Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Barnabei, Laura; Lamrini, Hicham; Castela, Mathieu; Jeremiah, Nadia; Stolzenberg, Marie-Claude; Chentout, Loïc; Mirshavalad, Sajedeh; Bouafia, Amine; Magérus, Aude; Moncan, Matthieu; Jacques, Sidonie; Pellé, Olivier; Bondet, Vincent; Duffy, Darragh; Parisot, Mélanie; Bras, Marc; Uggenti, Carolina; Salomon, Rémi; Bodemer, Christine; Rabant, Marion; Cavazzana, Marina; Miner, Jonathan J.; Belot, Alexandre; Hié, M.; Pïcard, Capucine; Bader‐Meunier, Brigitte; Kracker, Sven; Rieux‐Laucat, Frédéric

doi:10.1101/2020.04.27.046102

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…Consistent with the restriction of IFN-I/III in T cells, human T cells have not been previously identified as a cellular source of IFN-I or IFN-III in patients with interferonopathies so far ( Rodero et al, 2017 ). Intriguingly, patients carrying mutations in RELA have been described to have elevated IFN-I and an ISG signature at a steady state ( Barnabei et al, 2020 Preprint ). However, the mechanism of how these RELA mutants might induce unchecked IFN-I expression, the requirement for upstream intracellular sensors and cellular subtypes involved in the IFN-I induction in the pathology of these patients, is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

RELA tunes innate-like interferon I/III responses in human T cells

Jeremiah

Ferran

Antoniadou

et al. 2023

Journal of Experimental Medicine

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In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.

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Section: Discussionmentioning

confidence: 99%

RELA tunes innate-like interferon I/III responses in human T cells

Jeremiah

Ferran

Antoniadou

et al. 2023

Journal of Experimental Medicine

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“…Two observations from the literature suggests that loss-of-function in RELA may promote SLE manifestations. First, a recent study (preprinted in BioRxiv) identified novel RELA mutations in 3 early-onset cases of SLE (9). The authors reported that the p65 mutants translocated to the nucleus but were transcriptionally inactive towards NF-kB genes.…”

Section: Discussionmentioning

confidence: 99%

Case report: Novel variants in RELA associated with familial Behcet’s-like disease

Pimpale-Chavan

Stone

et al. 2023

Front. Immunol.

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RELA haploinsufficiency is a recently described autoinflammatory condition presenting with intermittent fevers and mucocutaneous ulcerations. The RELA gene encodes the p65 protein, one of five NF-κB family transcription factors. As RELA is an essential regulator of mucosal homeostasis, haploinsufficiency leads to decreased NF-κB signaling which promotes TNF-driven mucosal apoptosis with impaired epithelial recovery. Thus far, only eight cases have been reported in the literature. Here, we report four families with three novel and one previously described pathogenic variant in RELA. These four families included 23 affected individuals for which genetic testing was available in 16. Almost half of these patients had been previously diagnosed with more common rheumatologic entities (such as Behcet’s Disease; BD) prior to the discovery of their pathogenic RELA variants. The most common clinical features were orogenital ulcers, rash, joint inflammation, and fever. The least common were conjunctivitis and recurrent infections. Clinical variability was remarkable even among familial cases, and incomplete penetrance was observed. Patients in our series were treated with a variety of medications, and benefit was observed with glucocorticoids, colchicine, and TNF inhibitors. Altogether, our work adds to the current literature and doubles the number of reported cases with RELA-Associated Inflammatory Disease (RAID). It reaffirms the central importance of the NF-κB pathway in immunity and inflammation, as well as the important regulatory role of RELA in mucosal homeostasis. RELA associated inflammatory disease should be considered in all patients with BD, particularly those with early onset and/or with a strong family history.

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“…Immunofluorescence and confocal microscopy were conducted as already reported [ 40 ]; cells were treated for 6 h and coated on a poly-L-lysine matrix then fixed 20 min with Paraformaldehyde (PFA) 4% at room temperature (RT). Cells were permeabilized with PBS + 0.1% Triton X-100 10 min at RT.…”

Section: Methodsmentioning

confidence: 99%

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

Guidetti

Arribas

Sartori

et al. 2023

JCM

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Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.

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Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Cited by 3 publications

References 42 publications

RELA tunes innate-like interferon I/III responses in human T cells

RELA tunes innate-like interferon I/III responses in human T cells

Case report: Novel variants in RELA associated with familial Behcet’s-like disease

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

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