PDF(Pubmed)
Abstract：
Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (DPP9), a negative regulator of the NLRP1 and CARD8 inflammasomes, have recently been shown to cause an inborn error of immunity characterized by pancytopenia, skin manifestations, and increased susceptibility to infections.
We sought to study the molecular basis of autoinflammation in a patient with severe infancy-onset hyperinflammation associated with signs of fulminant hemophagocytic lymphohistiocytosis.
Using heterologous cell models as well as patient cells, we performed genetic, immunologic, and molecular investigations to identify the genetic cause and to assess the impact of the identified mutation on inflammasome activation.
The patient exhibited pancytopenia with decreased neutrophils and T, B, and natural killer cells, and markedly elevated levels of lactate dehydrogenase, ferritin, soluble IL-2 receptor, and triglycerides. In addition, serum levels of IL-1β and IL-18 were massively increased, consistent with inflammasome activation. Genetic analysis revealed a previously undescribed de novo mutation in DPP9 (c.755G>C, p.Arg252Pro) affecting a highly conserved amino acid residue. The mutation led to destabilization of the DPP9 protein as shown in transiently transfected HEK293T cells and in patient-derived induced pluripotent stem cells. Using functional inflammasome assays in HEK293T cells, we demonstrated that mutant DPP9 failed to restrain the NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation. These findings suggest that the Arg252Pro DPP9 mutation acts in a dominant-negative manner.
A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation because of unleashed inflammasome activation.
We sought to study the molecular basis of autoinflammation in a patient with severe infancy-onset hyperinflammation associated with signs of fulminant hemophagocytic lymphohistiocytosis.
Using heterologous cell models as well as patient cells, we performed genetic, immunologic, and molecular investigations to identify the genetic cause and to assess the impact of the identified mutation on inflammasome activation.
The patient exhibited pancytopenia with decreased neutrophils and T, B, and natural killer cells, and markedly elevated levels of lactate dehydrogenase, ferritin, soluble IL-2 receptor, and triglycerides. In addition, serum levels of IL-1β and IL-18 were massively increased, consistent with inflammasome activation. Genetic analysis revealed a previously undescribed de novo mutation in DPP9 (c.755G>C, p.Arg252Pro) affecting a highly conserved amino acid residue. The mutation led to destabilization of the DPP9 protein as shown in transiently transfected HEK293T cells and in patient-derived induced pluripotent stem cells. Using functional inflammasome assays in HEK293T cells, we demonstrated that mutant DPP9 failed to restrain the NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation. These findings suggest that the Arg252Pro DPP9 mutation acts in a dominant-negative manner.
A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation because of unleashed inflammasome activation.
摘要：
背景：炎性体成分的遗传缺陷可引起自身炎症。DPP9的双等位基因功能缺失突变，NLRP1和CARD8炎性体的负调节因子，最近被证明会导致以血细胞减少为特征的先天性免疫错误，皮肤表现，和增加对感染的易感性。
目的：我们研究了1例严重婴儿期发生的高度炎症与暴发性噬血细胞性淋巴组织细胞增多症相关的自身炎症的分子基础。
方法：使用异源细胞模型以及患者细胞，我们进行了遗传，免疫学，和分子调查，以确定遗传原因，并评估确定的突变对炎症小体激活的影响。
结果：患者出现全血细胞减少伴中性粒细胞减少，T,B,和NK细胞，LDH水平显著升高，铁蛋白,可溶性IL-2受体，和甘油三酯。此外,血清IL-1β和IL-18水平大幅升高，与炎症体激活一致。遗传分析显示DPP9中先前未描述的从头突变，c.755G>C，p.Arg252Pro,影响高度保守的氨基酸残基。如在瞬时转染的HEK293T细胞和患者来源的诱导多能干细胞中所示,突变导致DPP9蛋白的不稳定。在HEK293T细胞中使用功能性炎性体测定，我们证明突变体DPP9未能抑制NLRP1和CARD8炎性体，导致组成性炎性体激活。这些发现表明Arg252ProDPP9突变以显性阴性方式起作用。
结论：DPP9的从头突变导致严重的婴儿期发作的自身炎症，原因是炎症小体的释放。
目的：我们研究了1例严重婴儿期发生的高度炎症与暴发性噬血细胞性淋巴组织细胞增多症相关的自身炎症的分子基础。
方法：使用异源细胞模型以及患者细胞，我们进行了遗传，免疫学，和分子调查，以确定遗传原因，并评估确定的突变对炎症小体激活的影响。
结果：患者出现全血细胞减少伴中性粒细胞减少，T,B,和NK细胞，LDH水平显著升高，铁蛋白,可溶性IL-2受体，和甘油三酯。此外,血清IL-1β和IL-18水平大幅升高，与炎症体激活一致。遗传分析显示DPP9中先前未描述的从头突变，c.755G>C，p.Arg252Pro,影响高度保守的氨基酸残基。如在瞬时转染的HEK293T细胞和患者来源的诱导多能干细胞中所示,突变导致DPP9蛋白的不稳定。在HEK293T细胞中使用功能性炎性体测定，我们证明突变体DPP9未能抑制NLRP1和CARD8炎性体，导致组成性炎性体激活。这些发现表明Arg252ProDPP9突变以显性阴性方式起作用。
结论：DPP9的从头突变导致严重的婴儿期发作的自身炎症，原因是炎症小体的释放。
