PDF(Pubmed)
Abstract：
We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils < 500/mL, reticulocytes < 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T>C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient\'s inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8+ T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases.
摘要：
我们确定了一名32岁苍白女性的STAT1功能增益（GOF），弱点,咳嗽,和呼吸困难被我们的医学部收治。她有严重的口腔溃疡（OU），1型糖尿病（T1DM），和全血细胞减少症.骨髓（BM）活检显示没有红系前体。外周血参数，如中性粒细胞<500/mL，网织红细胞<2%,和BM低细胞允许诊断严重再生障碍性贫血。杂合变体(p.520T>C，发现了STAT1的p.Cys174Arg）。因此，研究了p.Cys174Arg突变可能导致患者的先天性免疫错误和再生障碍性贫血。虽然STAT1GOF是罕见的，再生障碍性贫血是一种更常见的疾病；因此，我们探讨了STAT1功能在BM衰竭病理生物学中的作用.有趣的是,在一组6名特发性再生障碍性贫血患者中，BM免疫染色观察到磷酸化STAT1水平增强.接下来,研究了与STAT1信号传导失调相关的最显着特征：在纯红细胞再生障碍性贫血中，CD8+T细胞遗传变体和突变显示与JAK-STAT途径相关的增强的信号活性。天生的免疫错误可能代表了一种典型的条件，以揭示常见病理状况所共有的关键病理生物学机制。我们基于病例的方法的结果以及与特发性再生障碍性贫血病例的表型对应关系提示了进一步的具有统计学意义的前瞻性研究，旨在阐明JAK/STAT靶向在这种临床背景下的确切作用和治疗不可知窗口。尽管如此，我们证明了对原发性免疫缺陷患者的全面研究如何在更广泛的再生障碍性贫血病例中获得病理生理学见解和潜在的治疗方法.
