NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity

Nigel Sharfe, Ilan Dalal, Zahra Naghdi, Diane Lefaudeux, Linda Vong, Harjit Dadi, Hector Navarro, Diana Tasher, Adi Ovadia, Tzili Zangen, Dorit Ater, Bo Ngan, Alexander Hoffmann, Chaim M. Roifman

Research output: Contribution to journalArticlepeer-review


Background: Genetic 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. Objective: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. Methods: Whole 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. Results: Patients 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 in RELB. 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. Conclusion: Incomplete 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.

Original languageEnglish
Article number102946
JournalJournal of Autoimmunity
StateAccepted/In press - 1 Jan 2022
Externally publishedYes


  • Autoimmunity
  • Combined immunodeficiency
  • Memory B cells
  • Naïve T cells
  • NFκB pathway
  • RelB

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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