Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease
Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease
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DOI：
10.1182/bloodadvances.2020004016
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发表时间：
2021-09-09
期刊：
影响因子：
7.5
通讯作者：
Fajgenbaum, David C.
中科院分区：
文献类型：
--
作者：
Pierson, Sheila K.;Shenoy, Sushila;Fajgenbaum, David C.
特发性多中心Castleman病（iMCD）是一种鲜为人知的血液系统疾病，涉及细胞因子诱导的多克隆淋巴细胞增殖、全身性炎症和潜在致命的多器官衰竭。尽管iMCD的病因尚不清楚，但在大约三分之一的患者中，白细胞介素-6 （IL-6）是一种确定的疾病驱动因素。抗il -6治疗，西妥昔单抗，是美国食品和药物管理局唯一批准的治疗方法。对西妥昔单抗无反应的选择很少，也没有有效的试验可用于预测反应的可能性。我们获得并分析了迄今为止最大的iMCD样本队列，从而将iMCD分类为疾病类别，发现了西妥昔单抗应答的生物标志物，并确定了西妥昔单抗无应答的治疗靶点。对88例iMCD患者、60例临床-病理重叠疾病患者（人疱疹病毒-8相关MCD， N = 20；霍奇金淋巴瘤，N = 20；类风湿关节炎，N = 20）和42名健康对照者的血清进行了1178种分析物的蛋白质组学定量。无监督聚类显示iMCD患者具有异质性血清蛋白质组，不与临床病理重叠疾病聚类。iMCD患者聚类发现了一个对西图昔单抗具有卓越反应的新亚组，并在一个独立队列中使用7种分析物（载脂蛋白E、双调节蛋白、血清淀粉样蛋白p组分、失活补体C3b、免疫球蛋白E、IL-6、促红细胞生成素）进行了验证。富集分析和免疫组织化学鉴定了Janus激酶(JAK)/信号转导和转录3信号激活因子作为候选治疗靶点，可以潜在地用JAK抑制剂靶向西妥昔单抗无反应的患者。我们的发现表明，通过多方利益攸关方合作，有可能加速罕见病的发现。
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.