Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity

Abstract

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3′ segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients’ cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.

The NF-κB RelA transcription factor is not required for CD8+ T-cell function in acute viral infection and cancer

“…As type I and type II IFN signaling impact T-cell function ( 23 – 25 ), this crosstalk may have consequences on the outcome of pathological conditions. This conclusion is in stark contrast to the observations made in patients with germline RELA haplo-insufficiency (loss-of-function mutations), who suffer from various autoimmune or inflammatory conditions and are characterized by enhanced IFNs and ISG expression ( 13 – 15 ). This suggests that these phenotypes mostly relied on CD8+T-cell extrinsic functions of RELA .…”

“…Consistent with mouse cells, enrichment analyses on down-regulated genes showed that RELA governed, in human CD8 + T cells, the expression of genes associated with the NF-κB pathway (NF-κB subunits and negative regulators of the pathway), markers of function, and cytokines, especially the response to type I and type III IFNs ( Figures 4D, E ). Thus, RELA controlled different aspects of human CD8 + T cell biology, suggesting a CD8 + T-cell-intrinsic role for RELA in the immunodeficiency features detected in patients with RELA LOF ( 13 – 15 ). After 4 days of stimulation with anti-CD3/28, a similar level of proliferation was observed in control and RELA -deficient cells, in accordance with our data from mouse experiments ( Figure 4F ).…”

“…Elegant studies have also demonstrated a direct function of RelA in IFNg production and proliferation, in mouse and human CD8 + T-cells, respectively (11,12). In patients with heterozygous, dominant negative loss-of-function (LOF) mutations in RELA, decreases in circulating central memory CD8 + T cells were reported (13,14), although this was not confirmed in another cohort of patients (15). However, whether RelA is intrinsically required to orchestrate CD8 + T-cell gene expression and function in vivo, is unknown.…”

The Yin and Yang of Plasmacytoid Dendritic Cells – SARS-CoV-2 Protection versus Susceptibility to Selected Autoimmune Diseases

“…Recently, a novel interferonopathy was discovered, where deletions of the 3' end of the RELA (also known as p65 in the NF-kB pathway) mRNA cause a dominant negative effect on the gene product 15 . Autoinflammation and autoimmunity in these patients was driven by an upregulation of TLR7 and MyD88 transcripts in pDCs, but also in classical and nonclassical monocytes and in myeloid DCs (mDCs).…”