NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
复制标题
RelB 表达减少导致 NFκB 通路失调，导致严重的自身免疫性疾病和免疫力下降。
DOI：
10.1016/j.jaut.2022.102946
复制
发表时间：
2023
影响因子：
12.8
通讯作者：
Roifman,ChaimM
中科院分区：
文献类型：
--
作者：
Sharfe,Nigel;Dalal,Ilan;Naghdi,Zahra;Lefaudeux,Diane;Vong,Linda;Dadi,Harjit;Navarro,Hector;Tasher,Diana;Ovadia,Adi;Zangen,Tzili;Ater,Dorit;Ngan,Bo;Hoffmann,Alexander;Roifman,ChaimM
背景 NFκB 通路中的遗传畸变会导致不同严重程度的原发性免疫缺陷。我们之前证明，替代途径的关键组成部分RelB转录因子的完全消除会导致早期表现出的联合免疫缺陷，需要干细胞移植。目的研究三名患者进行性严重自身免疫和免疫缺陷的分子基础。方法进行全外显子组测序以鉴定遗传缺陷。利用分子和细胞技术来评估变异对 NFκB 信号传导、经典和替代途径串扰的影响，以及对免疫功能的影响。 结果患者出现多种自身免疫性进行性严重症状，包括肝脏、肠道、肺和皮肤，在生命的第二个十年变得衰弱。伴随着免疫系统的恶化，显示出与年龄相关的幼稚 T 细胞和对有丝分裂原的反应的下降，并伴随着所有循环 CD19+ 细胞的逐渐丧失。全外显子组测序鉴定出一个新的纯合c。 RELB 中的 C1091T (P364L) 转换。 P364L RelB 蛋白不稳定，表达量极低，但保留了一些功能，并且在 Toll 样受体刺激后可以暂时部分上调。刺激 P364L 患者成纤维细胞导致促炎性高表达转录物簇显着增加，这与 RelB 对 RelA 功能的抑制作用的消除一致。这可能是这些患者自身免疫表现的主要驱动因素。 结论 RelB 的不完全缺失为深入了解 NFκB 通路相互作用以及自身免疫的发病机制提供了独特的机会。 P364L RelB 突变导致免疫功能逐渐下降，并导致严重的自身免疫衰弱。
BackgroundGenetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation.ObjectiveTo study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients.MethodsWhole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function.ResultsPatients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition inRELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients.ConclusionIncomplete loss of RelB provided a unique opportunity to gain insights into NFκB's pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.
登录
查看更多内容
决定 RelB 和 p50 二聚特性的元素表征
影响因子：
5.3
作者：
R. Ryseck;J. Novotný;R. Bravo
通讯作者：
R. Bravo
内质网应激对早期生长反应基因 1 (EGR1) 的诱导是由 MAPK 通路的细胞外调节激酶 (ERK) 臂介导的。
DOI：
10.1016/j.bbamcr.2018.09.009
发表时间：
2019
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
--
作者：
Shan,Jixiu;Dudenhausen,Elizabeth;Kilberg,MichaelS
通讯作者：
Kilberg,MichaelS
影响因子：
9.1
作者：
Liu, Yiwen;Hanson, Steven;Ibrahim, Mohammad A. A.
通讯作者：
Ibrahim, Mohammad A. A.
影响因子：
3.9
作者：
Granados, Eduardo Lopez;Keenan, Jeffrey E.;Jain, Ashish
通讯作者：
Jain, Ashish
影响因子：
20.3
作者：
Lee, Cindy Eunhee;Fulcher, David A.;Cook, Matthew C.
通讯作者：
Cook, Matthew C.