The most difficult clinical issue in the management of individuals with common variable immunodeficiency is autoimmune and inflammatory symptoms (CVID). The growing body of pathogenic information and possible therapeutic implications need a rethinking of the current quo. The puzzle of the coexistence of primary immunodeficiency and autoimmune disease (AID) is being unraveled by newly identified genetic abnormalities. Thus, cytotoxic T lymphocyte-associated antigen 4 or caspase-9 deficiency presenting with CVID-like characteristics reinforces immunological dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and autoimmune lymphoproliferative syndrome ideas. Defects in activating signaling downstream of antigen or cytokine receptors are frequently related to loss of tolerance in afflicted individuals. CVID-like individuals are increasingly being diagnosed with types of combined immunodeficiency. Although various autoimmune symptoms frequently coexist in the same patient, their immunopathology differs. Therapy of AID in CVID remains difficult, although early attempts at tailored treatment have been undertaken based on a better understanding of immunopathology.

The growing understanding of immunological principles driving AID in CVID will enable better and, in certain circumstances, tailored therapy. In this group of individuals, a genetic diagnosis provides critical information, especially given that some patients may require hematopoietic stem cell transplantation due to underlying immunodeficiency.