Common variable immunodeficiency and autoimmunity – an inconvenient truth

•Autoimmune disease is a common manifestation of combined variable immunodeficiency.•The co-existence of hypo- and hyper-immune states in the same individual at the same point in time is not implausible given the complexity of the immune system.•Both T and B cells abnormalities may contribute to the development of autoimmunity in CVID patients.•Increased autoreactive B cells and reduced T regulatory cells may be involved in the pathogenesis of autoimmunity in CVID.•The genetic influence on CVID is like polygenic, contributing to the heterogeneity of the disease and the variability in the incidence of autoimmunity and other comorbidities.

Coexisting morbidities in CVID include bronchiectasis, autoimmunity and malignancies. The incidence of autoimmune disease in CVID patients may approach 20% of cases. The most common autoimmune disease found in CVID patients is autoimmune cytopenia, but rheumatoid arthritis, lupus, and now primary biliary cirrhosis have also been reported. The coexistence of immunodeficiency and autoimmunity appears paradoxical, since one represents a hypoimmune state and the other a hyperimmune state. However, this paradox may not actually be all that implausible due to the complex nature of immune cells, signaling pathways and their interactions. The cellular alterations in combined variable immunodeficiency include a range of T and B cell abnormalities. Selective immune derangements found in CVID include a downregulation of regulatory T cells (Treg cells), accelerated T cell apoptosis, abnormal cytokine production secondary to cytokine gene polymorphisms and increased autoreactive B cell production. The impact of these abnormalities on T and B cell interaction may not only explain the immunodeficiency but also the development of autoimmunity in select groups of patients with CVID. The variability in the clinical manifestations of CVID as a result of this immune interaction suggests that CVID is not one disease but many. This is important because it follows that the treatment of CVID may not always be the same, but may need to be directed specifically towards each individual patient.