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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賈景山 | zh_TW |
| dc.contributor.advisor | Jean-San Chia | en |
| dc.contributor.author | 郭佑民 | zh_TW |
| dc.contributor.author | Yu-Min Kuo | en |
| dc.date.accessioned | 2025-02-20T16:30:23Z | - |
| dc.date.available | 2025-02-21 | - |
| dc.date.copyright | 2025-02-20 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-12-30 | - |
| dc.identifier.citation | 1.Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532-1535 (2004).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96680 | - |
| dc.description.abstract | 嗜中性白血球細胞外誘網 (NETs) 作為一種先天防禦機制，已被發現與 COVID-19 及與腺病毒載體疫苗相關的疫苗誘發性血栓性血小板減少症 (VITT) 以及全身性血管炎有關。我們假設，接種 COVID-19 加強劑後出現不良事件的健康受試者 (HDs) 及全身性血管炎患者中，與 NETs 相關的生物指標可能會升高。一項從 2021 年 3 月至 2022 年 1 月進行的研究，納入在國立台灣大學醫院接種 ChAdOx1-S (A)、mRNA-1273 (M) 及高端 MVC-COV1901 (G) 的健康受試者。研究包含三個亞群：MM-M、AA-M 和 GG-G。針對 citrullinated-histone 3 (citH3) 和髓過氧化物酶 (MPO) -DNA 複合物進行了三個時間點的序列測量：疫苗接種前(Naïve)、加強劑當天 (第 0 天) 以及加強劑後 30 天。此外，我們亦檢測了抗肝素血小板因子 4 (抗 HPF4) 和抗 NETs 的 IgG/IgM 抗體，並通過線上日誌收集HDs報告之不良事件 (AEs) 。結果顯示，在不良事件陽性的受試者 (n=100) 中，加強劑第 0 天及加強劑第 30 天的血清 citH3 數值顯著升高。特別是接種 mRNA-1273 和 ChAdOx1-S 的受試者中 citH3 數值較高，並與皮疹相關，但與發燒、頭痛、胸痛或心悸無關。在 AA-M 群組中，抗 HPF4 抗體比值 (加強劑第 0 天/ Naïve) 與 citH3 顯著正相關，這表明抗 HPF4 抗體可能像 VITT 患者一樣，在HDs亦刺激 NETs生物指標citH3之產生。相反地，在 MM-M 群組中，抗 NETs IgM比值 (加強劑第 30 天/加強劑第 0 天）) 與同一時間citH3上升比值顯著相關。另一項前瞻性的血管炎研究 (2017-2021 年) 顯示，血管炎患者的 MPO-DNA數值較高，並且與臨床嚴重程度相關，優於 C 反應蛋白和紅血球沉降率等傳統發炎指標。總結:考量施打mRNA-1273/ChAdOx1-S之HDs有NETs 生物指標上升與促NET自體抗體上升之情形，這兩種疫苗與 NETs 相關「免疫血栓」有潛在相關性。此外，MPO-DNA此NETs生物指標在監測血管炎活性中顯示有應用價值。 | zh_TW |
| dc.description.abstract | Neutrophil extracellular traps (NETs), an innate defense mechanism, have been linked to COVID-19 and vaccine-induced thrombotic thrombocytopenia (VITT) associated with adenovirus-vectored vaccines and systemic vasculitis. We hypothesize that NET-related biomarkers may be elevated in healthy donors (HDs) who develop adverse events after receiving COVID-19 boosters and in individuals with systemic vasculitis. A study from March 2021 to January 2022 enrolled HDs receiving ChAdOx1-S (AZ), mRNA-1273 (M), and MVC-COV1901 (G) at National Taiwan University Hospital. Three subgroups, MM-M, AA-M, and GG-G, were included. Serial measurements of citrullinated-histone 3 (citH3) and myeloperoxidase (MPO)-DNA complexes were taken at three points: pre-vaccination, Booster Day 0, and 30 days post-boosters. Anti-heparin platelet factor 4 (anti-HPF4) and anti-NET IgG/IgM antibodies were also examined, with HDs reporting adverse events (AEs) via online diaries. Serum citH3 levels were significantly higher in AE-positive enrollees (n=100) on Booster Day 0 and Day 30. Higher citH3 levels were noted in mRNA-1273 and ChAdOx1-S recipients, correlating with rash but not with fever, headache, chest pain, or palpitations. A significant positive correlation was observed between anti-HPF4 antibody ratios (Booster Day 0/Naïve) and citH3 in the AA-M group, suggesting that anti-HPF4 antibodies may trigger citH3 similarly to VITT. Conversely, a significant correlation was identified between anti-NET IgM ratios (Booster Day 30/Booster Day 0) and citH3 in the MM-M group. In another prospective vasculitis study (2017-2021), MPO-DNA levels were higher in vasculitis patients and correlated with clinical severity, outperforming traditional markers like C-reactive protein and erythrocyte sedimentation rate. These findings highlight a potential link between mRNA-1273/ChAdOx1-S vaccines and NET-associated immunothrombosis, as well as the utility of MPO-DNA in monitoring vasculitis activity. | en |
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| dc.description.provenance | Made available in DSpace on 2025-02-20T16:30:23Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract iv Table of Contents v Abbreviations viii Chapter 1 Introduction 1 1.1 Neutrophil extracellular traps 1 1.2 Neutrophil extracellular traps and immunothrombosis 1 1.3 NET-promoting factors and NET-promoting autoantibodies 3 1.4 Overview of small vessel vasculitis and pathophysiological mechanisms, including the role of NETs 4 1.5 Environmental triggers and clinical management of AAV 6 1.6 Hypothesis formulation and study design 8 Chapter 2 Methods 9 2.1 Healthy donors in a prospective COVID-19 cohort study 9 2.2 Measurement of MPO-DNA complex 10 2.3 Measurement of citH3 11 2.4 Measurement of anti-HPF4 antibodies 12 2.5 Measurement of anti-NET IgG/IgM 12 2.6 Measurement of total IgG and antineutrophil cytoplasmic antibody (ANCA) 13 2.7 A prospective cohort study on neutrophil-derived biomarkers in vasculitis disease activity and a case of vasculitis with longitudinal follow-up 14 2.8 Statistical analysis 15 Chapter 3 Results 17 3.1 Age discrepancy observed in study participants of COVID-19 vaccine immunogenicity and adverse events investigation 17 3.2 Positive adverse events following booster vaccinations linked to higher serum citH3 levels 18 3.3 Dynamic changes in citH3 and anti-NET antibody levels post-booster vaccination of three types of COVID-19 vaccines 19 3.4 Positive correlation between anti-HPF4 antibodies and citH3 levels post-booster in AA-M group and potential role for anti-NET IgM in elevation of citH3 after mRNA COVID-19 vaccines 21 3.5 No significant correlation between anti-S IgG levels and citH3 escalation post-COVID-19 boosters 22 3.6 Analysis of symptomatology post-booster COVID-19 vaccination reveals correlations with NETosis biomarkers 23 3.7 Vasculitis case presentation 23 3.8 Optimizing the use of vasculitis markers in trastuzumab-induced interstitial lung disease 25 3.9 Evaluating MPO-DNA efficacy in a prospective vasculitis cohort 27 3.10 Evaluation of NET biomarkers MPO-DNA in the vasculitis case associated with trastuzumab-ILD 28 Chapter 4 Discussion 30 4.1 Discussion of Part I: The roles of NETs and autoantibodies in adverse events following COVID-19 vaccines 30 4.2 Discussion of Part II: The use of neutrophil extracellular trap biomarkers for prognostic prediction in systemic vasculitis 34 Chapter 5 Perspective 40 5.1 Adenovirus-based vaccines: implications for safety and future research 40 5.2 NETs biomarkers are potentially linked to specific antibody production 42 5.3 Potential influence of age on NETosis in vaccine studies 42 5.4 The potential of MPO-DNA as a biomarker in systemic vasculitis and trastuzumab-induced ILD 43 5.5 Conclusion 44 Chapter 6 References 45 Chapter 7 Figures and Tables 56 FIGURE 1. Method of measurement of anti-NET IgG/IgM 56 FIGURE 2. Enrollment flow diagram of COVID vaccine cohort 57 FIGURE 3. Substantial elevation or inclination towards elevation was noted for the NETosis biomarkers citH3 and MPO-DNA in HDs who reported AEs 59 FIGURE 4. Evaluation of citH3 levels for AE prediction 61 FIGURE 5. Comparison of Anti-S and total IgG levels in AE(+) and AE(-)HDs 62 FIGURE 6. HDs who received adenovirus-vectored/mRNA COVID-19 vaccines exhibited heightened levels of serum citH3 upon serial testing 63 FIGURE 7. Dynamic changes in Anti-S antibodies across three subgroups 65 FIGURE 8. Temporal associations were observed among increases in anti-HPF4 antibodies, anti-NET IgM, and citH3 levels 66 FIGURE 9. Lack of temporal correlation between Anti-S antibody increases and citH3 levels 67 FIGURE 10. Absence of significant elevation in Anti-S antibodies stratified by NETosis biomarkers citH3 68 FIGURE 11. Symptomatology across three subgroups 69 FIGURE 12. Association of higher citH3 levels with rash, not fever or other AEs 70 FIGURE 13. Imaging studies of a case of vasculitis 71 FIGURE 14. Bronchoscopy findings of diffuse mucosal bleeding in the airway 72 FIGURE 15. Evidence of vasculitis from pathology specimen 73 FIGURE 16. Key inflammatory markers change prior to and after treatment 74 FIGURE 17. Study flowchart of a prospective cohort study on systemic vasculitis 75 FIGURE 18. MPO-DNA levels as a diagnostic biomarker in systemic vasculitis 76 FIGURE 19. MPO-DNA correlation with disease activity in vasculitis patients 77 FIGURE 20. A schematic diagram highlights the role of NETs and NET-promoting antibodies in vaccinated HDs 78 FIGURE 21. Interaction between anti-HER2 antibody and ANCA-associated vasculitis and neutrophil 80 TABLE 1. Baseline characteristics and dynamic changes in citH3 levels were analyzed for three subgroups 81 TABLE 2. Dynamic changes in citH3 serum levels and anti-HPF4 antibody levels in COVID-19 vaccine recipients were assessed using linear mixed models 82 TABLE 3. Case comparison of previously reported trastuzumab-related interstitial lung disease 83 TABLE 4. Clinical characteristics of vasculitis patients and healthy controls 84 Chapter 8 APPENDIX 85 | - |
| dc.language.iso | en | - |
| dc.title | 嗜中性白血球細胞外誘網與自體抗體在新冠疫苗後併發症與血管炎之角色 | zh_TW |
| dc.title | Adverse events following COVID-19 vaccines and systemic vasculitis—elucidating the roles of neutrophil extracellular traps and autoantibodies. | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 謝松洲 | zh_TW |
| dc.contributor.coadvisor | Song-Chou Hsieh | en |
| dc.contributor.oralexamcommittee | 蔡長祐;鍾筱菁;余家利;呂明錡 ;楊偉勛 | zh_TW |
| dc.contributor.oralexamcommittee | Chang-Youh Tsai;Chiau-Jing Jung;Chia-Li Yu ;Ming-Chi Lu;Wei-Shiung Yang | en |
| dc.subject.keyword | COVID-19 疫苗,mRNA 疫苗,嗜中性白血球細胞外誘網,自體抗體,全身性血管炎, | zh_TW |
| dc.subject.keyword | COVID-19 vaccines,mRNA vaccine,NETosis,autoantibodies,systemic vasculitis, | en |
| dc.relation.page | 85 | - |
| dc.identifier.doi | 10.6342/NTU202404782 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-01-02 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 臨床醫學研究所 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 臨床醫學研究所 | |
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