遗传性C1q缺乏症(C1QDef)是一种罕见的单基因疾病,导致补体途径激活缺陷和系统性红斑狼疮(SLE)样表现。补体级联受损与自身免疫之间的联系仍未完全理解。这里,我们评估了C1QDef患者的1型干扰素途径激活.通过国际合作招募了12名遗传证实为C1QDef的患者。临床,回顾性收集生物学和放射学数据.测量了一组标准化的干扰素刺激基因(ISGs)在外周血中的表达,和使用SIMOA技术测定脑脊液(CSF)中干扰素α(IFNα)蛋白的水平。中枢神经系统(包括基底神经节钙化,脑炎,血管炎,慢性硬脑膜炎),皮肤粘膜和肾脏受累,分别,在12名患者中的10名、11名和2名患者中,和严重感染记录在2/12的患者。在所有受试患者中观察到ISG表达升高(n=10/10),2/2患者血清和CSFIFNα升高。三名患者接受了Janus激酶抑制剂(JAKI)治疗,结果可变;在皮肤和神经系统特征方面表现出明显的良好反应,和另外两名尽管接受JAKI治疗但仍患有持续性疾病。据我们所知,我们报道了迄今为止最大的经基因证实的C1QDef原始系列。此外,我们对以前描述的所有C1QDef基因证实病例进行了回顾.总的来说,患有C1QDef的个体表现出许多公认的单基因干扰素病的特征:特别是,皮肤受累(黄斑皮疹,肢端血管炎/丘疹,冻疮),SLE样疾病,基底节钙化,外周血中ISGs的表达增加,和CSFIFNα水平升高。
Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1
interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of
interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of
interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.