PDF(Pubmed)
Abstract：
ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient\'s cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways.
摘要：
ALPS和IPEX是两种具有免疫调节失调的先天免疫错误，被认为是单基因自身免疫性疾病的两个主模型。因此，以自身免疫为主要临床表现，这两个实体可能显示临床重叠.传统上,免疫学生物标志物用于建立准确的鉴别诊断。在这里，我们描述了一名临床特征和生物标志物符合ALPS诊断标准的患者.在患者的细胞系和PHA激活的外周血淋巴细胞中也显示出严重的凋亡缺陷。FAS基因的Sanger测序没有发现任何因果突变。NGS筛选揭示了位于FOXP3的N末端阻遏物结构域中的新型有害变体，但在FAS途径相关基因中没有突变。TEMRA细胞（重新表达CD45RA的终末分化效应记忆细胞）和PD1表达增加，有利于T细胞耗尽，这可能是由于Treg缺乏导致的T效应细胞的无限制激活引起的。此外，在患者中观察到的缺陷FOXP3可以内在地诱导T效应细胞的增殖增加和对凋亡的抵抗。这一观察扩大了FOXP3缺乏症的范围，并强调了NGS在检测突变中的作用，这些突变在具有免疫失调的先天性免疫错误中诱导重叠表型。此外,这些发现提示FOXP3和FAS通路之间存在潜在的联系.
