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

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。

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.