Common Variable Immunodeficiency Clinical Manifestations Are Shaped by Presence and Type of Heterozygous NFKB1 Variants

Abstract

Background: NFKB1 encodes p105, which is processed to p50 to mediate canonical nuclear factor-κB (NF-κB) signaling. Although NF-κB is a central driver of inflammation and heterozygous NFKB1 variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how NFKB1 variants shape clinical course or inflammation in CVID.

Objective: We leveraged a regional cohort of patients with CVID with and without heterozygous NFKB1 variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants.

Methods: We compared clinical complications, immunologic features, and plasma cytokine levels of 15 patients with CVID with heterozygous NFKB1 variants and 77 genetically undefined patients with CVID from the same referral base. We also assessed differences between patients with CVID with frameshift or nonsense NFKB1 variants compared with those with missense NFKB1 variants.

Results: We found patients with CVID with heterozygous NFKB1 variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease, and plasma cytokines. These findings were more pronounced and included elevation of monocytes in patients with CVID with frameshift or nonsense NFKB1 variants relative to those with missense NFKB1 variants.

Conclusions: In a regional cohort, heterozygous NFKB1 variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. Patients with CVID with frameshift or nonsense NFKB1 variants had more significant increases in noninfectious complications and peripheral monocytes than those with missense NFKB1 variants. Presence of pathogenic NFKB1 variants in patients with CVID may worsen the disease course and warrant closer monitoring.

Keywords: Common variable immunodeficiency; Inflammation; Monocytes; NF-κB; NFKB1.

Figure 1.

Location of CVID-associated NFKB1 variants in this study using schematic illustration of p105. Black = missense variant, Red = frameshift or nonsense variant. RHD, Rel homology domain; ARD, ankyrin repeat domain; DD, death domain. Gray area indicates region with high number of post-translational modifications by PhosphoSite Plus. Intronic and gene deletion variants included in study are not shown. Not to scale.

Figure 2.

A. CVID non-infectious complication severity score. One point given for history of autoimmune cytopenia or IBD, for maximum score of 2. B. Peripheral blood monocyte count. P value calculated by Mann-Whitney U test.