cell parameters in hB2M KI mice. 97 Fig. 16. Hematoxylin and eosin staining of brain, heart, lung, and liver tissues in hB2M KI mice. 98 Fig. 17. Hematoxylin and eosin staining of thymus, spleen, kidney, and intestine tissues in hB2M KI mice. 99 Fig. 18. Immunological organ analysis of thymus and spleen size in hB2M KI mice. 100 Fig. 19. The expression of mouse MHC-I on the surface of CD8+ T cells in PBMCs and splenocytes. 101 Fig. 19. The expression of mouse MHC-I on the surface of CD8+ T cells in PBMCs and splenocytes. 102 Fig. 20. Mouse H-2Kb molecule expressed on cell surface and intracellularly. 103 Fig. 21. RT-qPCR results of mouse H-2Db gene and mouse H-2Kb gene. 104 Fig. 22. Normal thymic T cell development in hB2M KI mice. 105 Fig. 23. The differentiation of thymocytes in hB2M KI mice. 106 Fig. 24. Total numbers of thymocytes and T cells at different developmental stages in hB2M KI mice. 107 Fig. 25. Lymphoid populations in PBMCs and spleen from hB2M KI mice. 108 Fig. 26. T-cell subsets in PBMCs and spleen from hB2M KI mice. 109 Fig. 27. Total numbers of splenocytes and lymphocytes in hB2M KI mice. 110 Fig. 28. Microscopic images of anti-CD3/28 stimulated splenocyte cultures. 111 Fig. 29. Normal CD8 T cell activation in hB2M KI mice with anti-CD3/CD28. 112 Fig. 30. Normal CD4 T cell activation in hB2M KI mice with anti-CD3/CD28. 113 Fig. 31. IFN-γ production in T cells after anti-CD3/CD28 stimulation. 114 Fig. 32. Usage of TRV and TRD genes in CD8 T cells. 115 Fig. 33. Usage of TRJ genes in CD8 T cells. 116 Fig. 34. Usage of TRV and TRD genes in CD4 T cells. 117 Fig. 35. Usage of TRJ genes in CD4 T cells. 118 Fig. 36. Usage patterns of CD8 TRAV genes. 119 Fig. 37. Usage patterns of CD8 TRBV genes. 120 Fig. 38. Usage patterns of CD8 TRGV and TRDV genes. 121 Fig. 39. Usage patterns of CD8 TRBD and TRDD genes. 122 Fig. 40. Usage patterns of CD8 TRAJ and TRBJ genes. 123 Fig. 41. Usage patterns of CD8 TRGJ and TRDJ genes. 124 Fig. 42. Usage patterns of CD4 TRAV genes. 125 Fig. 43. Usage patterns of CD4 TRBV genes. 126 Fig. 44. Usage patterns of CD4 TRGV and TRDV genes. 127 Fig. 45. Usage patterns of CD4 TRBD and TRDD genes. 128 Fig. 46. Usage patterns of CD4 TRAJ and TRBJ genes. 129 Fig. 47. Usage patterns of CD4 TRGJ and TRDJ genes. 130 Fig. 48. Venn diagram of CDR3 diversity in CD8 T cells. 131 Fig. 49. Venn diagram of CDR3 diversity in CD4 T cells. 132 Fig. 50. Comparison of TCR CDR3 clone diversity by the Shannon-Weiner index. 133 Fig. 51. CDR3 diversity in CD8 and CD4 T cells among individuals. 134 Fig. S1. Experimental framework diagram. 135 Fig. S2. Flowchart for hB2M KI mice model validation. 135 Fig. S3. Health assessment flowchart for hB2M KI mice model. 136 Fig. S4. MHC-I presentation analysis diagram in hB2M KI mice. 136 Fig. S5. T cell stimulation experiment diagram for hB2M KI mice. 137 Fig. S6. Diagram of TCR repertoire analysis in hB2M KI mice. 137 Fig. S7. Gating strategy for thymocyte panel analysis. 138 Fig. S8. Gating strategy for analyzing lymphoid populations in PBMCs. 139 Fig. S9. Gating strategy for analyzing lymphoid populations in splenocytes. 140 Fig. S10. Gating strategy for analyzing the activated T cell subsets. 141 Fig. S11. Quality control results of the TCR library in CD8 T cells. 142 Fig. S12. Quality control results of the TCR library in CD4 T cells. 143 List of Tables Table 1. The primers used for the human B2M construct. 144 Table 2. Nucleotide sequences of genotyping primers. 145 Table 3. Nucleotide sequences of RT-PCR and RT-qPCR primers. 146 Table 4. Fluorescent antibodies used for thymic T cell development. 147 Table 5. Fluorescent antibodies for immunophenotyping and intracellular staining 148 Table 6. Fluorescent antibodies used for T cell activation assay. 149 Table 7. Fluorescent antibodies used for T cell sorting. 150 Table 8. Total RNA concentration, absorbance ratios, and RNA integrity number (RIN) specifically for PBMCs. 151 Table 9. Total RNA concentration, absorbance ratios, and RNA integrity number (RIN) specifically for splenocytes. 152 Table 10. Body and tail lengths in hB2M KI mice. 153 Table 11. Forelimb and hindlimb bone lengths in hB2M KI mice. 154 Table 12. Body weight of male hB2M KI mice. 155 Table 13. Body weight of female hB2M KI mice. 156 Table 14. Organ weight-to-body weight ratios in hB2M KI mice. 157 Table 15. Thymus and spleen lengths in hB2M KI mice. 158 Table 16. Total RNA concentration, absorbance ratios, and RNA integrity number (RIN) specifically for splenic CD8 T cells. 159 Table 17. Total RNA concentration, absorbance ratios, and RNA integrity number (RIN) specifically for splenic CD4 T cells. 160 | - |
| dc.language.iso | en | - |
| dc.title | 人類免疫相關疾病研究中擬人化 B2M 小鼠模式之表徵與可行性 | zh_TW |
| dc.title | Characterization and Feasibility of Humanized B2M Mice Model for the Study of Human Immune-related Diseases | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 莊雅惠;游益興;陳佑宗 | zh_TW |
| dc.contributor.oralexamcommittee | Ya-Hui Chuang;I-Shing Yu;You-Tzung Chen | en |
| dc.subject.keyword | MHC（主要組織相容性複合體）,HLA（人類白血球抗原）,β2-微球蛋白,CRISPR-Cas9,擬人化小鼠模式, | zh_TW |
| dc.subject.keyword | MHC (major histocompatibility complex),HLA (human leukocyte antigen),β2-microglobulin,CRISPR-Cas9,humanized mouse model, | en |
| dc.relation.page | 160 | - |
| dc.identifier.doi | 10.6342/NTU202302937 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2023-08-07 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | - |
| Appears in Collections: | 基因體暨蛋白體醫學研究所 | |
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