Abstract：
BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections.
OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease.
METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies.
RESULTS: Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients.
CONCLUSIONS: Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.
OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease.
METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies.
RESULTS: Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients.
CONCLUSIONS: Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.
摘要：
背景：单等位基因功能丧失IKZF1（IKAROS）变体导致B细胞缺陷或联合免疫缺陷，而单等位基因功能获得IKZF1变异体最近被报道引起高丙种球蛋白血症，浆细胞分化异常，自身免疫和过敏表现，和感染。
方法：我们研究了7名患有自身免疫性/炎性疾病和淋巴增生性疾病的亲属。我们分析了活检结果，并进行了全外显子组测序和免疫学研究。
结果：发病平均年龄25.2岁（范围：10-64岁）。六名患者患有自身免疫性/炎症性疾病，4人已确诊免疫球蛋白G4相关疾病（IgG4-RD），5例发展为B细胞恶性肿瘤：4例淋巴瘤和其余患者的多发性骨髓瘤。没有免疫抑制的患者并不特别容易发生感染性疾病。三名患者患有危及生命的COVID-19肺炎，其中一人具有中和干扰素（IFN）-α的自身抗体。最近描述的IKZF1功能获得p.R183H变体是在接受测试的五个受影响的亲戚和一个六岁无症状的女孩中发现的。免疫学分析显示高丙种球蛋白血症和某些淋巴细胞亚群的高频率（耗尽的B细胞，效应记忆CD4T细胞，TEMRA和CD28-CD57+CD4+和CD8+T细胞，Th2和Tfh2细胞）证明免疫失调。观察到利妥昔单抗和皮质类固醇的部分临床反应，和来那度胺治疗，这促进了IKAROS退化，在三名患者中开始。
结论：功能获得IKZF1变体的杂合性是自身免疫/炎性疾病的基础，IgG4-RD和B细胞恶性肿瘤，其发病可能发生在成年期。临床和免疫学数据与无法解释的IgG4-RD患者相似。因此，患者可能受益于抑制显示IKAROS介导的过度活性的途径的治疗。
方法：我们研究了7名患有自身免疫性/炎性疾病和淋巴增生性疾病的亲属。我们分析了活检结果，并进行了全外显子组测序和免疫学研究。
结果：发病平均年龄25.2岁（范围：10-64岁）。六名患者患有自身免疫性/炎症性疾病，4人已确诊免疫球蛋白G4相关疾病（IgG4-RD），5例发展为B细胞恶性肿瘤：4例淋巴瘤和其余患者的多发性骨髓瘤。没有免疫抑制的患者并不特别容易发生感染性疾病。三名患者患有危及生命的COVID-19肺炎，其中一人具有中和干扰素（IFN）-α的自身抗体。最近描述的IKZF1功能获得p.R183H变体是在接受测试的五个受影响的亲戚和一个六岁无症状的女孩中发现的。免疫学分析显示高丙种球蛋白血症和某些淋巴细胞亚群的高频率（耗尽的B细胞，效应记忆CD4T细胞，TEMRA和CD28-CD57+CD4+和CD8+T细胞，Th2和Tfh2细胞）证明免疫失调。观察到利妥昔单抗和皮质类固醇的部分临床反应，和来那度胺治疗，这促进了IKAROS退化，在三名患者中开始。
结论：功能获得IKZF1变体的杂合性是自身免疫/炎性疾病的基础，IgG4-RD和B细胞恶性肿瘤，其发病可能发生在成年期。临床和免疫学数据与无法解释的IgG4-RD患者相似。因此，患者可能受益于抑制显示IKAROS介导的过度活性的途径的治疗。
