Common variable Immunodeficiency (CVID) is a heterogeneous immunodeficiency characterized by hypogammaglobulinemia and immune dysregulation. In up to 30% of cases, there is a monogenic defect, with a fraction of these familial. The majority, however, are sporadic. The nuclear factor kappa B (NFκB) cell-signalling pathway plays a vital role in normal B cell development and function. In fact, genetic variants affecting genes of the NFκB pathway are the most common cause of monogenic disease in CVID. Although these cases present a clear link between the NFκB pathway and CVID, it remains unclear how single-gene defects in NFκB lead to CVID. We compared the nuclear translocation and binding to the consensus κB DNA sequence of four transcription factors in the NFκB signalling pathway in B cells between patients with CVID and healthy controls upon stimulation. We found that nuclear NFκB DNA-binding activity was significantly reduced in CVID compared with healthy individuals. In patients with infections-only CVID, lower responses were observed only in p50/p52 activity, whereas in patients with CVID with additional complications, a reduction in responses to RelA and RelB was particularly pronounced. Noncanonical NFκB hyporesponsiveness was more frequently seen in CVID with autoimmune and granulomatous disease and, to a lesser extent, lymphadenopathy. In contrast, canonical hyporesponsiveness was associated with CVID with autoimmune cytopenias. We also noted an inverse relationship between the number of complications and the activity of the NFκB pathway in CVID. Taken together, these observations suggest a role for functional defects in the NFκB pathway in CVID.
