NFKB1 Truncating Variants Associated with Significant Autoimmunity and Lymphoproliferation in Common Variable Immunodeficiency

Heterozygous NFKB1 variants have been increasingly identified in patients with common variable immunodeficiency. These patients, however, often experience substantial immune dysregulation beyond humoral deficiency. NFKB1 encodes p105, which undergoes proteolytic cleavage to release p50, the transcriptionally active subunit of canonical NF-κB. While several in vitro transfection systems have demonstrated loss-of-function of these variants regarding canonical NF-κB reporter activity, the immune-related phenotypes of these patients differ from those with well-characterized defects leading to impaired canonical NF-κB activation (i.e., IKBKG or NFKBIA variants). Notably, the C-terminal part of p105 contains ankyrin repeats, which can repress downstream signaling by retaining NF-κB dimers in the cytosol. We therefore hypothesize that loss of p105 inhibitory function may contribute to the immune dysregulation observed in some affected patients.In this study, we evaluated 8 patients from 8 unrelated kindreds presenting with early-onset common variable immunodeficiency, complicated by diverse and severe immune dysregulations, including multiple autoimmunity and lymphoproliferation (NCT00001355). In addition to immunoglobulin replacement therapy for hypogammaglobulinemia, all required multiple immunomodulatory therapies. One patient ultimately underwent allogeneic hematopoietic stem cell transplantation for disease control.All patients harbored private germline heterozygous NFKB1 truncating variants (nonsense, n = 2; frameshift, n = 5; splice, n = 1) located in the N-terminal p50 part of the protein, prior to the ankyrin repeats. Beyond the well-recognized B cell failure in these patients, peripheral blood mononuclear cells showed lower basal IκBα level and enhanced IκBα degradation following ex vitro stimulation, indicating activation of canonical NF-κB signaling. Their T cells showed increased phospho-AKT upon stimulation. Together, these findings suggest a potential loss of p105 inhibitory function in these patients. Further elucidation of the mechanisms underlying profound immune dysregulation is crucial because these patients may benefit from the PI3Kδ inhibitor leniolisib, given the observed PI3K signaling activation. A prospective clinical trial is currently recruiting such participants to investigate this targeted therapy (NCT06549114).