Asparaginase immune complexes induce Fc-γRIII-dependent hypersensitivity in naive mice.
Asparaginase immune complexes induce Fc-γRIII-dependent hypersensitivity in naive mice.
复制标题
天冬酰胺酶免疫复合物在幼鼠中诱导 Fc-γRIII 依赖性超敏反应。
DOI：
10.1096/fj.201900857
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Fernandez,ChristianA
中科院分区：
文献类型：
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作者：
Rathod,Sanjay;Ramsey,Manda;DiGiorgio,Danielle;Berrios,Roberto;Finkelman,FredD;Fernandez,ChristianA
天冬酰胺酶（Asparaginase，ASNase）是治疗白血病的重要药物。然而，对ASNase的超敏反应可增加白血病复发的风险。在小鼠中已经确定了ASNase超敏反应的两种机制。抗ASNase IgG和Fc-γ受体III（Fc-γRIII）参与的通路的存在意味着IgG和ASNase免疫复合物（IC）可以直接诱导超敏反应。本研究的目的是检测小鼠过敏反应后ASNase IC，并确定其在过敏反应中的作用。使用蛋白G珠通过流式细胞术检测血浆ASNase IC。从致敏小鼠的血浆中纯化抗ASNase IgG，并以ASNase与抗ASNase IgG的各种比例离体制备ASNase IC。超敏反应后检测到的ASNase IC水平与反应严重程度相关（R2 = 0.796; P = 0.0005）。离体制备的ASNase IC需要高水平的抗ASNase IgG才能形成，与初始和致敏免疫细胞的结合取决于可溶性抗ASNase IgG、抗原：抗体比例和Fc-γRIII。同样，ASNase IC对嗜碱性粒细胞的活化取决于抗原：抗体比和Fc-γRIII。与离体结果一致，接受ASNase IC的未处理小鼠发生超敏反应。我们的数据表明，ASNase IC可以直接导致ASNase超敏反应的发作和严重程度。Rathod，S.，Ramsey，M.，DiGiorgio，D.，贝里奥斯河Finkelman，F. D、费尔南德斯角A.天冬酰胺酶免疫复合物诱导未处理小鼠中的Fc-γ RIII依赖性超敏反应。
Asparaginase (ASNase) is an important drug for the treatment of leukemias. However, hypersensitivity to ASNase can increase the risk of leukemia relapse. Two mechanisms of ASNase hypersensitivity have been identified in mice. The existence of a pathway involving anti-ASNase IgG and Fc-γ receptor III (Fc-γRIII) implies that IgG and ASNase immune complexes (ICs) could directly induce hypersensitivity. The aim of this study was to detect ASNase ICs in mice after hypersensitivity reactions and determine their role in hypersensitivity. Protein G beads were used to detect plasma ASNase ICs by flow cytometry. Anti-ASNase IgG was purified from the plasma of sensitized mice, and ASNase ICs were prepared ex vivo at various ratios of ASNase to anti-ASNase IgG. The levels of ASNase ICs detected after hypersensitivity reactions correlated with reaction severity (R2 = 0.796; P = 0.0005). ASNase ICs prepared ex vivo required high levels of anti-ASNase IgG for formation, and binding to naive and sensitized immune cells depended on soluble anti-ASNase IgG, antigen:antibody ratio, and Fc-γRIII. Similarly, basophil activation by ASNase ICs depended on the antigen:antibody ratio and Fc-γRIII. Consistent with the ex vivo results, naive mice receiving ASNase ICs developed hypersensitivity reactions. Our data demonstrate that ASNase ICs can directly contribute to the onset and severity of ASNase hypersensitivity.—Rathod, S., Ramsey, M., DiGiorgio, D., Berrios, R., Finkelman, F. D., Fernandez, C. A. Asparaginase immune complexes induce Fc-γRIII–dependent hypersensitivity in naive mice.