Wang Wenjie, Liu Luyao, Hui Xiaoying, Wang Ying, Ying Wenjing, Zhou Qinhua, Hou Jia, Yang Mi, Sun Bijun, Sun Jinqiao, Wang Xiaochuan
Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China.
BMC Immunol. 2021 Mar 17;22(1):19. doi: 10.1186/s12865-021-00411-1.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
我们旨在报告一名通过下一代测序鉴定出具有新发STAT3功能获得性突变患者的临床特征、免疫特性及治疗情况。我们研究了托珠单抗治疗由STAT3突变引起的免疫失调疾病的疗效。
该患者为一名16岁女孩。她出生后即出现反复呼吸道感染和慢性腹泻。14岁时患危及生命的自身免疫性全血细胞减少症。接受糖皮质激素治疗后，她患上了糖尿病。然而，当糖皮质激素减量时，她的全血细胞减少症复发。下一代测序显示STAT3基因存在新发杂合突变，即c.1261G＞A（p.G421R），该突变先前被描述为功能获得性突变。接受托珠单抗治疗后，她的全血细胞减少症完全缓解，胰岛素和糖皮质激素治疗在12个月内逐渐停用。治疗前她有淋巴细胞减少和CD4/CD8比值倒置。淋巴细胞亚群分析表明效应记忆CD4+、效应记忆CD8+和中枢记忆CD4+T细胞扩增。记忆B细胞和初始CD4+T细胞比例降低，初始B细胞比例增加。淋巴细胞的这些异常变化均未显著改善。通过下一代基因测序在早发性多器官自身免疫患者中鉴定出STAT3功能获得性突变。包括我们的患者在内，13例具有STAT3功能获得性突变的患者接受了靶向治疗。其中12例单独接受托珠单抗治疗或托珠单抗与JAK抑制剂联合治疗，10例患者病情改善。
对于早发性难治性或多器官免疫失调疾病患者应进行基因测序。靶向药物可有效改善与STAT3功能获得性突变相关的临床问题，而非靶向免疫抑制治疗通常不足。
