Inborn Errors of Immunity in the NF-κB Pathway

Inborn errors of immunity (IEIs) affecting the NF-κB pathway impair innate and/or adaptive immune responses and may present with or without developmental abnormalities. In this review, we summarize our recent findings from two studies. Monoallelic variants in the RELA gene that result in haploinsufficiency have been linked to tumor necrosis factor-dependent chronic mucosal ulcers and autoimmune cytopenias. However, we have identified a novel form of IEIs caused by dominant-negative RELA mutations, which lead to chronic mucocutaneous ulcerations accompanied by additional autoinflammatory and autoimmune features. Notably, patients exhibit increased expression of Toll-like receptor 7 (TLR7) and MYD88 mRNA in both plasmacytoid dendritic cells and non-plasmacytoid myeloid dendritic cells, resulting in heightened TLR7-mediated production of type I interferons (IFNs). This study provides a mechanistic link between previously distinct groups of IEIs: those involving the NF-κB pathway and those classified as type I interferonopathies. RelB is a critical molecule involved in immune regulation through the non-canonical NF-κB pathway. We describe two families with RelB deficiency caused by novel variants, and we performed detailed functional analyses. As a result, inherited human RelB deficiency disrupts the non-canonical NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections.