Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome.
Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome.
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DOI：
10.1172/jci162137
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发表时间：
2023-01-03
影响因子：
15.9
通讯作者：
Leung, Thomas H.
中科院分区：
文献类型：
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作者：
Bhattacharya, Shreya;Basu, Sayon;Sheng, Emily;Murphy, Christina;Wei, Jenny;Kersh, Anna E.;Nelson, Caroline A.;Bryer, Joshua S.;Ashchyan, Hovik A.;Steele, Katherine;Forrestel, Amy;Seykora, John T.;Micheletti, Robert G.;James, William D.;Rosenbach, Misha;Leung, Thomas H.
急性发热性嗜中性粒细胞皮肤病（Sweet综合征）是一种潜在的致命性多器官炎性疾病，其特征是发热、白细胞增多和伴有嗜中性粒细胞浸润的皮疹。疾病的病理生理学仍然难以捉摸，目前的教条表明，甜综合征是一个过程的反应性未知抗原。皮质类固醇和类固醇保留剂仍然是一线治疗，但难治性病例构成了临床挑战。一名51岁的女性多器官Sweet综合征发展严重的皮质类固醇相关的副作用，是难治性的类固醇保留剂。血细胞计数、肝酶和皮肤组织病理学支持诊断。对患者的皮肤和中性粒细胞进行全基因组测序、转录组学分析和细胞测定。我们确定了由中性粒细胞中特异性发现的PIK 3R 1功能获得性突变引起的病变性Sweet综合征皮肤中的IL-1信号传导升高。该突变增加了中性粒细胞向IL-1β的迁移和中性粒细胞呼吸爆发。用IL-1受体1拮抗剂对患者进行靶向治疗导致了显著的治疗反应，并使皮质类固醇逐渐减少。PI 3 K/AKT信号转导失调是与Sweet综合征相关的第一个信号转导途径，表明该综合征可能是由调节中性粒细胞功能的获得性突变引起的。此外，跨多个水平的分子数据的整合在异质性疾病中鉴定了不同的亚型，从而导致合理和成功的临床干预。未来的患者将受益于识别潜在突变的努力。直接询问患病皮肤的能力使得该方法可推广到其他炎性疾病，并为患有临床挑战性疾病的患者展示了潜在的个性化医学方法。Berstein基金会、NIH、退伍军人事务部（VA）管理局、莫斯利基金会和H.T.梁氏基金会。
Acute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge. A 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient’s skin and neutrophils were performed. We identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1β and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids. Dysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease. Berstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.