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

Background NFKB1 encodes p105, which is processed to p50 to mediate canonical NF-κB signaling. Though 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 CVID patients 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, immunological features, and plasma cytokine levels of 15 CVID patients with heterozygous NFKB1 variants with 77 genetically undefined CVID patients from the same referral base. We also assessed differences between CVID patients with frameshift or nonsense NFKB1 variants compared with those with missense NFKB1 variants. Results We found CVID patients with heterozygous NFKB1 variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease (IBD), and plasma cytokines compared with genetically undefined CVID patients. These findings were more pronounced and included elevation of monocytes, in CVID patients with frameshift or nonsense NFKB1 variants relative to those with missense NFKB1 variants. Conclusion In a regional cohort, heterozygous NFKB1 variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. CVID patients 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 CVID patients may be associated with more severe disease course and warrant closer monitoring.