Background/Purpose:

Behçet’s disease (BD) is a chronic multi-system inflammatory disorder associated clinically with oral and genital ulceration, uveitis, erythema nodosum, and other inflammatory disease. The cause of BD is unknown. A current hypothesis is that an autoinflammatory reaction in individuals with a permissive genotype may arise due to altered cellular signal transduction events and hence altered immune cell function. This reaction may be triggered in these individuals due to infectious agents or microbes not generally considered pathogenic. The family of NF-kB transcription factors are activated in various  signaling pathways involved in microbial sensing, immunity, and inflammatory disease. Previously, a case of familial Behcets was described in two females harboring a mutation in the C-termial Zinc finger domain of NEMO, the NF-kB essential modulator, a key regulator of NF-kB activation.

Methods:

We evaluated female patients diagnosed with Behcets disease who harbor mutation in the NEMO C-terminus, in addition to those with mutation affecting another ubiquitin binding domain. Patient mononuclear cells in addition to patient-mutation-reconstituted NF-kB reporter T cell lines were stimulated with TNF, Toll-like Receptor (TLR) ligands Flagellin and LPS, in addition to anti-CD3/CD28, and PMA/Ionomycin. Gene expression, cytokine production and biochemical assays including co-immunoprecipitation of endogenous proteins implicated in the regulation of NF-kB activation were performed to characterize signaling and cellular responses.

Results:

Mutation leading to premature truncation of the C-terminal Zinc finger in females is associated with a BD phenotype. NF-kB activation by reporter assay in cells harboring the patient mutation reveals enhanced NF-kB activation in response to TNF and TLR5 stimulation compared to the response seen in cells harboring other NEMO mutation not associated with BD. Cytokine production by capture assay indicates LPS induced IL-1b, TNF and GMCSF were approximately 2-fold increased compared to unrelated control, whereas other cytokine responses were normal or reduced. Co-immunoprecipitation studies following cell stimulation with TNF reveal impaired stabilization of the NF-kB negative regulator A20 at the receptor in cells harboring the patient mutation.

Conclusion:

These results illustrate that single gene defects may lead to phenotypes observed in complex genetic disease.  Molecular characterization of the altered signaling resulting from NEMO mutation may yield important insights into more common rheumatic disease such as BD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/behcets-disease-in-females-due-to-mutation-in-nemo-the-nf-kb-essential-modulator/